Volume 54, Number IPrinted in the U.S.A.

INTERNATIONAL JOURNAL OF LEPROSY

INTERNATIONAL JOURNAL OF LEPROSYand Other Mycobacterial Diseases

OFFICIAL ORGAN OF THE INTERNATIONAL LEPROSY ASSOCIATION

EDITORIAL OFFICE

National Hansen's Disease CenterCarville, Louisiana 70721, USA

VOLUME 54, NUMBER I^ MARCH 1986

EDITORIALS

Editorial opinions expressed are those of the writers.

The 1985 JOURNAL—a Continuing Perspective

The year 1985 was an exciting one forleprosy. New findings and new possibilitiesfor better care of patients appeared in abun-dance. The JOURNAL completed its 53rd yearof publication in 1985, having taken finalnote of the magnificent New Delhi Congressin 1984 and now looking forward to theupcoming Congress at The Hague in 1988.It again seems appropriate to review theprogress that has been made in our under-standing of leprosy as reflected in the pagesof the JOURNAL.

In the March issue, Meyers, et al. (1 - 14)*carefully documented the landmark findingof naturally acquired leprosy in a "sooty"mangabey monkey, a finding offering thepromise of a much-needed primate modelfor leprosy. Cartel, et a!. (15-18) found a16.5% incidence of hepatotoxicity amongpatients treated with daily 5 mg/kg pro-thionamide, 10 mg/kg rifampin, and 400mg dapsone, and concluded that thioamideshould not be used in combination with ri-fampin unless the daily dose is 5 mg/kg andliver function is monitored monthly. Jesu-dasan and Christian (19-21) studied 51 re-lapsed patients among a group of 1701 pau-

* Numbers in parentheses refer to page numbers inthe INTERNATIONAL JOURNAL or LLPROSN", Volume 53,1985.

cibacillary cases in whom treatment withdapsone monotherapy had been discontin-ued. Lepromin-negative paucibacillary caseswere 2.4 times more likely to relapse thanlepromin-positive paucibacillary patients,and 11 of 29 lepromin-negative pauciba-cillary cases relapsed with multibacillarydisease compared with 0 of 18 in the lep-romin-positive group. The advisability ofuniform, short-course chemotherapeuticregimens being applied to paucibacillarycases without regard to their lepromin reac-tivity requires evaluation. Rook (22-27)found no evidence of antibodies to rifampinin sera from 239 leprosy patients beingtreated with the drug. Chiewsilp, et a!. (28-32) pointed out the necessity for carefullyselected control populations in studying se-rum immunoglobulin class variations inleprosy patients. Sinha, et al. (33-38) ap-plied a competitive inhibition assay to es-timate antibody levels to the species-spe-cific antigenic epitope of Mycobacteriumleprae designated as MY2a (recognized bya murine monoclonal antibody designatedas MLO4). The test results satisfied the re-quirements expected of a leprosy-specificserodiagnostic test. Of considerable inter-est, 13 (46%) of 28 healthy household con-tacts of multibacillary leprosy patients were

88

54,1^ Editorials^ 89

antibody positive, while none of 15 similarcontacts of paucibacillary cases was posi-tive. Narayanan, et al. (39-44) ingeniouslyprepared single cell suspensions from tu-berculoid and lepromatous leprosy granu-lomas with collagenase and quantitated vi-able lymphocytes, E-rosetting cells, and cellsstaining for nonspecific esterase. Lympho-cytes were abundant from tuberculoid gran-ulomas, a higher percentage rosetted withsheep erythrocytes, and most showed thepresence of esterase as dots in the cytoplasmcompared to those from lepromatous gran-ulomas. "Large cells" (epithelioid cells andmacrophages) from both types of granu-lomas were similar in that most were ester-ase positive and peroxidase positive, butthose from tuberculoid granulomas werenon-adherent to plastic while those fromlepromatous granulomas were. Datta, et al.(45-51) analyzed the patterns of methyl my-colates of various mycobacteria by thin-lay-er chromatography and found that Al. lep-rae-derived methyl mycolates are alpha- andketo-derivates and not methoxy or dicar-boxy compounds. This pattern distinguish-es M. leprae from a variety of other my-cobacteria which have been isolated fromleprosy lesions. Nakamura (52-55) dem-onstrated that virulence of Al. lepraenui-rilon can be maintained for 30 years if thebacilli are lyophilized in the proper suspen-sion. There is clearly a need to apply theseprinciples to M. leprae. Xu, et al. (56-63)meticulously analyzed HLA haplotype dis-tributions among siblings in families withleprosy and concluded that HLA-linkedgenes do not seem to confer susceptibilityor resistance to leprosy per se. On the otherhand, predisposition to lepromatous lep-rosy does seem to be controlled by HLA-linked genes. In view of other studies, it canbe postulated that there are at least fourdifferent HLA-linked genes which controlleprosy type, one each for LL, BL, BT, andTT disease. Burchard and Bierther (64-69)carefully studied macrophages and lympho-cytes in the skin of lepromatous and bor-derline leprosy patients by electron micros-copy, describing how macrophages areactivated and phagocytose Al. leprae in lep-romatous leprosy, and the differentiation ofmacrophages into epithelioid cells and giantcells in borderline disease. They further (70—

74) studied small dermal blood vessels inuntreated lepromatous patients and empha-sized the important role of these vessels inthe multiplication and spread of the bacillifrom both pericytes and endothelial cells.Fukunishi (75-78) showed with electronmicroscopy that M. leprae-infected nudemice developed peripheral nerve lesionswith the same fundamental pathologicalfeatures as those in armadillos and humanswith lepromatous leprosy. Li, et al. (79-85)summarized the highly successful compre-hensive leprosy control program in Shan-dong Province of the People's Republic ofChina since 1955, and demonstrated the ep-idemiologic similarities of the disease in thisarea with findings in other countries in whichleprosy is disappearing.

In the Editorial section of the March is-sue, we were fortunate to have the prize-winning LEPRA essay by Strickland (86-100). The author brilliantly reviewed theimmunologic deficiencies of leprosy andtuberculosis, and logically considered thevarious possible mechanisms of immuno-suppression and immunodeficiency capableof influencing the infections. Hastings (101-112) reviewed the contents of the 1984JOURNAL.

The Correspondence section of the Marchissue was both lively and informative. Arora,et al. (113-114) confirmed several earlierstudies which were unable to demonstrateany effect of levamisole on the cell-medi-ated immune response of lepromatous pa-tients to M. leprae. Lyons, et al. (114-115)made the very interesting observation thattypical Langerhans' giant cells can be foundin the lesions of otherwise typical borderlinelepromatous to subpolar lepromatous casesif they have rapidly downgraded. Neelanand Reddy (115-116) and Grosset, et al.(118-120) critically evaluated the series ofpapers by Almeida, et al. which appearedin the September 1983 issue of the JOURNAL,pointing out areas of disagreement. Almei-da and Chacko (116-118 and 120-121) am-plified their published findings and defend-ed their point of view.

The News and Notes section of the Marchissue noted the well-deserved Padma Shriaward by the President of India to Dr. H.Srinivasan (123). The sanatorium of Fon-tilles (Alicante, Spain) celebrated its 75th

90^ International Journal of Leprosy^ 1986

anniversary (125). The Robert CochraneFund for Leprosy was established (128).

In the Current Literature section of theMarch issue, an interesting review of theattitudes of medieval Islamic society towardleprosy patients was provided by Dols (132).Anderson analyzed the immunopharma-cology of antileprosy agents (133). Cottenot,et al. (133) described two additional casesof lepromatous leprosy clinically resistantto rifampin. Ji, et al. (134) emphasized thehepatotoxicity of prothionamide, particu-larly in combination with rifampin. Jopling,et al. (134-135) continued to follow up 116multibacillary leprosy patients treated withmultiple drugs for 5-89 months in Maltabeginning in 1972, and who have been fol-lowed since without chemotherapy. No signsof clinical relapse have been found, but 36of these patients had positive skin smearsand 10 of the 36 had solidly staining bacilliin their smears. Pitchenick (135-136) sug-gested that former patients who had beenmodels of compliance with drug therapy berecruited to help administer chemotherapyin the hope that they would improve com-pliance. Sarojini and Mshana (136) reportedthat colchicine in doses of 1.5 to 2.0 mgdaily was dramatically effective in control-ling erythema nodosum leprosum (ENL),and that a maintenance dose of 1 mg dailyprevented recurrences. On the other hand,Stanley, et al. (136) found that colchicine,2 mg daily, clearly had little or no benefitin ENL. Chen, et al. (136) reported a caseof ENL regularly accompanied by purpura.Furukawa, et al. (137-138) sought correla-tions between circulating immune com-plexes and anti-ssDNA antibodies in the seraof lepromatous leprosy and systemic lupuserythematosus (SLE) patients and found thatthe two were not associated in lepromatousleprosy but were significantly associated inSLE. The authors concluded that the rea-sons for these serological abnormalities inlepromatous leprosy are completely differ-ent from those in SLE. Brett, et al. (139)did not find any effect of the phenolic gly-colipid antigen of M. leprae on a variety ofcell-mediated immune responses and de-layed-type hypersensitivity responses to M.leprae in mice. Cho, et al. (139-140) re-ported comparable results in sero-reactivityusing the native phenolic glycolipid antigen

of M. leprae and a synthetic glycoconjugatebased on the 3,6-di-O-methyl-13-D-gluco-pyranosyl epitope. Ferluga, et al. (140) sug-gested that lepromatous leprosy might de-velop as a result of chronic suppression ofspecific cell-mediated immunity by anti-idiotypic antibodies and idiotypic-restrict-ed suppressor lymphocytes. Fliess, et al.(140) showed a close relationship betweencell-mediated immune responses to AI. lep-rae and those to M. mailman among lep-rosy patients and healthy subjects, and sug-gested that this might be on the basis ofcrossreactivity between the two organisms.Haregewoin, et al. (141) provided evidencethat the unresponsiveness of many cases oflepromatous leprosy in their peripheralblood mononuclear cells to M. leprae wason the basis of a deficiency in interleukin-2production. Khande, et al. (142) analyzedthe lipids in the skin of lepromatous leprosypatients. Six distinct phosphatidyl inositomannosides were identified in infected tis-sue, a triacyl dimannoside being mostprominent quantitatively. Narayanan, et al.(143-144) found normal numbers of T6+Ia+ Langerhans' cells in the epidermis inall types ofleprosy patients, but noted a highproportion of these cells in the mononuclearinfiltrate surrounding the epithelioid cells inthe dermal granulomas of tuberculoid pa-tients, gradually decreasing across the lep-rosy spectrum to a virtual absence in thedermis in polar lepromatous disease. Olcen,et al. (144) detected precipitating antibodiesdirected against M. leprae antigens 5, 6 and7 in the concentrated urine of 50% of lep-romatous patients by crossed immunoelec-trophoresis. Ninety percent of these patientshad higher levels of anti-M. leprae antibod-ies in their urine than did controls. Salgame,et al. (144) found that lysates of leproma-tous macrophages induced membranechanges in normal macrophages. Fine (147)made a detailed analysis of the similaritiesand differences in the epidemiology of lep-rosy and tuberculosis. Ottenhoff, et al. (148),in a population study, found a significantincrease in the frequency of the HLA spec-ificity LB-E12 (MB1, DC1, MT1) amonglepromatous leprosy patients compared tohealthy controls in Venezuela. Aronson, etal. (148) reported sensory peripheral neu-ropathy developing in 3 of 4 patients with

