J ALLERGY CLIN IMMUNOL

FEBRUARY 2008

S168 Abstracts

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643 Individually Constant C1-Inhibitor Levels During the Course ofthe Day-C1-Inhibitor Shows no Evidence of CircadianVariation

E. Aygoren-Pursun, H. Stoll, E. Rusicke, I. Martinez Saguer, W. Kreuz;

Johann-Wolfgang-Goethe University Hospital, Frankfurt, GERMANY.

RATIONALE: C1-inhibitor (C1-INH) belongs to the family of serpins,

similar to plasminogen activator inhibitor type 1 (PAI-1). Significant

diurnal variations of PAI-1 are known, leading to a more than 10-fold

decrease of PAI-1 activity between morning and afternoon. This circadian

rhythm is mainly confined to the 4G-allele of PAI-1. Recently, it has been

shown that circadian clock genes cause allele-specific activation of the

PAI-1 gene with preference of the 4G-allele. So far, no information is

available concerning possible circadian fluctuations of C1-INH, which

could potentially effect diagnosis of C1-INH-deficiency.

METHODS: Citrated blood was collected of 12 healthy individuals (3 m/

9 f; median age 42 yrs.) within 3 time intervals (7.45 h -9.00 h; 11.45 h

- 12.45 h.; 14.45 h - 15.45 h) over one day. Of 4 individuals blood could

additionally be obtained between 2.45 h and 3.15 h in the night. The plasma

samples were assessed for C1-INH activity and C1-INH antigen with

commercially available kits.

RESULTS: Median C1-INH activity was 107% between 7.45 h and 9.00 h,

111% between 11.45 h and 12.45 h, 105% between 14.45 h and 15.45 h,

and 107% between 2.45 h and 3.15 h (normal range 64-146%). Median C1-

INH antigen was 22.2 mg/dl between 7.45 h and 9.00 h, 22.9 mg/dl

between 11.45 h and 12.45 h, 21.7 mg/dl between 14.45 h and 15.45 h, and

25.3 mg/dl between 2.45 h and 3.15 h (normal range 15.4 - 35.1 mg/dl).

However, particularly intraindividual levels of C1-INH activity were rather

constant over the course of the day.

CONCLUSIONS: Neither C1-INH activity, nor C1-INH antigen levels

demonstrate any significant circadian variation. C1-INH activity is stable at

individual levels.

644 Genetic Analyses and Outcomes of Hematopoietic Stem CellTransplantation in 12 Patients With T-B1NK1 SCID

G. P. Yu1, D. R. Berk2, G. de Saint Basile3, N. Lambert4, P. Knapnougel4,

E. R. Stiehm5, D. T. Umetsu6, D. B. Lewis7, K. C. Nadeau1, M. J. Cowan8;1Lucile Packard Children’s Hospital at Stanford Department of Pediatrics

Division of Allergy and Immunology, Palo Alto, CA, 2Washington Uni-

versity Department of Medicine Division of Dermatology, St. Louis,

MO, 3INSERM, U768, Hopital Necker Enfants-Malades, Paris, FRANCE,4Assitance Pulique, Immunologie et Hematologie Pediatrique; Universite

Paris Descartes, Paris, FRANCE, 5Mattel Children’s Hospital at the Uni-

versity of California Los Angeles, Los Angeles, CA, 6Children’s Hospital

Boston Department of Pediatrics Division of Allergy and Immunology,

Boston, MA, 7Lucile Packard Children’s Hospital at Stanford Department

of Pediatrics Division of Immunology and Transplantation Biology, Palo

Alto, CA, 8University of California San Francisco Children’s Hospital

Department of Pediatrics Division of Bone Marrow Transplant, San Fran-

cisco, CA.

RATIONALE: Controversy exists regarding the need for conditioning

prior to hematopoietic stem cell transplantation (HSCT) in T-B1NK1

SCID patients. We report the genetic defects and clinical outcomes of

12 T-B1NK1 SCID patients treated with HSCT.

METHODS: The patients’ genomic DNA were analyzed for IL-7Ra,

CD3d, CD3e, and CD3z gene mutations and a retrospective chart review

was conducted.

RESULTS: Deficiencies of IL-7Ra (n 5 4) or CD3d (n 5 2) were

identified in 6 of the 12 patients. No patients with CD3e or CD3z

deficiencies were identified. Of the 4 patients with IL-7Ra deficiency, only

one patient received conditioning prior to HSCT. All patients with the

IL-7Ra deficiency engrafted and are currently alive and healthy. Of the 2

patients with CD3d mutations, one was resistant to engraftment and died

despite 3 HSCTs with progressively more aggressive conditioning regi-

mens. The other patient with CD3d deficiency survived after HSCT with a

conditioning regimen of antithymocyte globulin and cyclophosphamide.

