Intravenous transfusion of BCR-activated B cells protects NOD mice from type 1 diabetes in an IL-10-dependent manner.
Although B cells play a pathogenic role in the initiation of type 1 diabetes (T1D) in NOD mice, it is not known whether activated B cells can maintain tolerance and transfer protection from T1D. In this study, we demonstrate that i.v. transfusion of BCR-stimulated NOD spleen B cells into NOD mice starting at 5-6 wk of age both delays onset and reduces the incidence of T1D, whereas treatment initiated at 9 wk of age only delays onset of T1D. This BCR-activated B cell-induced protection from T1D requires IL-10 production by B cells, as transfusion of activated B cells from NOD.IL-10(-/-) mice does not confer protection from T1D. Consistent with this result, severe insulitis was observed in the islets of NOD recipients of transfused NOD.IL-10(-/-) BCR-stimulated B cells but not in the islets of NOD recipients of transfused BCR-stimulated NOD B cells. The therapeutic effect of transfused activated NOD B cells correlates closely with the observed decreased islet inflammation, reduced IFN-gamma production and increased production of IL-4 and IL-10 by splenocytes and CD4(+) T cells from NOD recipients of BCR-stimulated NOD B cells relative to splenocytes and CD4(+) T cells from PBS-treated control NOD mice. Our data demonstrate that transfused BCR-stimulated B cells can maintain long-term tolerance and protect NOD mice from T1D by an IL-10-dependent mechanism, and raise the possibility that i.v. transfusion of autologous IL-10-producing BCR-activated B cells may be used therapeutically to protect human subjects at risk for T1D.
Hussain
Shabbir
S
Laboratory of Autoimmune Diabetes, Robarts Research Institute, University of Western Ontario, London, ON, Canada.
Delovitch
Terry L
TL
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D014181:Transplantation Immunology / Q000276:immunology
D011947:Receptors, Antigen, B-Cell; D016753:Interleukin-10