reply from liblau, singer and mcdevitt

1
Reply from Liblau, Singer and McDevitt We fully agree with McLachlan and Rapoport that human organ- specific autoimmune diseases are not a monolithic group of diseases and that several, such as Graves’ disease myasthenia gravis and pemph$us vulgaris, are antibody mediated. However, the respective role of autoreactive T helper 1 (Thl) and Tb2 cells in generating this patho- genic autoantibody response is un- clear at present. As stated at the end of the introduction section of our Viewpoint article, we focused ‘on the pathogenic role of Thl cells, and the possible protective role of Th2 cells, in the T-cell-mediated organ- specific autoimmune diseases”. Experimental autoimmune en- cephalomyelitis (EAE) is a proto- typic organ-specific autoimmune dis- ease mediated by Thl cells. The protective role of autoreactive CD4+ Th2 cells is being increasingly rec- ognized in this induced autoimmune diseasezA. We suggested that a simi- lar process could be involved in animal models of insulin-dependent diabetes mellitus (IDDM), a spon- taneous autoimmune disease. In- deed, favoring Thl development, through the use of IL-12, increases disease severity’ (we were propos- ing the use of anti-IL-12 reagents to inhibit disease), while favoring Th2 development, through the use of IL-4, protects mice from diabetes8. Recently, using an adoptive transfer system in the NOD mouse, Mathis and colleagues have shown that islet-specific CD4+ Thl cells are pathogenic, whereas Th2 cells shar- ing the same specificity are not. At odds with our hypothesis, these authors could not demonstrate a protective effect of autoreactive Th2 cells in cotransfer experiments, al- though a protective effect of these Th2 cells in the natural progression of diabetes in NOD mice remains to be tested9. Whether the same rea- soning applies to human multiple sclerosis and type 1 diabetes remains to be verified. We are fully aware that boosting an autoimmune Th2 response could be deleterious and we clearly under- lined this possibility when we indi- cated that ‘suppressing a delayed- type hypersensitivity response at the expense of an increased hu- moral response to an autoantigen may also lead to pathological con- sequences”. Immuno-intervention strategies aimed at inducing an autoantigen-specific immune diver- sion away from Thl cells have already provided a wealth of infor- mation regarding the pathophysiol- ogy of experimental T-cell-mediated autoimmune diseases and have proved useful in the treatment of several murine organ-specific auto- immune diseases such as collagen- induced arthritis and autoimmune myocarditis, as well as EAE and dia- betes. Whether this approach could be extended to some human organ- specific autoimmune diseases de- pends on understanding the patho- genic role of autoreactive CD4’ Thl and Th2 cells in these diseases. Roland S. Liblau Laboratoire d’lmmunologie Cellulaire et Tissulaire, 1NSERM U. 134, HGpital de la Salpbtribre, 7.5651 Paris Cedex 13, France. Steven M. Singer Dept of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Hugh 0. McDevitt Dept of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5402, USA. References 1 Liblau, R.S., Singer, S.M. and McDevitt, H.O. (1995) Immunol. Today 16,34-38 2 Chen. Y., Kuchroo, V.K., Inobe, J., Hafler, D.A. and Weiner, H.L. (1994) Science 265, 1237-1240 3 Racke, M.K., Bonomo, A., Scott, D.E. et al. (1994) J. Exe. Med. 180, 1961-1966 4 Rott, O., Fleisher, B. and Cash, E. ( 1994) Eur. J. lmmunol. 24, 1434-1440 5 Leonard, J.P., Waldburger, K.E. and Goldman, S.J. (1995)J. Exp. Med. 181, 381-386 6 Kuchroo, V.K., Prabhu Das, M., Brown, J.A. et al. (1995) Cell 80, 707-718 7 Trembleau, S., Penna, G., Bosi, E., Morrara, A., Gately, M.K. and Adorini, L. (1995) /. Exp. Med. 181, 817-821 8 Rapoport, M.J., Jaramillo, A., Zipris, D. et al. (1993) J. Exp. Med. 178,87-99 9 Katz, J.D., Benoist, C. and Mathis, D. (1995) Science 268,1185-1188 immunology Today 45 8 Vol. 16 No. 9 1995

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Page 1: Reply from Liblau, Singer and McDevitt

Reply from Liblau, Singer and McDevitt

We fully agree with McLachlan and Rapoport that human organ- specific autoimmune diseases are not a monolithic group of diseases and that several, such as Graves’ disease myasthenia gravis and pemph$us vulgaris, are antibody mediated. However, the respective role of autoreactive T helper 1 (Thl) and Tb2 cells in generating this patho- genic autoantibody response is un- clear at present. As stated at the end of the introduction section of our Viewpoint article, we focused ‘on the pathogenic role of Thl cells, and the possible protective role of Th2 cells, in the T-cell-mediated organ- specific autoimmune diseases”.