54,1^ Editorials^ 91

prurigo nodularis who had been treated withthalidomide. Garcia Montelongo, et al.(150) found that clofazimine 200 mg dailywas beneficial in 35 of 45 patients with"chronic" lupus erythematosus. Goren, etal. (150-151) compared the virulence forguinea pigs and various cultural and bio-chemical patterns in AI. tuberculosis strainsisolated from India and strains isolated fromthe West. A number of differences were not-ed between the Indian and Western strains,and the authors postulate that these patternsmight be due to parallel evolution occurringamong organisms widely separated geo-graphically. Guitierrez-Rodriguez (151)found thalidomide useful in treating rheu-matoid arthritis. Neva, et al. (151-152) re-ported that local heat treatment was effec-tive in lesions of diffuse cutaneousleishmaniasis.

The March issue included the abstractsof papers presented at the First U.S. Han-sen's Disease Conference held at Carville inAugust 1984. Schauf, et al. (163) confirmedresults obtained in other countries in findingthat tuberculoid leprosy was associated withHLA-DR2 in Thailand. Cynamon, et al.(165) found that the combination of am-picillin plus sulbactam enhanced the in vitroactivity of ampicillin some fourfold againstM. tuberculosis, indicating that at least somemycobacteria have a functional13-lactamasewhich, if inhibited by sulbactam, might re-sult in useful susceptibility of the organismsto f3-lactam antibiotics. Harris and Prab-hakaran (165) detected malonyl-CoA de-carboxylase activity in M. leprae and sug-gested that it could result from the reversereaction of an avidin-sensitive acetyl-CoAcarboxylase. Shannon, et al. (165-166)showed that thalidomide enhanced humor-al immune responses of mice to the T-in-dependent antigen, DNP-Ficoll, implyingthat the drug's immunosuppressive activityin response to T-dependent antigens is onthe basis of a site of action involving helperT cells, and not B cells or macrophages.Skinsnes, et al. (167-168) presented resultsof detailed numerical taxonomic and im-munologic studies on 36 leprosy-derivedmycobacterial isolates and 17 members ofthe M. avitn - intracellulare-scrofidaceumcomplex (MAIS). Martin, et al. (169) dem-onstrated a progressive decrease in mito-

gen-induced lymphocyte blastogenic re-sponses of M. leprae-infected mangabeymonkeys as the disease progressed. De-creases in lymphocyte blastogenic responsesto mitogens were associated with increasesin the percentage of OKT8 + lymphocytes.Kvach, et a!. (169-170) described a newtechnique for rapidly purifying Al. lepraefrom armadillo liver using Percoll buoyantdensity centrifugation. The bacilli had ATPlevels similar to cultivable mycobacteria anddied, as measured by ATP, exponentiallyunder defined conditions. Clofazimine ac-celerated the rate of ATP decay in a dose-responsive fashion. Jacobs, et al. (170)demonstrated the expression of polypep-tides from recombinant Al. leprae DNAcloned into the cosmid vector pHC79 andthe plasmid vector pYA626. Imaeda andPortaels (170-171) found little homologybetween DNA from AI. leprae and that fromleprosy-derived corynebacteria or leprosy-derived mycobacteria, suggesting that thepresence of these organisms in leprosy tis-sues may not be directly related to the dis-ease. Gelber (171-172) reported a numberof experiments testing compounds for anti-microbial activity against M. leprae inmouse foot pad infections. Active com-pounds included dapsone, rifampin, cyclo-serine, the combination of bromidoprimwith low levels of dapsone, minocycline, ce-phradine, and the combination of amoxi-cillin and clavulanic acid. Inactive com-pounds were beta alanyl and glycylderivatives of hydroxamic acid, trimetho-prim combined with low levels of dapsone,doxycycline, erythromycin, cefoxitin, cefa-mandole, cefotoxamine, moxalactam, andcephradine. Gelber, et a!. (172-173) foundthe neonatally thymectomized Lewis ratmodel to be useful in detecting viable Al.leprae after the initiation of chemotherapyin previously untreated lepromatous lep-rosy patients. Navalkar and Ibegbu (173)studied the antigens of M. leprae by iso-electric focusing and chromatofocusing sep-arations. Patterns obtained with Al. lepraewere different from those of other myco-bacteria and differences were seen betweenuntreated and autoclaved M. leprae prep-arations. Humphres and Winters (174-175)used Lewis rats to study enhanced cell-me-diated immunity after intradermal vacci-

92^ International Journal of Leprosy^ 1986

nation with M. leprae and antigen-specifictolerance following intravenous or intra-peritoneal administration of Al. leprae athigh doses. Truman, et al. (175) found se-rologic reactivity against the phenolic gly-colipid I (PGL-I) antigen of Al. leprae insamples taken from armadillos between theyears 1960 and 1964, before the first ex-perimental inoculations of armadillo withAl. leprae in 1968. Baskin, et al. (175- 176)presented necropsy findings in a mangabeymonkey with experimental leprosy. Malaty,et al. (176) described the histopathologicchanges in the eye of the same mangabeymonkey. Long, et al. (176-177) describedan interesting, specific, glucose oxidase im-munoenzyme stain for the identification ofM. leprae in tissue. Krotoski and Mc-Cormick (177-178) utilized an indirect im-munofluorescence technique to demon-strate antigens of M. leprae in infectedarmadillo liver and to demonstrate differ-ences among lepromatous patients in thepatterns of antigens which they recognized.Mohagheghpour, et a!. (178) described theproduction of two human monoclonal an-tibodies to M. leprae. Gillis, et al. (178)developed a competitive antibody bindingassay to detect human serum antibody to aunique epitope on the 68KD protein antigenof M. leprae. Job, et al. (179-180) foundthat purified PGL-I elicited positive late skintest responses in lepromin-positive arma-dillos and negative responses in lepromin-negative armadillos. Mehra, et al. (180)found that the PGL-I antigen was as effec-tive as integral M. leprae in inducingsuppression of lymphocyte proliferation inConA. Douglas, et (11(180- 181) showed thatserum antibody levels to the PGL-I antigenand to whole M. leprae fell over time inpatients under effective chemotherapy.Modlin, et al. (181-182) characterized thecellular infiltrates in the granulomas of tu-berculoid leprosy, lepromatous leprosy (LL),localized cutaneous leishmaniasis, and dif-fuse cutaneous leishmaniasis. In tubercu-loid granulomas, interleukin-2 (IL-2) pro-ducing cells and suppressor/cytotoxic T cellswere both found in the mantle surroundingthe granuloma, while helper/inducer cellsand IL-2 receptor cells were distributedthroughout the granuloma. In LL, localizedcutaneous leishmaniasis, and diffuse cuta-

neous leishmaniasis, all cells were distrib-uted throughout the granuloma. IL-2-pro-ducing cells were rare in LL and diffusecutaneous leishmaniasis but were an orderof magnitude greater in tuberculoid leprosyand localized leishmaniasis. IL-2 receptorcells were present in all four disorders. Thedata suggest that the M. leprae-specific fail-ure of cell-mediated immunity in lepro-matous patients is secondary to reduced,probably inhibited, IL-2 production. Mil-ler, et al. (182-183) found few autoanti-bodies among their leprosy patients in Se-attle, Washington, U.S.A. An interestingobservation was that the erythrocyte sedi-mentation rate was moderately elevatedduring acute ENL reactions, but in all pa-tients tested during acute reversal reactionsthe erythrocyte sedimentation rate was ex-tremely low. Schuller-Levis, et al. (183-184)showed a significant loss of chemotactic ac-tivity in monocytes in response to lympho-cyte-derived chemotactic factor in active LLpatients but not in inactive LL cases. Tausk,et a!. (184) demonstrated fewer C3b recep-tors on erythrocytes from LL patients thanthose on erythrocytes from normal individ-uals or tuberculoid leprosy patients. Sinceimmune complexes bind to erythrocytes andare delivered to the liver where they areapparently removed by local macrophages,this reduced number of C3b receptors onerythrocytes from LL patients could have abearing on the ability of LL patients to in-activate or clear immune complexes fromthe circulation. Campbell, et al. (184-185)found that many plasma samples from alltypes of leprosy patients contained an in-hibitor of monocyte leukotaxis.

