Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice

J Immunol. 2009 Mar 15;182(6):3492-3502. doi: 10.4049/jimmunol.0803052.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / therapeutic use
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / pathology
  • B-Lymphocyte Subsets / transplantation
  • CD40 Antigens / agonists*
  • CD40 Antigens / immunology*
  • Cell Differentiation / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / pathology
  • Lupus Erythematosus, Systemic / therapy*
  • Lymphocyte Count
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Transgenic
  • Th1 Cells / immunology
  • Th1 Cells / pathology

Substances

  • Antibodies, Monoclonal
  • CD40 Antigens