title: Murine islet allograft tolerance upon blockade of the B-lymphocyte stimulator, BLyS/BAFF.
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.
authors.affiliation: Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Parsons
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Kumar
authors.initials: K
authors.lastname: Vivek
authors.forename: Ghazal
authors.initials: G
authors.lastname: Zekavat
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Rostami
authors.forename: Amin S
authors.initials: AS
authors.lastname: Ziaie
authors.forename: Yanping
authors.initials: Y
authors.lastname: Luo
authors.forename: Brigitte
authors.initials: B
authors.lastname: Koeberlein
authors.forename: Robert R
authors.initials: RR
authors.lastname: Redfield
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ward
authors.forename: Thi-Sau
authors.initials: TS
authors.lastname: Migone
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cancro
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.forename: Hooman
authors.initials: H
authors.lastname: Noorchashm
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000601:surgery*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006648:Histocompatibility / Q000187:drug effects; D056724:Immunity, Humoral / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D053264:B-Cell Activating Factor; D016207:Cytokines; D007166:Immunosuppressive Agents; C505720:Tnfsf13b protein, mouse; D020123:Sirolimus