The Original Articles of the June issuebegan with the very interesting paper byWarndorff van Diepen and Mengistu (189-197). Lepromatous leprosy patients on dap-sone monotherapy were divided into fourgroups. The first group continued on dap-sone monotherapy, the second receivedsupplemental thiacetazone and isoniazid for12 months, the third group received dailythiacetazone and daily isoniazid for 12months plus rifampin daily during months1 and 7, and the fourth group received ri-fampin as above but no thiacetazone orisoniazid. Supplemental thiacetazone andisoniazid had no significant effect on either

54, 1^ Editorials^ 93

the overall relapse rate or the incidence ofdapsone-resistant leprosy. Rifampin, on theother hand, significantly lowered relapserates and only a single case of dapsone re-sistance was detected in those groups re-ceiving rifampin. Of considerable interest,the average annual relapse rate in the con-trol group receiving dapsone monotherapyover the five-year follow-up period ap-peared to be 2.3%, and the incidence of dap-sone-resistant leprosy in this group was 0.7%per year. The apparent decrease in both re-lapse rates and incidence of dapsone-resis-tant leprosy in this area compared to earlierreports may well be related to the re-intro-duction of full-dosage dapsone therapy, un-interrupted during reactions. Bera and Sen(198-200) found that supplemental ley-amisole accelerated the fall in bacterial in-dices in BL and LL patients treated withdapsone. Moncada, et al. (201-205) foundstatistically significant increases in percent-ages of helper T cells in 3 ENL patients afterreceiving thalidomide in doses of 300 mgper day. Jain, et al. (206-210) devised anapparatus to measure the "minimum tem-perature felt as hot" on the skin surface andused it to assess the degree of sensory lossin leprosy skin lesions. Andreoli, et al. (211—217) measured circulating antibody levelsto the PGL-I antigen of M. leprae and sol-uble M. leprae antigens before, during, andfollowing ENL episodes in 12 patients. Dur-ing ENL, there was a fall in circulating IgM-class antibody levels to the PGL-I antigenbut no apparent changes in IgM, IgG, andIgA antibody levels to a soluble antigenicextract from purified M. leprae suspen-sions. de la Barrera, et al. (218-224) showednormal antibody-dependent cellular cyto-toxicity and normal total and normal alter-native pathway complement activity in LLpatients in the presence of elevated circu-lating immune complexes. Heat inactiva-tion of the LL sera resulted in the sera in-hibiting the antibody-dependent cellularcytotoxicity of normal mononuclear leu-kocytes. This inhibition, in turn, could bereversed with fresh normal human serum,suggesting that complement prevents the in-hibition of antibody-dependent cellular cy-totoxicity by the immune complexes pres-ent in lepromatous sera. Heat-inactivatedLL sera containing immune complexes were

able to activate and fix 74-80% of totalcomplement activity and 40-50% of alter-native pathway complement activity. Itwould seem that compensatory mecha-nisms exist in LL patients which are able tomodify the potentially harmful effects of cir-culating immune complexes. Wright, et al.(225-232) showed that Vietnamese LL pa-tients had significantly raised levels of se-rum IgG, IgA, IgM, and IgE, while border-line tuberculoid (BT) leprosy patients hadonly increased IgG in comparison with localcontrols. The IgG, subclass was not in-creased in the leprosy patients, but the othersubclasses of IgG were increased. Vaish-navi, et al. (233-237) found that infectionwith Al. leprae resulted in a decreased bac-tericidal activity of peritoneal macrophagestoward Staphylococcus azireus in both nor-mal and thymectomized-irradiated mice. Ingeneral, phagocytic activity was not im-paired in these cells. Haimanot, et al. (238-246) studied tissue muramidase activity inneural and skin tissues from leprosy pa-tients. A saccular pattern of distribution ofthe enzyme was noted in the majority oflepromatous tissues and a granular patternat the tuberculoid end of the leprosy spec-trum. The muramidase-positive cells in pe-ripheral nerves were probably derived fromblood monocytes since Schwann cells andaxons did not show muramidase activity.Fukunishi (247-250) illustrated M. lepraecells dividing by transverse fission insidethe phagolysosomes of lepra cells of nudemice and armadillos. Bahlinger, et a!. (251-254) suggested that leprosy patients expe-rience psychosocial stresses which havemany characteristics in common with thoseexperienced by all patients with chronic ill-nesses. These similarities may allow the ap-plication of psychosocial techniques devel-oped for patients with other chronic illnessesto be applied to leprosy patients. Colemanand Madrigal (255-257) explored the psy-chosocial ramification of sensory loss in lep-rosy. Rojas-Espinosa, et a!. (258-261) usedlevels of serum lactic dehydrogenase, glu-tamate-pyruvate transaminase, and gluta-mate-oxalacetate transaminase to monitorthe progression of M. lepraenntrium infec-tions in mice. Rojas-Espinosa, et al. (262-268) also found these serum enzyme levelsto be useful in following the progression of

94^ International Journal of Leprosy^ 1986

M. leprae infections in armadillos. Baskin,et al. (269-277) documented necropsy find-ings in a mangabey monkey that died 46months after an inoculation with M. lepraeand that had developed generalized lepro-matous leprosy. The necropsy findings werevery similar to those seen in untreated hu-man LL patients.

In the Editorial section of the June issue,Lagrange and Stach (278-288) presentedtheir views on a strategy for the control ofleprosy. Based on the observation thatmononuclear phagocytic cells from LL pa-tients, but not tuberculoid leprosy patients,can inherently inhibit the growth of intra-cellular BCG, the authors postulate that LLpatients correspond to naturally resistantanimal models. In mice there is an auto-somal dominant gene on chromosome 1,the BCG gene, which is phenotypically ex-pressed on mononuclear phagocytic cells andfunctions to prevent the multiplication ofBCG in these cells. Mice which are classifiedas resistant based on presence of the BCGgene do not develop additional resistanceor acquire resistance to BCG after immu-nization. Naturally sensitive mice, lackingthe BCG gene, can respond with acquiredresistance to infection after immunization.If naturally resistant humans, correspond-ing to mice with the BCG gene, constitutethe true primary nonreactive subjects whodevelop LL after exposure to M. leprae, thenthey can be identified by means of testingthe ability of their macrophages to inhibitthe growth of BCG. Thus, paradoxically,individuals whose macrophages can inhibitthe growth of BCG would be those individ-uals incapable of developing acquired re-sistance to leprosy. If operationally feasible,these individuals could be identified, if thehypothesis is correct, by a series of serolog-ical testing, lepromin and tuberculin skintesting, and testing for the ability of theirmononuclear phagocytes to inhibit thegrowth of BCG in vitro. Once identified,these individuals with true primary non-reactivity to M. leprae would require con-tinuous chemotherapy.

The second editorial in the June issue wasa magnificent review of the history of lep-rosy in China by Skinsnes and Chang (289-307).

The deaths of two giants in leprosy re-

search, Professor Mitsugu Nishiura and Dr.Charles C. Shepard, were noted (308-310)in the June issue.

In the Correspondence section of the Juneissue, Gelber (311-312) presented a mostunusual nodular lepromatous patient withtypical clinical features but only exceedinglyrare acid-fast bacilli in a biopsy of his skin.Imkamp (313-317) reviewed the treatmentof reactions in leprosy and offered stan-dardized schemes of corticosteroid treat-ment for these complications.

In the Current Literature section of theJune issue, Manchester (326) explained thedecline in leprosy in medieval England asbeing fundamentally due to an increasedpopulation density. Increased populationdensities would favor the transmission ofpulmonary tuberculosis; the survivors of theprimary infections with M. tuberculosis(mostly young children) would be relativelyimmune to leprosy thereafter, therefore lep-rosy would decline. Anderson (327) foundthat dapsone inhibited and clofazimine en-hanced both the spontaneous and inducedrelease of prostaglandin E, from humanneutrophils in vitro. This could be relatedto the immunostimulating and immuno-suppressive properties of dapsone and clo-fazimine, respectively. Bhatia, et al. (327)reviewed their experience with dapsone-re-sistant M. leprae as detected in mouse footpad infections in Chingalpattu, South India,since 1974. There were 23 primary dap-sone-resistant isolates, 16 (70%) of whichwere mild or low level and only 1 (4%) ofwhich was fully resistant or resistant to highlevels of dapsone in the mouse diet. In con-trast, of 76 secondary resistant isolates, 69(91%) were at a high level and none were ata low level. Foucauld, et al. (327-328) re-ported a case of aplastic anemia felt to bedue to dapsone. In mouse foot pad infec-tions, Gelber, et al. (328) found kanamycin,streptomycin, and amikacin to have bac-tericidal activity against M. leprae with less-er activity with gentamicin and tobramycin.Gonzalez Vazquez (328) pointed out the twopossible mechanisms by which a leprosy pa-tient being treated with sulfones can havethe disease recur; a) through relapse withendogenous bacilli which have developedsulfone resistance or b) re-infection with ex-ogenous sulfone-resistant organisms. Joshi,

54,1^ Editorials^ 95

et al. (328-329) found no evidence thatdapsone induces the metabolism of oralcontraceptives. Mester de Parajd and Gar-nier (329) fed mice with a dietary supple-ment rich in tryptophan, unsaturated fattyacids and glucose, and found inhibition ofthe multiplication of M. leprae in conven-tional foot pad infections. The effectivenessof this diet was thought to be due to in-creased biosynthesis of deoxyfructo-sero-tonin in the mice which, in turn, inhibitedthe multiplication of the bacilli. Niwa, et al.(330) found that clofazimine increased thegeneration of OH • , decreased the genera-tion of F120 2 , and had no effect on super-oxide dismutase activity in neutrophils andmonocytes from active multibacillary lep-rosy patients. Pattyn, et al. (330) performeda survey among 994 LL patients in UpperVolta, and concluded that at least 7% hadsecondary dapsone-resistant disease.Schwab, et al. (330-331) showed a progres-sive decrease in serial nerve conduction ve-locities in rabbits chronically treated withthalidomide. Fleury and Opromolla (331)reviewed 16 cases of carcinoma arising inplantar ulcers in leprosy patients. Hobbs andHempstead (332) described an interestingcase of disseminated coccidioidomycosiswhose skin findings resembled those of le-promatous leprosy. Kale, et al. (332) foundvariable degrees of cardiovascular auto-nomic dysfunction among a group of LLpatients including some with reactions.Laing, et a!. (333) described an LL patientwho developed a squamous cell carcinomaat the site of a preceding plantar ulcer. Afteran amputation, new lesions appeared andleprosy bacilli were found within the squa-mous cell carcinoma with occasional organ-isms in the cytoplasm of the neoplastic cells.Roy, et al. (334) determined the prevalenceof gynecomastia among leprosy patients inSouth India. The prevalence was higheramong lepromatous patients, those with fre-quent ENL reactions, those patients inwhom treatment was delayed after the onsetof the disease, and/or those with an overalllong duration of the disease. Duncan, et a!.(336) studied 81 placentae from women withleprosy and found no morphological evi-dence of infection of the placenta with M.leprae. No acid-fast bacilli were seen on lightmicroscopy, although homogenates from 2

out of 7 placentae from women with veryactive LL contained very small numbers ofacid-fast bacilli. Gonzalez-Abreu, et al.(336) found that standard lepromin skintesting induced anti-M. leprae antibodies bythe FLA-ABS test up to 180 days after test-ing. Khandke, et al. (337) found that mono-nuclear cells from LL patients which wereunresponsive to intact M. leprae, I. lepraesonicates, M. leprae cytoplasm, cell wall orlipid fractions would respond strongly in vi-tro to delipified cell wall fractions of thebacilli. Mehta and Antia (338) described theultrastructural features of sciatic nerves fromarmadillos infected with IIf. leprae. Modlin,et al. (338) showed that ENL tissue had morenumerous cells of the helper-inducer phe-notype and fewer of the suppressor-cyto-toxic type as compared with nonreactionallepromatous tissues. Nath, et al. (339) foundthat supernatants from 24-hr cultures ofmonocytes (adherent cells) from borderlineand lepromatous patients inhibited IL-2production by a T-cell line. It is possiblethat the unresponsiveness associated withlepromatous leprosy is related to the inhi-bition of IL-2 production by soluble sup-pressive factors from monocytes. Nath, etal. (340) demonstrated heterogeneity amongLL patients regarding the presence of M.leprae-reactive T cells in vitro. AutologousT cells co-cultured with autologous adher-ent cells showed significant improvement invi. leprae antigen-induced lymphoprolifer-

ation in 9 of 16 LL patients. Some LL pa-tients responded in vitro to exogenous,purified human IL-2 with enhanced lym-phoproliferation in response to M. lepraeantigens. A proportion of clinically similarLL patients remained unresponsive to M.leprae antigens despite a variety of manip-ulations in vitro. Ridel, et a!. (340-341)found the immunogenicity of M. leprae tobe markedly enhanced in mice if the bacilliwere presented after having been incorpo-rated into mouse peritoneal macrophages,as compared to being administered alone.Ridley, et al. (341) studies the levels anddistribution of lysozyme-positive cells inleprosy lesions throughout the spectrum.Lysozyme proved to be a useful means offollowing cell turnovers in the lesions. In-terestingly, peak numbers of monocytes wereseen in the lesions of active LL as well as

