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

• Published in: Transplantation Vol. 93; no. 7; p. 676
• Main Authors: Parsons, Ronald F, Yu, Ming, Vivek, Kumar, Zekavat, Ghazal, Rostami, Susan Y, Ziaie, Amin S, Luo, Yanping, Koeberlein, Brigitte, Redfield, Robert R, Ward, Christopher D, Migone, Thi-Sau, Cancro, Michael P, Naji, Ali, Noorchashm, Hooman
• Format: Journal Article
• Language: English
• Published: United States 15.04.2012
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Neutralizing - pharmacology; B-Cell Activating Factor - antagonists & inhibitors; B-Cell Activating Factor - immunology; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cytokines - metabolism; Diabetes Mellitus, Experimental - immunology; Diabetes Mellitus, Experimental - surgery; Graft Rejection - immunology; Graft Rejection - prevention & control; Graft Survival - drug effects; Histocompatibility - drug effects; Immunity, Humoral - drug effects; Immunosuppressive Agents - pharmacology; Islets of Langerhans Transplantation - immunology; Lymphocyte Activation - drug effects; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Sirolimus - pharmacology; Time Factors; Transplantation Tolerance - drug effects; Transplantation, Homologous
• ISSN: 1534-6080
• DOI: 10.1097/TP.0b013e318246621d

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. 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. 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. 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.