B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in FcgammaR effector functions. Export

@article{citeulike:3046195, abstract = {NOD mice deficient for B lymphocytes from birth fail to develop autoimmune or type 1 diabetes. To assess whether B cell depletion influences type 1 diabetes in mice with an intact immune system, NOD female mice representing early and late preclinical stages of disease were treated with mouse anti-mouse CD20 mAbs. Short-term CD20 mAb treatment in 5-wk-old NOD female mice reduced B cell numbers by approximately 95\%, decreased subsequent insulitis, and prevented diabetes in >60\% of littermates. In addition, CD20 mAb treatment of 15-wk-old NOD female mice significantly delayed, but did not prevent, diabetes onset. Protection from diabetes did not result from altered T cell numbers or subset distributions, or regulatory/suppressor T cell generation. Rather, impaired CD4+ and CD8+ T cell activation in the lymph nodes of B cell-depleted NOD mice may delay diabetes onset. B cell depletion was achieved despite reduced sensitivity of NOD mice to CD20 mAbs compared with C57BL/6 mice. Decreased B cell depletion resulted from deficient FcgammaRI binding of IgG2a/c CD20 mAbs and 60\% reduced spleen monocyte numbers, which in combination reduced Ab-dependent cellular cytotoxicity. With high-dose CD20 mAb treatment (250 microg) in NOD mice, FcgammaRIII and FcgammaRIV compensated for inadequate FcgammaRI function and mediated B cell depletion. Thereby, NOD mice provide a model for human FcgammaR polymorphisms that reduce therapeutic mAb efficacy in vivo. Moreover, this study defines a new, clinically relevant approach whereby B cell depletion early in the course of disease development may prevent diabetes or delay progression of disease.}, address = {Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.}, author = {Xiu, Y. and Wong, C. P. and Bouaziz, J. D. and Hamaguchi, Y. and Wang, Y. and Pop, S. M. and Tisch, R. M. and Tedder, T. F.}, citeulike-article-id = {3046195}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/18292508}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=18292508}, day = {1}, issn = {0022-1767}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, keywords = {bcells, cd20, fcgr, nod}, month = {March}, number = {5}, pages = {2863--2875}, posted-at = {2008-07-27 14:52:48}, priority = {2}, title = {B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in FcgammaR effector functions.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/18292508}, volume = {180}, year = {2008} }

TY - JOUR ID - citeulike:3046195 L3 - citeulike-article-id:3046195 N2 - NOD mice deficient for B lymphocytes from birth fail to develop autoimmune or type 1 diabetes. To assess whether B cell depletion influences type 1 diabetes in mice with an intact immune system, NOD female mice representing early and late preclinical stages of disease were treated with mouse anti-mouse CD20 mAbs. Short-term CD20 mAb treatment in 5-wk-old NOD female mice reduced B cell numbers by approximately 95%, decreased subsequent insulitis, and prevented diabetes in >60% of littermates. In addition, CD20 mAb treatment of 15-wk-old NOD female mice significantly delayed, but did not prevent, diabetes onset. Protection from diabetes did not result from altered T cell numbers or subset distributions, or regulatory/suppressor T cell generation. Rather, impaired CD4+ and CD8+ T cell activation in the lymph nodes of B cell-depleted NOD mice may delay diabetes onset. B cell depletion was achieved despite reduced sensitivity of NOD mice to CD20 mAbs compared with C57BL/6 mice. Decreased B cell depletion resulted from deficient FcgammaRI binding of IgG2a/c CD20 mAbs and 60% reduced spleen monocyte numbers, which in combination reduced Ab-dependent cellular cytotoxicity. With high-dose CD20 mAb treatment (250 microg) in NOD mice, FcgammaRIII and FcgammaRIV compensated for inadequate FcgammaRI function and mediated B cell depletion. Thereby, NOD mice provide a model for human FcgammaR polymorphisms that reduce therapeutic mAb efficacy in vivo. Moreover, this study defines a new, clinically relevant approach whereby B cell depletion early in the course of disease development may prevent diabetes or delay progression of disease. IS - 5 JF - Journal of immunology (Baltimore, Md. : 1950) SN - 0022-1767 AD - Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA. EP - 2875 TI - B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in FcgammaR effector functions. VL - 180 SP - 2863 KW - bcells KW - cd20 KW - fcgr KW - nod AU - Xiu, Y AU - Wong, CP AU - Bouaziz, JD AU - Hamaguchi, Y AU - Wang, Y AU - Pop, SM AU - Tisch, RM AU - Tedder, TF PY - 2008/03/01/ UR - http://view.ncbi.nlm.nih.gov/pubmed/18292508 ER -