96^ International Journal of Leprosy^ 1986

those of TT lesions. Schwerer, et al. (341)found a linear correlation between serumIgM-class anti-PGL-I antibody levels andthe bacterial index in leprosy patients. An-tibody levels were significantly lower inpatients with ENL as compared to thosewithout ENL, suggesting that 1gM-classanti-PGL-I antibodies may be involved inthe pathogenesis of ENL. Sharp and Baner-jee (341-342) found that macrophages fromnude mice were hyperactive as compared tonormal mice but that nude mice were un-able to control the growth of M. leprae incontrast to the limited infection seen in nor-mal mice. Sharp, et al. (342) studied the fateof intracellular M. leprae in macrophagesfrom nude mice and showed that the bacilliwere susceptible to the bactericidal effectsof hydrogen peroxide. Clark-Curtiss, et al.(344) reviewed their work on the molecularanalysis of DNA from M. leprae,"AI.101,"and Al. vaccae. Papa, et al. (345-346) usedan anti-BCG antigen 60 monoclonal anti-body and showed that Al. leprae and severalcorynebacteria shared this antigenic deter-minant. Some of the corynebacteria wereisolated from leprosy lesions, but others hadno relation with leprosy patients. Portaels,et al. (346) studied the lipids of four bac-terial strains isolated from the livers of ar-madillos experimentally infected with M.leprae, and concluded that their mycolatesand glycolipids clearly differentiated themfrom M. leprae. Ryter, et al. (346-347)studied the formation of electron-transpar-ent zones following the phagocytosis of my-cobacteria including M. leprae by macro-phages. The electron-transparent zoneformed within 1 hr after ingestion and oc-curred equally well with heat-killed AI. lep-rae, showing that its formation does not re-quire the active participation of the bacillus.Silva, et al. (347) reported detailed analysesof individual M. leprae by electron micros-copy. Degenerating M. leprae cells largelypredominated in most samples. Wieten, etal. (348) described a pyrolysis high-resolu-tion gas chromatographic technique for de-tecting wax-ester mycolates capable of de-tecting contamination levels as low as 5%of the total number of acid-fast bacilli inpreparations of M. leprae. Brett (349) stud-ied macrophage activity in mice infectedwith M. lepraemurium and showed that the

most susceptible mouse strain exhibited thehighest levels of macrophage activation.Bahmer (354) collected data on the preva-lence of leprosy in West Germany. A totalof 106 patients were reported by a ques-tionnaire. Most cases were among refugeesfrom South East Asia and from farm work-ers from southern Europe. A total of 16 caseswere Germans. No secondary cases havebeen reported. Basset (354) reviewed the ep-idemiology of leprosy in France. In met-ropolitan France there are about 1000 lep-rosy patients, most of them from overseascountries. de Lange, et al. (355) found sig-nificant differences between LL and BT pa-tients with regard to distributions of im-munoglobulin haplotypes in Vietnameseleprosy patients. Ganapati, et al. (355-356)pointed out the value of an intensive healtheducation program in an urban area in iden-tifying new cases. Jesudasan, et al. (356)made a detailed analysis of leprosy inci-dence rates among household contacts.Household contacts of nonlepromatous pa-tients had a relative risk twice as high asindividuals not exposed to leprosy in thesame area, while household contacts of lep-romatous and borderline lepromatous pa-tients had a relative risk three times as high.The peak age-specific incidence rate amonghousehold contacts was between the ages of5 and 9 years. Jesudasan, et al. (356-357)examined the effect that variation in the in-terval between successive cross-sectionalsurveys might have on estimates of the in-cidence rates for leprosy. When the intervalbetween surveys increased from 1 year to 3years, the estimated incidence rate for lep-rosy was halved. Ji, et al. (357) studied FLA-ABS tests in endemic areas. Rates of sub-clinical infection ranged from 11.4% to16.3% and were at least 200 times higherthan the cumulative prevalence rate for overtclinical infections. Koffi, et al. (357) de-scribed impressive declines in the incidenceand prevalence of leprosy in the Ivory Coastsince 1960. van Eden, et al. (358-359) stud-ied HLA haplotype segregation patterns inmulti-case families and found that HLA-DR3 was inherited preferentially by chil-dren with polar tuberculoid leprosy andHLA-MT1 was inherited preferentially bychildren with lepromatous leprosy. Bales-trino, et al. (360) studied enzyme-linked

54, 1^ Editorials^ 97

immunosorbent assays (ELISA) for IgG an-tibody to M. tuberculosis antigen 5 and tu-berculin purified protein derivative (PPD)among pulmonary tuberculosis patients andfound that the ELISA with antigen 5 had asensitivity of 81.4% at a serum dilution of1:40 and a specificity of 93.4% for tuber-culosis. Overall, antigen 5 was more accu-rate than PPD for the diagnosis of tuber-culosis using ELISA. Bhargava, et al. (360-361) found reduced abilities of patients withintestinal tuberculosis to be sensitized toDNCB compared to normal control sub-jects. Thalidomide was found to be effectivein hyperkeratotic discoid lupus erythema-tosus by Frias Iniesta, et al. (361) and insevere orogenital ulceration by Jenkins, etal. (362). Heifets, et al. (361-362) found anumber of cephalosporins and cephamycinsto be promising based on in vitro screeningagainst M. tuberculosis. Mackett, et al. (363)demonstrated the feasibility of incorporat-ing DNA from an infectious agent into thevaccinia genome and inducing protectiveimmunity against that agent after intra-dermal vaccination with the live recombi-nant virus.

The Original Articles in the Septemberissue began with an interesting new tech-nique to measure the physiologic state ofM. leprae by Seydel, et al. (365-372). Ba-cilli isolated from patient biopsies werestudied using single cell mass spectrometryby laser microbe mass analysis and by ATPmeasurements in the same populations ofbacilli. Low intracellular sodium to potas-sium ratios were characteristic of presum-ably healthy M. leprae cells. Under dapsonechemotherapy, the bacilli showed higher so-dium to potassium ratios which correlatedwith a decrease in ATP content. Lamas-Robles, et al. (373-377) found that humanskin sections were much better substrates todemonstrate the anti-nuclear antibodiespresent in the sera of LL patients than con-ventionally used rat liver sections. Sathish,et al. (378-384) showed an excellent cor-relation between standard mouse foot paddapsone sensitivity determinations and ra-diometric macrophage assays based on theincorporation of 3H-thymidine into M. lep-rae in macrophage cultures. Longley, et al.(385-394) conducted sophisticated studieson the immune cell phenotypes and IL-2

production in naturally occurring leprosyskin lesions. In absolute terms, the numberof T suppressor cells (OKT8 +) were un-changed across the leprosy spectrum. In lep-romatous patients' lesions, the absolutenumbers of total T cells (Lcu-1 +) were de-creased. The absolute number of helper Tcells (Leu-3+, OKT4 +) decreased mark-edly from tuberculoid to lepromatous le-sions. The absolute numbers of Langerhans'cells (OKT6 +) a) were higher in tubercu-loid than in lepromatous lesions, b) corre-lated with the percentage of T cells withreceptors for IL-2 (Tac+), and c) correlatedbut less strongly with the percentage of Tcells producing IL-2 (DMS-1 +). Variabilitywas noted in the lesions of tuberculoid pa-tients with regard to the percentage of T cellsproducing IL-2 with some overlap with le-promatous lesions in this regard. Samuel, etal. (395-403) made a detailed analysis ofthe cellular infiltrates following the intrader-mal inoculation of leprosin A. Similar cellswere found to infiltrate both positive andnegative responses to the skin test antigen.At the lepromatous end of the leprosy spec-trum, the infiltrates were largely neutro-phils. Dugan, et al. (404-409) studied thecellular infiltrates of Mitsuda reactions insitu. Interleukin-2 positivity and the epi-dermal triad of lymphocytic infiltration,Langerhans' cell hyperplasia, and Ia-posi-tive kerotinocytes appeared to be consistentcorrelates ofa delayed-type hypersensitivityresponse and provided evidence that the 21to 28 day Mitsuda reaction may be a de-layed-type hypersensitivity phenomenon.Teruel, et al. (410-411) reported a success-ful kidney transplantation in a lepromatouspatient. The patient experienced a transi-tory recurrence of the disease which re-sponded to sulfone treatment in spite of theimmunosuppression associated with therenal transplantation. Douglas-Jones andWatson (412-420) presented details ofa mi-croculture assay for measuring the responseof murine T lymphocytes to M. leprae an-tigens, and showed that it was the T lym-phocytes that proliferated in response to an-tigen in the microcultures and that thelymphocyte response varied with the mousestrain used. Nagata, et al. (421-427) foundno effect of rifampin or dapsone on im-munologic responses in mice. Datta, et al.