Of the 6 T-B1NK1 SCID patients without identified deficiencies,

2 received no conditioning regimen prior to their haploidentical HSCT.

Of these 2 patients, one engrafted but died 5 months later of presumed

sepsis while the other had incomplete engraftment and died 10 months

later of presumed sepsis. Of the remaining 4 patients without identified

deficiencies who received conditioning regimens, 3 patients engrafted and

are currently alive and healthy, while the remaining patient died secondary

to poor engraftment and presumed sepsis.

CONCLUSIONS: Specific genetic defects leading to SCID may be

important in mediating engraftment resistance and the need for condition-

ing prior to HSCT.

Funding: American Academy of Pediatrics

645 Pharmacokinetics of a Novel Liquid 10% ImmunoglobulinPreparation for Intravenous Use (Privigen) in Subjects withPrimary Immunodeficiency

R. L. Wasserman1, J. A. Church2, H. H. Peter3, J. W. Sleasman4, I. Mel-

amed5, M. R. Stein6, J. Bichler7; 1Pediatric Allergy/Immunology Associ-

ates, Dallas, TX, 2Childrens Hospital Los Angeles and Keck School of

Medicine, University of Southern California, Los Angeles, CA, 3Division

of Rheumatology and Clinical Immunology, University Hospital Freiburg,

Freiburg, GERMANY, 4University of South Florida, All Children’s Hos-

pital, St. Petersburg, FL, 51st Allergy and Asthma Center, Thornton, CO,6Allergy Associates of the Palm Beaches, N Palm Beach, FL, 7CSL Behr-

ing, Bern, SWITZERLAND.

RATIONALE: Intravenous IgG (IVIG) should have pharmacokinetic

properties similar to endogenous IgG. We investigated the pharmacoki-

netics of a new 10% liquid IVIG (Privigen), in patients with primary

immunodeficiency (PID). Privigen is purified with an innovative chromat-

ographic process and is formulated with proline at ph 4.8. This formulation

allows long-term storage at room temperature.

METHODS: Pharmacokinetic evaluations were performed in a subset

(n 5 25) of patients included in a larger study of the safety and efficacy of

Privigen in PID. Serum concentrations of total IgG, IgG subclasses, and

specific IgGs (anti-CMV, anti-Haemophilus influenzae type b, anti-tetanus

and anti-Streptococcus pneumoniae [pool of 23 serotypes]) were measured

over time, and pharmacokinetic parameters were calculated.

RESULTS: Total serum IgG concentrations increased from a median pre-

infusion level of 10.2 g/L to 23.2 g/L at the end of the infusion. The serum

IgG concentrations decreased in a biphasic manner, with a median terminal

half-life of 36.6 days (20.6 to 96.6 days). The median half-lives for IgG

subclasses were 33.2 for IgG1, 36.3 for IgG2, 25.9 for IgG3 and 36.4 days

for IgG4. Specific antibody concentrations decreased with median half-

lives between 22.3 and 30.5 days. Median trough levels were 6.1 IU/mL

for anti-CMV, 2.7 mg/L for anti-H. influenzae, 2.5 IU/mL for anti-tetanus

and 85 mg/L for anti-S. pneumoniae.

CONCLUSIONS: The pharmacokinetic properties of Privigen were as

expected for an intact IgG product and similar to other IVIG products.

Administration at 3-4 week intervals achieves sufficient levels of total IgG,

IgG subclasses, and specific antibodies to important pathogens.

Funding: CSL Behring

646 TLR7 Activation is Defective in Common VariableImmunodeficiency

J. E. Yu, R. Dockray, L. Radigan, C. Cunningham-Rundles; Mount Sinai

Medical Center, New York, NY.

RATIONALE: We previously demonstrated that the toll-like receptor 9

(TLR9) activation of B cells and plasmacytoid dendritic cells (pDCs) is

impaired in Common Variable Immunodeficiency (CVID). The TLR9

signaling pathway is structurally similar to other TLRs, particularly TLR3

and TLR7. Therefore, we sought to assess whether activation via these

pathways is also abnormal in CVID.

METHODS: Peripheral blood mononuclear cells (PBMCs) from healthy

controls and CVID subjects were stimulated for 24 hours with ligands for

TLR1-9; activation was evaluated by ELISA assay of TNF-a and IFN-a.

IFN-a secretion by isolated pDCs of CVID subjects or controls was

measured by ELISA after 5 days stimulation with the TLR7 agonist,