Journal
JOURNAL OF IMMUNOLOGY
Volume 182, Issue 6, Pages 3492-3502Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0803052
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Funding
- Wellcome Trust [068629]
- University College of London Hospital charities Clinical Research Development Committee [G140]
- equipment Arthritis Research Campaign [ID 17746]
- Oliver Bird Rheumatism Programme [RHE/001124/G]
- Instituto Mexicano Del Seguro Social
- National Institutes of Health [R01AR044077]
- Versus Arthritis [17707] Funding Source: researchfish
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We have previously reported that IL-10(+) regulatory B cells, known to play an important role in controlling autoimmunity and inflammatory disorders, are contained within the transitional 2 immature (T2) B cell pool (T2 Bregs). Therapeutic strategies facilitating their enrichment or enhancing their suppressive activity are highly attractive. In this study, we report that agonistic anti-CD40 specifically targets T2 B cells and enriches Bregs upon short-term in vitro culture. Although transfer of unmanipulated T2 B cells, isolated from mice with established lupus, failed to confer protection to diseased mice, transfer of in vitro anti-CD40-generated T2 B cells (T2-like-Bregs) significantly improved renal disease and survival by an IL-10-dependent mechanism. T2-like-Bregs readily accumulated in the spleen after transfer, suppressed Th1 responses, induced the differentiation of IL-10(+)CD4(+)T cells, and conveyed a regulatory effect to CD4(+)T cells. In addition, in vivo administration of agonistic anti-CD40, currently on trial for the treatment of cancer, halted and reversed established lupus. Taken together, our results suggest a novel cellular approach for the amelioration of experimental lupus. The Journal of Immunology, 2009, 182: 3492-3502.
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