98^ International Journal of Leprosy^ 1986

(428-432) studied the protein binding ofdapsone, using hen egg white lysozyme. Thedrug most probably interacts with trypto-phan residues through 7r-7 - interactions.Hirata (433-440) studied the ultrastructuralcharacteristics of the cell walls and cyto-plasmic membranes of Al. leprciemu•iumand Al. leprae. The cytoplasmic mem-branes of the two organisms seemed to havea similar structure but the fine structure ofthe cell walls was slightly different. Larsson,et a!. (441-446) found two long-chain sec-ondary alcohols, 2-octadecanol and 2-ei-cosanol, by gas chromatography in hydro-lysates of Al. avium/intracellulare, incultivable, armadillo-derived mycobacte-ria, and in M. lepraemurium but not in pu-rified suspensions of M. leprae. The tech-nique is a rapid means of detecting andquantifying contaminating mycobacteria inpreparations of Al. leprae. Fukunishi, et al.(447-454) identified PGL-I and phthioceroldimycocerosate in lepromas from a nine-banded armadillo which had been inocu-lated with M. leprae from a mangabey mon-key with naturally acquired leprosy. Theselipids were thought to originate from thespherical droplets (peribacillary substance)surrounding M. leprae in the tissues. Date,et al. (455-460) reported necropsy findingsin 133 leprosy patients and showed that re-nal disease, pyogenic infections, and tuber-culosis were the most frequent causes ofdeath. A variety of kidney lesions were en-countered and, in many cases, the renal le-sions were secondary to infections in otherorgans. Lechat, et al. (461-467) developeda newer version of an epidemiometric mod-el for leprosy which takes into account age-and sex-specific incidence rates accordingto type of leprosy and which includes morerealistic parameters for death rates, popu-lation variations, and natural growth rates.The model was used to simulate the effectsof various vaccines and drug resistance onthe incidence of leprosy in a population.

In the Editorial section of the Septemberissue, Duncan (468-473) reviewed theproblem of leprosy in young children in lightof recent findings. Huikeshoven (474-480)thoughtfully reviewed the problem of com-pliance among leprosy patients, arguing thattreatment compliance is more importantnow than ever before.

In the Correspondence section of the Sep-tember issue, Sebille, et a!. (481-483) de-scribed reductions in motor nerve conduc-tion velocities in the sciatic nerves of miceinoculated into the foot pad with Al. leprae,and found that rifampin treatment couldprevent and, in some cases, reverse this dis-order. Caticha-Alfonso (483-484) found nocorrelation between NADH-methemoglo-bin reductase activity and hemoglobulinlevel or reticulocyte rate in leprosy patientson chronic sulfone therapy. Hunter, et al.(484-486) provided very valuable, detailedmethodology for the purification of PGL-Iantigen from Al. leprae from armadillo andhuman tissues. Vemuri, et al. (487-489) de-scribed a procedure for the isolation ofPGL-I from human leprosy nodules, andshowed that PGL-I from human and in-fected-armadillo tissues was chemically andimmunologically identical.

In the Current Literature section of theSeptember issue, Kumar, et al. (493) sug-gested the feasibility of involving commu-nity leaders in providing support for leprosyhealth education and control programs.Amokhina (493) described a technique forin vitro incubation of leprosy granulationtissue which seemed useful in studying theeffects of antileprosy drugs. Daneshmend(494) reviewed the relatively rare reports ofneurotoxicity of dapsone. Gnenjuk (494) re-ported the effectiveness of a drug called di-mociphon in the treatment of lepromatousleprosy. Jagannathan and Mahadevan (495)found brodimoprim to be synergistic withdapsone in inhibiting the reduction of Fcreceptor-bearing macrophages caused by liveM. leprae after phagocytosis. Juscenko, etal. (495) reported preliminary results of ex-periments using liposomes for the targetedtransport of drugs in leprosy. Kadantsev andKogan (495) found annual relapse rates of1.3% in recent years among leprosy patientsin Russia. Defaulting from treatment playeda particularly important part in relapses. Karand Roy (495) reported a case of reversibleacute renal failure at the time of the secondand third monthly doses of rifampin in apatient being treated for lepromatous lep-rosy according to the WHO regimen. Pattyn(496-497) found that 50% of relapses inpaucibacillary leprosy occur within 31/2 yearsand 50% of relapses in multibacillary lep-

54, 1^ Editorials^ 99

rosy occur within 2 years after discontinuingtreatment. The author feels that it is pos-sible to reduce the duration of treatment ofmultibacillary leprosy to 1 year, and thereare indications that regimens of 6 months'duration may be effective. Reddy and Nee-lan (497) found that responses to dapsonemonotherapy were comparable in cohortsof bacteriologically positive patients beingtreated in the years 1960-1962 and in thosetreated from 1968-1970. Samuel, et al. (497)found that 7 of 15 isolates ofM. leprae frompreviously untreated leprosy patients in Ne-pal were resistant to 0.01% dapsone in themouse diet. Samuel, et al. (497) found that29 out of 56 patients suspected of havingdeveloped dapsone-resistant leprosy wereproved to have secondary dapsone-resistantdisease by the mouse foot pad test. Durairaj,et al. (498) reported diminished responsesin serum cortisol levels after stimulationwith ACTH in both reactional and non-reactional patients with lepromatous lep-rosy of over 10 years' duration. Thus, ad-renal corticol reserve was felt to bediminished in both reactional and nonreac-tional lepromatous leprosy. Gupta, et al.(499) reported an interesting case of inde-terminate leprosy developing at the site ofa dog bite. Gupta, et al. (499) found im-paired sympathetic respiratory reflexes in12 of 25 polar lepromatous leprosy patientswith and without lepra reaction. Jesudasanand Christian (499) studied 88 paucibacil-lary leprosy patients and found that 40-75%underwent spontaneous regression within aperiod of 5 years from detection. Lucht, etal. (500) reported a patient with type 1 (re-versal) reaction whose condition improveddramatically after 5 plasma exchanges on 5successive days. Seang Hoo Nah, et al. (501)found a correlation between the duration ofconfirmed untreated lepromatous leprosyand the degree of alveolar bone loss in theanterior maxilla. Gad, et al. (502) showedthat thalidomide induced a reduction in thepercentage and absolute number of T-helpercells in the circulation of healthy subjects.Jeevan and Bapat (502-503) showed thatICRC bacilli were capable of sensitizing miceto lepromin, and this sensitization could beadoptively transferred to syngeneic recipi-ents by sensitized spleen cells. Mathew, etal. (503) analyzed the granulomas induced

in draining lymph nodes of guinea pigs im-munized with BCG and Al. leprae. TheBCG-induced granulomas were well orga-nized and contained epithelioid cells withmacrophage-specific antigen on their sur-face, but no detectable Ia antigen. In M.leprae-induced granulomas, there was anabsence of organization and an absence ofepithelioid cells; the macrophages in thegranuloma expressed both macrophage-specific and Ia antigens. Mathur, et al. (503)found reduced numbers and ultrastructuralmorphological changes in Langerhans' cellsin the epidermis of lepromatous (LL) casescompared to those in tuberculoid (TT) pa-tients. Modlin, et al. (503-504) character-ized the cells in human leprosy granulomasin situ using a variety of monoclonal anti-bodies and concluded that the defective cell-mediated immunity in lepromatous leprosyseems to be associated with diminished IL-2production and disorganization of the gran-uloma. Narayanan, et al. (504) studied T-cell phenotypes in reactional BT patients(reversal or type 1) and found a significantinflux of OKT8 + (suppressor/cytotoxic)cells compared to nonreactional BT lesions.In reactional BL lesions (both reversal andENL), there were increases in pan T cellswith a proponderance of the helper/inducersubset. OKT6+ Langerhans' cells were in-creased in all reactional lesions. Poulter, etal. (505) studied macrophages, interdigitat-ing cells, and Langerhans' cells in the der-mal infiltrates of BL lesions and found theproportion of cells parasitized by M. lepraewithin each subpopulation was equivalentto the overall proportion of each cell typewithin the infiltrate. Saha, et al. (505) foundcorrelations between various clinical statesin leprosy and serum beta-2-microglobulinlevels. Umerov, et al. (506) found a com-mon antigen in human peripheral nervesand in Al. leprae. Umerov, et al. (506) foundthat sera from patients with active leprosyexerted myelinotoxic activity in cultures ofspinal ganglia which is due to the presenceof antibodies against specific mycobacterialantigen which is, in turn, similar to the an-tigen of human peripheral nerves. Yushin(506) presented evidence for the activationof the mononuclear phagocytic system inlepromatous patients. Mankar, et al. (507-508) used the ability of live M. leprae to

100^ International Journal of Leprosy^ 1986

reduce the number of EA-rosetting macro-phages as a means of testing bacterial sus-ceptibility to drugs. Mukherjee, et a!. (508)found that radiolabeled acetate could be in-corporated into the PGL-I antigen of M.leprae maintained in a Schwannoma cellline. The synthesis of PGL-I antigen couldbe inhibited with dapsone and rifampin. Sulaand Sulova (509) described a newly isolatedphage A1-1 obtained from a laboratorystrain of M. lepraemurium "Douglas." Ta-lati and Mahadevan (509) found that pen-icillinase was expressed by M. leprae whenincubated with penicillin. Live M. lepraehad demonstrable lipase activity. Hoffen-bach, et al. (510) saw no evidence of a directinfluence of the Bcg gene on lymphokineproduction and antibody secretion in miceinfected with M. lepraemurium. Juscenko(510) reported an interesting case of an ar-madillo which developed reversal reactionduring the course of an experimental infec-tion. Bharadwaj, et al. (510-511) saw higherrates of FLA-ABS positivity among con-tacts of LL and BL patients than amongcontacts of nonlepromatous patients. All 11contact children who have developed thedisease to date belonged to a group whowere lepromin negative and FLA-ABS pos-itive. Jesudasan, et al. (511) reported thatthe incidence rates remained high even 10years after treatment was started in 4 pri-mary case among household contacts.Berreman (512-513) pointed out the effec-tiveness of a policy of not confronting peo-ple with a diagnosis of leprosy in problem-atic childhood cases, but of asserting insteadthat leprosy can be prevented if treatmentis accepted. Brandsma and Brand (513)studied long-term median nerve function inleprosy patients who originally had had pureulnar palsy for which they had tendon trans-fers to correct claw hands. The use of thecarpal tunnel as a pathway for tendon graftsdid not significantly affect the long-term sta-tus of the median nerves in these cases. Shahand Pandit (513) found reconstruction ofthe heel with a flexor digitorum brevis myo-cutaneous flap was useful in the manage-ment of chronic nonhealing plantar ulcerson the heel in leprosy patients. Horney, etal. (514) reported a case of cutaneous in-oculation tuberculosis occurring in a tattoo.Wulff, et al. (514-515) described predom-

inantly sensory peripheral neuropathy,mainly involving the lower limbs, in 7 pa-tients with prurigo nodularis and 1 withaphthous stomatitis treated with thalido-mide.

