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Journal of Allergy and Clinical Immunology

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Effect of rituximab on human in vivo antibody immune responses - 30/11/11

Doi : 10.1016/j.jaci.2011.08.008 
Mark D. Pescovitz, MD a, b, †, Troy R. Torgerson, MD, PhD c, Hans D. Ochs, MD, Dr Med c, Elizabeth Ocheltree, BS c, Paula McGee, MS d, Heidi Krause-Steinrauf, MS d, John M. Lachin, ScD d, Jennifer Canniff, BS e, Carla Greenbaum, MD f, Kevan C. Herold, MD g, Jay S. Skyler, MD h, ⁎ , Adriana Weinberg, MD i

Type 1 Diabetes TrialNet Study Group

  Members of the Type 1 Diabetes TrialNet Study Group are shown in Appendix E1.

a Department of Surgery, Indiana University, Indianapolis, Ind 
b Department of Microbiology and Immunology, Indiana University, Indianapolis, Ind 
c Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, Wash 
d George Washington University Biostatistics Center, Rockville, Md 
e Department of Pediatrics, University of Colorado Denver, Aurora, Colo 
i Departments of Medicine and Pathology, University of Colorado Denver, Aurora, Colo 
f Benaroya Research Institute, Seattle, Wash 
g Departments of Immunobiology and Internal Medicine, Yale University, New Haven, Conn 
h Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Fla 

Corresponding author: Jay S. Skyler, MD, University of Miami Miller School of Medicine Diabetes Research Institute, 1450 NW 10th Ave, Suite 3054, Miami, FL 33136.

Abstract

Background

B-lymphocyte depletion with rituximab has been shown to benefit patients with various autoimmune diseases. We have previously demonstrated that this benefit is also apparent in patients with newly diagnosed type 1 diabetes.

Objectives

The effect of rituximab on in vivo antibody responses, particularly during the period of B-lymphocyte depletion, is incompletely determined. This study was designed to assess this knowledge void.

Methods

In patients with recent-onset type 1 diabetes treated with rituximab (n = 46) or placebo (n = 29), antibody responses to neoantigen phiX174 during B-lymphocyte depletion and with hepatitis A (as a second neoantigen) and tetanus/diphtheria (as recall antigens) after B-lymphocyte recovery were studied. Anti- tetanus, diphtheria, mumps, measles, and rubella titers were measured before and after treatment by means of ELISA. Antibody titers and percentage IgM versus percentage IgG to phiX174 were measured by means of phage neutralization. B-lymphocyte subsets were determined by means of flow cytometry.

Results

No change occurred in preexisting antibody titers. Tetanus/diphtheria and hepatitis A immunization responses were protective in the rituximab-treated subjects, although significantly blunted compared with those seen in the controls subjects, when immunized at the time of B-lymphocyte recovery. Anti-phiX174 responses were severely reduced during the period of B-lymphocyte depletion, but with B-lymphocyte recovery, anti-phiX174 responses were within the normal range.

Conclusions

During the time of B-lymphocyte depletion, rituximab recipients had a decreased antibody response to neoantigens and significantly lower titers after recall immunization with diphtheria and tetanus toxoid. With recovery, immune responses return toward normal. Immunization during the time of B-lymphocyte depletion, although ineffective, does not preclude a subsequent response to the antigen.

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Key words : B lymphocytes, human, diabetes, antibodies, immunization, CD20

Abbreviations used : AUC, Kv, MMR, PFU, Td, T1D


Plan


 The sponsor of the trial was the Type 1 Diabetes TrialNet Study Group. TrialNet is a clinical trials network funded by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Center for Research Resources; the Juvenile Diabetes Research Foundation International; and the American Diabetes Association.
 Disclosure of potential conflict of interest: T. R. Torgerson has consultant arrangements with Baxter Biosciences. J. M. Lachin has consultant arrangements with Genentech, Bayhill Therapeutics, GlaxoSmithKline, and TolerRx. C. Greenbaum receives research support from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, the Juvenile Diabetes Research Foundation International, and the National Institutes of Health/National Institute of Allergy and Infectious Diseases. J. S. Skyler is on the Board of Directors for Amylin Pharmaceuticals and DexCom Inc, has consultant arrangements with Sanofi-Aventis and BD Technologies, and has received research support from Bayhill Therapeutics, Halozyme Inc, and Osiris Therapeutics. The rest of the authors have declared that they have no conflict of interest.


© 2011  American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 128 - N° 6

P. 1295 - décembre 2011 Retour au numéro
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