Murine islet allograft tolerance upon blockade of the B-lymphocyte stimulator, BLyS/BAFF

Ronald F. Parsons, Ming Yu, Kumar Vivek, Ghazal Zekavat, Susan Y. Rostami, Amin S. Ziaie, Yanping Luo, Brigitte Koeberlein, Robert R. Redfield, Christopher D. Ward, Thi Sau Migone, Michael P. Cancro, Ali Naji, Hooman Noorchashm

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Background. Immunologic rejection is a major barrier to successful long-term outcomes in clinical transplantation. The importance of B lymphocytes-and their secretory products, alloantibodies-in the pathogenesis of allograft rejection is accepted. Furthermore, it is now clear that the dominant regulator of peripheral B-cell homeostasis and tolerance is the B-Lymphocyte Stimulator (BLyS), also referred to as the B-cell activating factor (BAFF). Recently, a novel class of clinical immunotherapeutic agents specific for BLyS, and its family of cytokines, has emerged for the treatment of B-cell-mediated diseases. In this study, we demonstrate the potential utility of BLyS-directed immunotherapy in preventing allograft rejection using a murine islet transplantation model. Methods. A transient period of mature peripheral B-cell depletion was induced by means of in vivo BLyS neutralization using a murine analog of the monoclonal antibody, Benlysta. Subsequently, fully major histocompatibility complex-mismatched islets were transplanted into naïve diabetic mice followed by a short course of rapamycin. Results. After BLyS neutralization, indefinite islet allograft survival was achieved. Induction therapy with rapamycin was necessary, but not sufficient, for the achievement of this long-term graft survival. The tolerant state was associated with (1) abrogation of the donor-specific antibody response, (2) transient preponderance of immature/transitional B cells in all lymphoid organs, (3) impaired CD4 T-cell activation during the period of B-cell depletion, and (4) presence of a "regulatory" cytokine milieu. Conclusions. In vivo BLyS neutralization effectively induces humoral tolerance and promotes long-term islet allograft survival in mice. Therefore, B-lymphocyte-directed immunotherapy targeting the homeostatic regulator, BLyS, may be effective in promoting transplantation tolerance.

Original languageEnglish (US)
Pages (from-to)676-685
Number of pages10
JournalTransplantation
Volume93
Issue number7
DOIs
StatePublished - Apr 15 2012
Externally publishedYes

Keywords

  • B-lymphocytes
  • BLyS
  • Islet transplantation
  • Tolerance

ASJC Scopus subject areas

  • Transplantation

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    Parsons, R. F., Yu, M., Vivek, K., Zekavat, G., Rostami, S. Y., Ziaie, A. S., Luo, Y., Koeberlein, B., Redfield, R. R., Ward, C. D., Migone, T. S., Cancro, M. P., Naji, A., & Noorchashm, H. (2012). Murine islet allograft tolerance upon blockade of the B-lymphocyte stimulator, BLyS/BAFF. Transplantation, 93(7), 676-685. https://doi.org/10.1097/TP.0b013e318246621d