The Original Articles in the Decemberissue began with the definitive review ofleprosy occurring in children one year of ageand under by Brubaker, et a!. (517-523).Leprosy was diagnosed in 91 infants oneyear of age and under. The source of theinfection in at least 43% of the infants wassomeone other than the mother. The young-est patient was 2-3 months of age. Som-merfelt, et al. (524-532) studied leprosyprevalence in South India, and found thatleprosy prevalence rates were significantlylower in field areas than in villages, and thatthere was a significant correlation betweenthe occurrence of malnutrition in youngchildren and the prevalence of leprosy. Nosignificant correlations were found betweenthe occurrence of malnutrition in the gen-eral population, the occurrence of povertyor illiteracy and leprosy prevalence rates.Hackel and Beiguelman (533-539) studiedchromosomal aberrations in cultures of skinfibroblasts of leprosy patients and found thatstructural chromosomal abnormalities wereassociated with treatment with dapsonealone or with combined therapy. Petri, etal. (540-545) measured clinical and histo-logical reactions to lepromin in healthyadults with no known contacts with leprosy.Surprisingly, the intensity of the clinicallyread Mitsuda reaction was not correlatedwith the intensity of the histological re-sponse. Waters and Stanford (546-553)provided a detailed description of a phe-nomenon termed "giant reactions" to tu-berculin. The reaction may occur in up toa fifth of predominantly lepromatous pa-tients during their first 1 to 3 years ofchemotherapy. Yoder, et al. (554-558) de-scribed an unusual patient with document-ed lepromatous leprosy presenting as a soli-tary lesion with a high bacterial count. Brown,et al. (559-564) saw essentially no enhance-ment of cell-mediated immunity in patientswith lepromatous leprosy being given ci-metidine. Wu, et a!. (565-570) applied anenzyme-linked immunosorbent assay withsoluble antigens of M. leprae to blood sam-ples collected from earlobes of leprosy pa-

54, 1^ Editorials^ 101

ticnts and healthy controls. The blood sam-ples were absorbed with M. vaccae, BCG,cardiolipin, and lecithin before being testedin the assay. While there were areas of over-lap, antibody activity gradually increasedfrom TT to LL. Mukherjee, et al. (571-576)described the ultrastructure of leprous phle-bitis, demonstrating bacilli in endothelialcells and the release of Al. leprae into thelumen of veins by exophagocytosis. Bacilliwere able to grow and multiply in the en-dothelial and smooth muscle cells, and thesmooth muscle cells showed no evidence ofreaction due to the presence of the bacilliin their cytoplasm. Hirata (577-581) de-scribed the ultrastructure of Al. leprae in thenasal mucosa of leprosy patients. Cree, etal. (582-586) described a technique to de-termine the proportion of the dermis oc-cupied by granuloma in histological sec-tions of skin biopsies from leprosy patientsby planimetry. Shepard, et al. (587-594)carefully studied the structure-activity pat-tern of a series of substituted thioamidesagainst M. leprae and concluded that thestructural requirements for antileprosy andantituberculosis activity are probably sim-ilar, with ethionamide and prothionamidebeing found to be most active. Balina, et al.(595-599) summarized their experience inthe experimental reproduction of leprosy inthe seven-banded armadillo (Dasypus hy-bridus). The seven-banded armadillo, un-like the more commonly used nine-bandedarmadillo, breeds readily in captivity. Mori,et al. (600-609) summarized elegant workon the purification and biochemical studiesof M. leprae. It seemed possible to enrichfor solidly staining bacilli by means of den-sity gradient centrifugation. Endogenousrespiration was higher in more dense bacillithan in fractions containing less dense ba-cilli. Cytochrome B, was detected but cy-tochromes A, A 2 , and C were not detected.No catalase activity was found and no NAD-peroxidase activity was detected.

The Editorial section of the December is-sue began with an elegant review of the ep-idemiologic patterns observed during de-clining incidence rates of leprosy by Irgens(610-617). In a number of settings, declin-ing incidence rates are associated with in-creases in mean age at onset. Evidence ispresented that these changes in age at onset

are not caused by postponement of the in-fection to a later time in life, but that theseolder patients represent cases with long in-cubation periods who become relativelymore frequent as time goes on compared topatients with shorter incubation periods be-coming ill at the same time. Since lepro-matous patients have a longer incubationperiod than patients with other types of lep-rosy, when the fraction of new cases withlong incubation periods increases, the frac-tion of the new cases with lepromatous dis-ease also increases. Thus increases in theproportion of lepromatous cases and in-creases in average age at onset are both as-sociated with decreasing incidence rates.

We were delighted to have the prize-win-ning essay on monoclonal antibodies andrecombinant DNA technology by Seckl asa Guest Editorial in the December issue(618-640). These two powerful technolo-gies have opened vast new areas of researchin leprosy and tuberculosis, and we join inthe hope that they will hasten the day when"both leprosy and tuberculosis will dwindleinto the historical annals of medical litera-ture."

In the Obituary section of the Decemberissue, the death of Dr. James Cecil Pedleywas noted with sadness.

The Correspondence section of the De-cember issue began with a description ofgood results using silastic implants to sim-ulate the contour of the first dorsal inter-osseous muscle in leprosy patients with lossof this muscle mass by Zacharia and Gelber(643-644). Pavithran (645-646) describeda patient who developed generalized exfo-liative dermatitis after being treated withclofazimine who showed a recurrence of theexfoliative dermatitis upon rechallenge withthe drug. Furukawa, et al. (647-648) dem-onstrated that anti-cardiolipin antibodies inthe sera of LL patients have the ability tocrossreact with double-stranded DNA.Shankar, et al. (649-652) studied the in vi-tro proliferative responses of peripheralblood mononuclear cells to M. leprae andPPD in lepromatous leprosy patients, tu-berculoid patients, and healthy controls inthe presence and absence of supplementalIL-2. The data indicate that a majority ofM. leprae nonresponders, including all lep-romatous patients, a few borderline tu-

102^ International Journal of Leprosy^ 1986

berculoid patients, and some healthy sub-jects not exposed to M. leprae, may acquirein vitro proliferative response to Al. lepraeupon the addition of IL-2. This capacityseemed to be closely related with the abilityof these individuals to develop a prolifer-ative response to PPD, strongly suggestingthat the IL-2-induced proliferative responseto M. leprae is directed against epitopesshared between Al. leprae and Al. bollsBCG, the source of the PPD. Shepard andLevy (653-655) commented on earlier sug-gestions by Humber regarding the techniqueused for counting M. leprae. Humber (656-657) continued to feel that application of astratified sampling technique would be pref-erable.

In the News and Notes section of the De-cember issue, Dr. and Mrs. Olaf Skinsnes'return to China (659) was noted. Well-de-served recognition to Dr. Indira Nath (660),Dr. M. G. Deo (660), Baba Amte (660), andDr. B. R. Chatterjee (660) was recorded.The inauguration of trials of leprosy vac-cines in Malawi and Venezuela were noted(660-661).

In the Current Literature section of theDecember issue, Alvarenga, et al. (667-668)described excellent results with the combi-nation of rifampin and Isoprodian in almost800 patients in Paraguay. Some 126 lepro-matous cases have completed therapy andhave been observed for 2 years or longerwith no sign of relapse. Arora, et al. (668)found that levamisole was not effective inENL. Khalil, et al. (669) found that antacidssignificantly reduced the bioavailability ofconcomittantly administered rifampin. Levy(669-670) outlined the role of chemother-apy in both the management of an individ-ual patient and in the control of leprosy inthe community. Li (670) reported favorableclinical results with a clofazimine (B663)analogue designated B628 in a total of 9lepromatous patients treated for fivemonths. Mathur, et al. (670) found that ap-proximately 45% of orally administered clo-fazimine was absorbed in single doses of upto 600 mg. Mester de Parajd, et al. (670)reviewed the antileprosy potential of de-oxyfructo-serotonin and its analogues. Mit-tal, et al. (671) tested the effects of clofazi-mine and 6 analogues on the viability of Al.leprae in macrophage cultures as measured

by 3 1-1-thymidine incorporation. In general,clofazimine appeared to have a more rapidonset of action and an action at a lowerconcentration than the other analoguestested. Nair and Mahadevan (671) mea-sured the inhibition of the preferential ac-cumulation of cholesterol ester by macro-phages that have ingested live M. leprae bydapsone and rifampin as a measure of bac-terial drug sensitivity. Pandian, et al. (671-672) reviewed results of dapsone monother-apy in nonlepromatous and intermediateleprosy. Relapse rates appeared to remainsteady at about 5/1000 for each year fol-lowing release from control for 7 years.Schroder and Matthiesen (672) adminis-tered large doses of thalidomide to rabbitsfor prolonged periods of time and foundthat there was a reduction in the thicknessof the myelin sheaths in their sural nerves.This was associated with a reduction in sen-sory conduction velocity. Sharma, et al.(672-673) felt that levamisole was useful inshortening the duration of both reversal re-actions and ENL. Agrawal and Agrawal(673) found vascular changes in the arteriesin the hands and feet of a majority of lep-rosy patients as measured by percutaneousarteriography. Arora, et al. (673) found sta-tististically significant changes in leprominreactivity following levamisole in a groupof borderline leprosy patients. ffytche andMcDougall (674) reviewed ocular leprosy,making a distinction between "potentiallysight-threatening" lesions and those consid-ered only as "academic." Kiran, et al. (674-675) suggested an unsupervised outpatientmethod of treating recent loss of nerve func-tion in patients with borderline leprosy us-ing a semi-standardized course of cortico-steroids. Robertson, et al. (675) describedan LL patient diagnosed finally on the basisof histopathologic changes in an eye whichhad been enucleated for bilateral anterioruveitis for which no cause had been found.Foci of inflammation containing Al. lepraewere found in the vitreous extending to theretina at the posterior pole. Wright (677)studied plasma phospholipid essential fattyacids in leprosy patients and found a sig-nificant reduction in linoleic acid with anincrease in its metabolite, dihomo-gamma-linoleic acid. No difference was found be-tween patients with multibacillary and pau-

