Treatment of diabetes in NOD mice by gene transfer of Ig-fusion proteins into B cells: role of T regulatory cells.
We previously reported that retrovirally mediated gene expression of Ig fusion proteins leads to specific immunologic tolerance and successful treatment of autoimmune conditions. Thus, a single dose of GAD65-IgG- or (Pro) Insulin-IgG-transduced B cells delays the onset and decreases the incidence of diabetes in young (7-12 weeks old) NOD female mice. Herein, we tested the role of regulatory T cells by in vivo treatment with anti-CD25 before B-cell gene therapy or by in vitro ablation of CD25+ cells from tolerized hosts in an adoptive transfer model. Our results demonstrate that anti-CD25 treatment, like cyclophosphamide, partially blocks the efficacy of gene therapy for tolerance. Moreover, B-cell therapy is effective at preventing diabetes transfer by female T cells (from older diabetic mice) into intact male recipients with normal islets, but failed to do so in NOD-scid recipients. This is due in part to homeostatic proliferation but also to the absence of CD25+ T cells in the latter hosts. Tolerance induced in younger NOD females can be stably transferred to NOD-scid recipients. However, physical removal of CD25+ cells abrogates the transfer of tolerance. Therefore, we conclude that CD4+, CD25+ regulatory T cells are required for the induction as well as maintenance of tolerance in this gene therapy model. The phenotype of these induced regulatory T cells is under investigation.
Soukhareva
Nadejda
N
Department of Surgery and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Jiang
Yufei
Y
Scott
David W
DW
D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D049109:Cell Proliferation; D003920:Diabetes Mellitus / Q000235:genetics* / Q000628:therapy*; D005260:Female; D005452:Fluoresceins; D015316:Genetic Therapy; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D041681:NIH 3T3 Cells; D015375:Receptors, Interleukin-2 / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D013388:Succinimides; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D014161:Transduction, Genetic
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D005452:Fluoresceins; D007136:Immunoglobulins; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D013388:Succinimides; D005968:Glutamate Decarboxylase