Experimental autoimmune en- cephalomyelitis (EAE) is a proto- typic organ-specific autoimmune dis- ease mediated by Thl cells. The protective role of autoreactive CD4+ Th2 cells is being increasingly rec- ognized in this induced autoimmune diseasezA. We suggested that a simi- lar process could be involved in animal models of insulin-dependent diabetes mellitus (IDDM), a spon- taneous autoimmune disease. In- deed, favoring Thl development, through the use of IL-12, increases disease severity’ (we were propos- ing the use of anti-IL-12 reagents to inhibit disease), while favoring Th2 development, through the use of IL-4, protects mice from diabetes8. Recently, using an adoptive transfer system in the NOD mouse, Mathis and colleagues have shown that islet-specific CD4+ Thl cells are pathogenic, whereas Th2 cells shar-

ing the same specificity are not. At odds with our hypothesis, these authors could not demonstrate a protective effect of autoreactive Th2 cells in cotransfer experiments, al- though a protective effect of these Th2 cells in the natural progression of diabetes in NOD mice remains to be tested9. Whether the same rea- soning applies to human multiple sclerosis and type 1 diabetes remains to be verified.

We are fully aware that boosting an autoimmune Th2 response could be deleterious and we clearly under- lined this possibility when we indi- cated that ‘suppressing a delayed- type hypersensitivity response at the expense of an increased hu- moral response to an autoantigen may also lead to pathological con- sequences”. Immuno-intervention strategies aimed at inducing an autoantigen-specific immune diver- sion away from Thl cells have already provided a wealth of infor- mation regarding the pathophysiol- ogy of experimental T-cell-mediated autoimmune diseases and have proved useful in the treatment of several murine organ-specific auto- immune diseases such as collagen- induced arthritis and autoimmune myocarditis, as well as EAE and dia- betes. Whether this approach could be extended to some human organ- specific autoimmune diseases de- pends on understanding the patho- genic role of autoreactive CD4’ Thl and Th2 cells in these diseases.

Roland S. Liblau

Laboratoire d’lmmunologie Cellulaire et Tissulaire,

1NSERM U. 134,

HGpital de la Salpbtribre, 7.5651 Paris Cedex 13,

France.

Steven M. Singer

Dept of Biological Chemistry and Molecular Pharmacology, Harvard Medical School,

Boston, MA 02115, USA.

Hugh 0. McDevitt

Dept of Microbiology and Immunology,

Stanford University School of Medicine, Stanford,

CA 94305-5402, USA.

References 1 Liblau, R.S., Singer, S.M. and McDevitt, H.O. (1995) Immunol. Today 16,34-38 2 Chen. Y., Kuchroo, V.K., Inobe, J., Hafler, D.A. and Weiner, H.L. (1994) Science 265, 1237-1240 3 Racke, M.K., Bonomo, A., Scott, D.E. et al. (1994) J. Exe. Med. 180, 1961-1966 4 Rott, O., Fleisher, B. and Cash, E. ( 1994) Eur. J. lmmunol. 24, 1434-1440 5 Leonard, J.P., Waldburger, K.E. and Goldman, S.J. (1995)J. Exp. Med. 181, 381-386 6 Kuchroo, V.K., Prabhu Das, M., Brown, J.A. et al. (1995) Cell 80, 707-718 7 Trembleau, S., Penna, G., Bosi, E., Morrara, A., Gately, M.K. and Adorini, L. (1995) /. Exp. Med. 181, 817-821 8 Rapoport, M.J., Jaramillo, A., Zipris, D. et al. (1993) J. Exp. Med. 178,87-99 9 Katz, J.D., Benoist, C. and Mathis, D. (1995) Science 268,1185-1188

immunology Today 45 8 Vol. 16 No. 9 1995