54, 1^ Editorials^ 103

cibacillary leprosy and treatment seemed toresult in normalization of these measure-ments. Atlaw, et al. (677-678) describedtheir experience in producing human mono-clonal antibodies against Al. leprae. The re-sults suggest that a combination of Epstein-Barr virus transformation and hybridiza-tion may be an optimal method in produc-ing human monoclonal antibodies from lep-rosy patients. Bloom and Mehra (678)reviewed the immunology of leprosy. Coll-ings, et al. (678-679) described an interest-ing technique to quantitate the class II MHCantigens (HLA-DR) expressed by cells with-in tissue sections. The method was appliedto the lesions of tuberculoid and leproma-tous leprosy and significant differences inthe HLA-DR expression by cells in the in-filtrates were observed. Gillis, et al. (679)described a 65,000 apparent molecularweight protein associated with cell wall ofM. leprae which contained at least 1 species-specific and 4 crossreactive antigenic deter-minants as defined by a variety of mono-clonal antibodies. Kundu, et al. (679-680)found that corticosteroids could induce anegative lepromin reaction in polar tuber-culoid leprosy patients. Levamisole was in-effective in converting lepromin reactivityin polar lepromatous cases. Mehra, et al.(680) presented evidence that the PGL-I an-tigen of M. leprae is capable of inducingsuppression of mitogenic responses of lep-romatous patients' lymphocytes in vitro andthat the suppressor T cells recognize the spe-cific terminal trisaccharide moiety on thisantigen. Mohagheghpour, et al. (680-681)studied the ability of LL patients' mono-nuclear leukocytes to produce IL-1 and IL-2 upon stimulation with Al. leprae and de-termined the ability of exogenous IL-1 andIL-2 to reconstitute the responses of thesepatients in vitro to this antigen. Results withIL-1 were comparable in BT and LL pa-tients' cells. On the other hand, T cells ofLL patients failed to express receptors forIL-2 or to produce IL-2 in response to M.leprae in contrast to cells from BT patients.Recombinant human IL-2 failed to recon-stitute the response of LL patients' cells toM. leprae. The failure of T cells of LL pa-tients to respond to M. leprae may be onthe basis of their failure to express receptorsfor IL-2. Praputpittaya and Ivanyi (681)

partially characterized a repeating epitope(MY4b) common to M. tuberculosis and M.leprae. Ramanthan, et al. (681-682) foundthat sera from BT and LL patients in re-action had markedly decreased abilities tosolubilize immune preciptates in vitrothrough the complement system. Thesechanges did not seem to be related to totalor alternative pathway hemolytic levels ofcomplement, circulating immune com-plexes, or serum C3d levels. Tausk, et al.(683) found reduced numbers of receptorsfor C3b on the erythrocytes of LL patientsas compared to tuberculoid patients or nor-mal controls. Teuscher, et al. (683) studiedthe responses of inbred strains of mice toAl. leprae by measuring the resulting anti-bodies to PGL-I. Antibody levels were con-trolled by multiple genes and low antibodyresponses to the PGL-I seemed to be in-herited as a dominant trait. Young, et al.(684) described the use of a polysulfonemembrane as a solid support for chroma-tography and immunoblotting of the PGL-Iantigen of M. leprae. There was very littlenonspecific background binding and the as-says could be carried out with IgM anti-bodies from human sera. Young, et al. (684)described studies characterizing a 28,000dalton protein antigen of M. leprae bymonoclonal antibodies. One epitope onmolecule appears to be specific for Al. lep-rae, one partially specific, and one broadlycrossreactive among all mycobacteria.Brennan (685) reviewed the evidence thatthe phthiocerol-containing lipid capsule ofM. leprae may be directly responsible forthe intracellular survival of the organism.David and Rastogi (685-686) described aninteresting system of exposing M. auriun tosublethal concentrations of colistin (poly-myxin E), resulting in synchronized cell di-vision once the antibiotic was removed.Kato (686) found that extracts of AI. lepraedid not contain mycobactin and speculatedthat Al. leprae might be dependent uponsecondary mycobacteria present in Al. lep-rae - infected tissues to provide it mycobac-tin for its own multiplication. Katoch, et al.(686) studied LDH isoenzyme patterns ofmycobacteria and concluded that they couldbe of identification value at the species level.Minnikin, et al. (686-687) identified the freelipids of the leprosy bacillus over the total

104^ International Journal of Leprosy^ 1986

polarity range and showed that the patternswere particularly related to those of M. bo-vis, M. kansasii, and M. niarinuni. Min-nikin, et al. (687) did not find a particularlyclose relationship between Al. leprae andM. gordonae on the basis of fatty and my-colic acid compositions. Mukherjee andAntia (687) observed a significant multipli-cation ofacid-fast bacilli within the Schwanncell component of organized nerve culturesof dorsal root ganglia from neonatal micewhich had been infected with AI. leprae.Portaels, et a!. (687-688) reviewed their ex-perience in cultivating mycobacteria from16 out of 32 samples of tissues from ar-madillos inoculated with M. leprae and in3 out of 7 samples from noninoculatedarmadillos held in captivity. AI. avium - in-tracellulare-scrofulaceum complex, AI.gordonae, M. terrae, and new armadillo-de-rived mycobacteria (ADM) were identified.Wang, et al. (689) studied the viability ofM. leprae in normal saline by the mousefoot pad technique and found that at roomtemperature for 3 days the viability of thebacilli decreased slightly, and after 2 weeksthe viability was lost. At refrigerator tem-perature viability decreased by 8 days andafter 20 days the viability was lost. Ganguly,et al. (689-690) found no effect of levami-sole on the rate of growth of M. leprae inmice. Job, et al. (690) studied armadilloswhich developed disseminated disease afterinoculation with M. leprae and noted thefirst lesion occurring at the site of inocula-tion in 14 of the 16 animals infected intra-venously and in 4 of the 4 infected intra-dermally. Lefford (690) found that M.lepraemurium grew equally well in nu/+(heterozygous, euthymic) mice from aBALB/c background as they did in nu/nu(nude, athymic) littermates, and concludedthis was due to the intrinsic genetic suscep-tibility of both types of mice. Rojas-Espi-nosa, et al. (691) inoculated turtles with M.lepraernurium and M. leprae. Limited mul-tiplication of M. lepraernurirn occurred andM. leprae persisted for up to 23 monthspostinoculation but without clear evidenceof multiplication. Ferreira, et al. (691-692)analyzed the patterns of leprosy incidenceby age and type of disease and concludedthat these patterns could be explained bythe proportions of Mitsuda-positive indi-

viduals increasing with age and the numberof contagious patients and consequently the"supply" of bacilli capable of causing in-fections being greater in high-prevalenceareas. The conclusions reached to explainthese patterns in leprosy epidemiology dif-fer from those outlined by Irgens (610-617).Schlagel, et al. (692-693) reported 89 casesof leprosy among active duty U.S. militarypersonnel during the period 1970-1983.Chaise and Sedel (694) measured the carpaltunnel and intraneural pressures in 15 casesof leprous neuritis of the median nerve atthe wrist and found markedly increasedpressures compared to those at the samelocation in healthy volunteers. Dickinsonand Mitchison (695) found evidence thatfludalanine acted synergistically with cyclo-serine against rapidly growing mycobacte-rial species. When tested against slowlygrowing mycobacteria, the combination wasno more active than cycloserine alone. Mi-zuguchi, et al. (696-697) described in vitroactivity of 0-lactam antibiotics againststrains of AI. avium - intracellulare. Mook-erjee and Pauly (697) presented evidencethat purified recombinant human IL-2 canserve as the first signal for T-cell prolifera-tion for lymphocytes of healthy human do-nors. Perkus, et al. (698) inserted codingsequences for the hepatitis B virus surfaceantigen, the herpes simplex virus glycopro-tein D, and the influenza virus hemagglu-tinin into a single vaccinia virus genome.Rabbits immunized with this polyvalentvaccinia virus recombinant produced an-tibodies reactive to all 3 authentic foreignantigens. It thus seems feasible that this ap-proach can be used to immunize againstmultiple pathogens. Young, et al. (699) de-scribed the recombinant DNA approachused to systematically survey the Al. tuber-culosis genome for sequences that encodespecific antigens as detected by monoclonalantibodies.

The December issue contained the ab-stracts for the Twentieth Joint Leprosy Re-search Conference of the U.S.—Japan Co-operative Medical Science Program.Nomaguchi, et al. (706-707) found in gen-eral that exogenous interferon-alpha, -betaor agents which induced the in vivo pro-duction of interferons did not affect the sur-vival of mice infected with viable M. lep-

54, 1^ Editorials^ 105

raemurium. Modlin, et al. (707-708)cloned T4 and T8 lymphocytes from tuber-culoid and lepromatous skin granulomasand found that lepromin-induced suppres-sor cells were found only in cells derivedfrom lepromatous granulomas. Kaplan, etal. (708-709) found that peripheral bloodmononuclear cells from lepromatous pa-tients were heterogeneous in their responseto M. leprae in vitro as assessed by T-cellproliferation and gamma-interferon release.Exogenous IL-2 had no significant effect onthe response of T cells from nonresponderpatients, although it was effective on T cellsfrom low-responder patients. Similarly,deletion of monocytes and/or OKT8+ Tcells had no effect on the response to M.leprae by nonresponder patients. Uyemura,et al. (709) evaluated the in vitro effect ofcyclosporin A on lepromin-induced sup-pression in the peripheral blood of LL pa-tients and in LL patients with ENL. Lep-romin-induced suppression was present inlepromatous leprosy but not in ENL, andcyclosporin A treatment of peripheral bloodmononuclear cells from ENL patients re-stored the lepromin-induced suppression tolevels observed in LL patients. These find-ings may provide evidence that cyclosporinA has potential efficacy in the treatment ofENL. Izaki, et al. (709-710) extracted plas-minogen activator activity from hyper-sensitivity-type murine lepromas andextensively characterized the materialbiochemically. Truman, et al. (710-711) es-timated antibodies to the PGL-I antigen ofAl. leprae among hospitalized leprosy pa-tients, staff members at a leprosy hospital,and a leprosy-naive population. Antibodieswere detected in 12-14% of presumedhealthy hospital staff members. Thalido-mide significantly decreased specific IgMantibodies to the PGL-I antigen. Jacobs, etal. (711-712) described genomic librariesDNA prepared using the plasmid expres-sion vector pYA626. A 46KD polypeptidewas produced which complements the glt Amutation in the E. coli host strain. Theexpression of M. leprae genes in E. coli todate seems to depend upon the presence ofpromotors recognized by the E. coli tran-scription system. Cocito (712) compared theproperties of Al. leprae and leprosy-derivedcorynebacteria. Hunter, et al. (712-713)

isolated a family of major carbohydrate-containing macromolecular antigens for M.leprae, all of which contain mannose andarabinose. These are highly lipidated, acy-lated exclusively by 10-methyloctadecoan-oate. One of these, designated lipoarabi-nomannan-B (LAM-B), is the dominantimmunogen in M. leprae. Miller, et al. (713-714) found evidence that antibody to the14,000 molecular weight antigen of T. pal-lidum which develops in a subset of leprosypatients is the most common cause of false-positive FTA-ABS tests in this population.Tsutsumi and Gidoh (714-715) reported onthe abilities of various antileprosy drugs toscavenge active oxygen radicals. Abe, et al.(715) studied salivary anti-Al. leprae anti-bodies using a modified technique for thefluorescent leprosy antibody absorption test.The test was positive in 59% of householdcontacts, 39% of school children, and 17%of adults in an endemic area. A significantnumber of individuals showed a positivereaction with saliva but a negative reactionwith sera, possibly suggesting subclinical in-fection through the mucous membrane. Cho,et a!. (715-716) described the results of se-rologic testing using a variety of synthesizedneoglycoproteins based on the PGL-I an-tigen of Al. leprae. The natural terminal di-saccharide conjugated to bovine serum albu-min via an 8-methylene (octyl) linker armshows the greatest sensitivity and specificityamong these neoglycoprotein antigens todate. Additionally, techniques were de-scribed for the estimation of the PGL-I an-tigen itself from clinical samples with a sen-sitivity down to 0.5 ng. Buchanan (716-717)summarized analyses of 33 monoclonal an-tibodies to Al. tuberculosis done as part ofa workshop sponsored by the World HealthOrganization. Mohagheghpour, et al. (717-718) described initial findings in efforts toproduce human monoclonal antibodies toM. leprae antigens. Gillis (718) described atechnique for the affinity purification of a65KD protein of M. gordonae using amonoclonal antibody. Tung, et al. (719)quantitated soluble receptors for IL-2 in thesera from a variety of leprosy patients andtheir contacts. Receptors for IL-2 weregreatly elevated in BL patients with reversalreactions but were only slightly elevated inpatients with ENL. Nakamura and Yogi

106^ International Journal of Leprosy^ 1986

(720) found differences in the susceptibilityof nude rats for the growth of M. leprae,depending upon the genetic background ofthe animals. Chehl, et al. (720-721) studiedthe adoptive transfer of cell-mediated im-munity in Al. leprae-infected nude mice andconcluded that adoptively transferred help-er T cells were responsible for inducing re-versal reactions in this model. Tung, et a!.(721-722) found that murine antibody re-sponses to PGL-I antigen exhibited strainvariations. Eustis-Turf, et a!. (722-723)found IgG-type antibody in the sera of 17of 43 leprosy patients which bound to pe-ripheral nerves at the junction of the axonand the myelin sheath. The positive serareacted with a protein band migrating atapproximately 50KD prepared from an in-termediate filament fraction from humanspinal cord. Job, et al. (723-724) surveyedfor the problems of leprosy among wild ar-madillos and found a prevalence rate of 3.1%in Louisiana. In 1 animal evidence was pre-sented that the M. leprae entered the tissuealong with a thorn. Thomas, et al. (724-725) presented epidemiologic evidence thatboth direct and indirect exposure to arma-dillos appeared to be significant risk factorsin the development of lepromatous leprosy.Cohn, et al. (725-726) reviewed the role oflymphokines in cell-mediated immunity inleprosy. Goren, et a!. (726-727) reviewedthe functionality of secondary lysosomes inmurine resident peritoneal macrophages.Fujiwara, et al. (727) described the syn-thetic methods employed in producing neo-glycoconjugates based on the PGL-I antigenof M. leprae. Mehra, et al. (727-728) pro-vided an overview on the recombinant DNAstrategy to isolate genes from AI. leprae andM. tuberculosis that encode for immuno-logically relevant proteins of these organ-isms. Recombinant DNA expression li-braries containing Al. leprae and Al.tuberculosis genomic DNA fragments havebeen constructed in the bacteriophage vec-tor lambda gt11. These libraries have beenscreened with monoclonal antibodies di-rected against many of the major proteinsof both bacilli. Recombinant DNA clonesproducing relevant antigens which react withthese antibodies have been isolated. Partic-ular attention is focused on the 65KD an-tigen gene of Al. leprae which is being se-quenced.

Once again a great deal of progress hasbeen made in our understanding of leprosyin the past year. From a personal perspec-tive a number of developments and direc-tions appear particularly relevant.

In general there seems to be an increasingawareness and interest in the history of lep-rosy in different parts of the world as evi-denced by papers on leprosy in medievalIslam, China, medieval England, etc.

In the field of chemotherapy, the additivehepatotoxicity of daily rifampin andthioamide now appears clear. The leprominstatus of paucibacillary patients may be im-portant in their risk for relapse after dis-continuation of short-term chemotherapy.Considerable interest has been evident inlevamisole as immunotherapy for leprosy,but, in general, disappointing results havebeen reported from a number of studies.Cimetidine also does not appear to bepromising. The status of the multibacillarypatients in the Malta Project continues tobe followed with interest. There have beenno relapses but a number of these patientscontinue to show acid-fast bacilli in skinsmears. Colchicine was reported by some,but not by others, to be effective in ENL.Increasingly, there are reports of thalido-mide neuropathy occurring in nonleprosycases. Rifampin, when given daily for 30days followed by another 30-day course sixmonths later, significantly prevents relapsein lepromatous patients receiving dapsonemonotherapy. The suggestion was made thatfull-dose dapsone therapy, uninterruptedduring reactions, may decrease the inci-dence of dapsone resistance. It was notedthat primary dapsone resistance as mea-sured by mouse foot pad studies is usuallyof low level; whereas secondary resistanceis usually at a high level. Interest has beenevident in (3-lactam antibiotics, either withor without inhibitors of f3-lactamase, as po-tential chemotherapy for M. leprae. Exper-imental and clinical interest has been ex-pressed in clofazimine analogues.

Clinically, there have been reports of pos-sible respiratory and cardiovascular auto-nomic dysfunction in leprosy patients. Anew apparatus has been described for test-ing sensation to heat. A large necropsy seriesemphasizing renal disease in leprosy pa-tients has appeared. "Giant reactions" totuberculin have been described. It has been

54, 1^ Editorials^ 107

re-emphasized that as many as 75% of truepaucibacillary leprosy patients undergospontaneous regression within five years ofdetection without chemotherapy.

Our knowledge in the field of immunol-ogy is expanding rapidly. Serologic studieswith specific antigens of M. leprae continueto point to rather frequent infection in re-lation to overt disease. Overt disease seemsclearly to be more common in individualswith a positive antibody test and a negativelepromin skin test. Salivary antibodies toM. leprae have been described and appearto be common. A significant number of in-dividuals in endemic areas show antibodiesin saliva but not in blood, and this maysuggest that subclinical infection is occur-ring via mucous membranes. The nature ofthe failure of cell-mediated immunity inlepromatous leprosy to Al. leprae continuesto be the subject of intense interest. Thisfailure seems to be associated with de-creased, possibly inhibited, IL-2 productionwithin the granuloma of lepromatous lep-rosy. This inhibition could come from mac-rophages. T cells are being cloned from lep-rous skin granulomas and analyzedfunctionally. IL-2 restores specific respon-siveness of peripheral blood mononuclearcells from some but not all LL patients invitro. The suggestion has been made thatthis may be related to crossreactions to oth-er mycobacteria to which these individualsare sensitive. The infiltrates of reactionalskin lesions are being analyzed for T sub-sets. ENL lesions seem to be associated withincreases in helper T cells and functionalassays show a loss of suppression in ENLover what is normally observed in non-reactional lepromatous leprosy. It has beenreported that reversal reactions in BT le-sions are associated with increases in sup-pressor T cells, while those in BL patientsare associated with increases in helper Tcells. Emphasis continues on lipid antigensof M. leprae. The PGL-I antigen of M. lep-rae seems to have little if any activity incell-mediated immunity or delayed-typehypersensitivity reactions to M. leprae inmice but was able, in one study, to elicit apositive late skin reaction in a lepromin-positive armadillo. Anti-PGL-I antibodylevels of the IgM type clearly seem to fallwith chemotherapy and are related to thebacterial index in outpatients. The sugges-

tions have been made that the IgM-classantibody to the PGL-I antigen is involvedin ENL and that thalidomide preferentiallyreduces this antibody. A number of syn-thetic antigens based on the PGL-I havebeen produced and a number of methodsdeveloped for detecting the PGL-I antigenin biologic samples. Lipoarabinomannan-Bhas been isolated from M. leprae and is ap-parently a major immunogen of the bacillus.Two groups have produced human mono-clonal antibodies to M. leprae. Two groupshave suggested that there are shared anti-gens between M. leprae and human periph-eral nerve tissue. Antibodies and antigensof M. leprae have been demonstrated in theurine of LL patients. An interesting reportshowed that the intensity of clinically readMitsuda skin reactions was not correlatedwith the histologic intensity of the responsein normal individuals. Field antileprosyvaccine trials have been initiated in Malawi,India, and Venezuela.

In the microbiology of leprosy, workcontinues in defining the chemical compo-sition, particularly the lipid composition, ofM. leprae. Improved rapid isolation tech-niques for the bacilli have been reported andmore sophisticated estimates of its viabilitydescribed with measurements of ATP, ra-diometric assays, single cell spectrometrywith laser microbe mass analysis, etc. Re-combinant M. leprae DNA is being ex-pressed and the stage is being set for com-plete DNA mapping of a number ofimportant antigens of the bacillus.

In experimental infections, a primatemodel for the disease seems to be availablein the mangabey monkey. Infections in sev-en-banded armadillos have been more fullydescribed. Antibodies to the PGL-I antigenhave been found in serum samples fromarmadillos taken in 1960-1964, implyingthat the natural infection in armadillos ex-isted prior to the first experimental inocu-lations of these animals with M. leprae. Aspontaneous reversal reaction has been de-scribed in an armadillo infected with M.leprae.

In the field of epidemiology, genetic stud-ies are suggesting that HLA-linked genescontrol for leprosy type although not forsusceptibility or resistance to the disease perse. Epidemiologic patterns of leprosy as itdeclines in a population now seem to be

108^ International Journal of Leprosy^ 1986

clearer. A new refined epidemiometricmodel of leprosy has been described. Em-phasis has been placed on leprosy in infantsand young children as well as the possibleplacental transmission of the disease to thefetus in utero.

In the field of rehabilitation, a possiblemouse model for progressive leprous neu-ropathy has been described. Marked in-creases in intraneural pressure were mea-sured in leprous neuritis.

From the perspective of the 1985

JOURNAL, a great many of the promises of1984 now appear to be bearing fruit. A rev-olution has occurred and is now under wayin our understanding of leprosy at a basiclevel. As never before, we are being chal-lenged to use this new information as rap-idly, efficiently, and wisely as possible toimprove the care of leprosy patients and to,hopefully, prevent the disease altogether infuture generations. This is indeed an excit-ing time for leprosy workers. I look forwardwith impatient optimism to 1986.— RCH