Short-Term Administrations of a Combination of Anti–LFA-1 and Anti-CD154 Monoclonal Antibodies Induce Tolerance to Neonatal Porcine Islet Xenografts in Mice

Abstract

OBJECTIVEThe objective of this study was to determine whether tolerance to neonatal porcine islet (NPI) xenografts could be achieved by short-term administrations of anti–LFA-1 and anti-CD154 monoclonal antibodies (mAbs).RESEARCH DESIGN AND METHODSDiabetic B6 mice received NPI transplants and short-term injections of combined anti–LFA-1 and anti-CD154 mAbs. Mice with long-term islet graft function were treated with depleting anti-CD25 mAb or re-transplanted with a second-party NPI. At the end of the study, grafts from mice with long-term islet function were examined. Their spleen cells were characterized and used for in vitro proliferation and adoptive transfer studies.RESULTSAll mAb-treated NPI recipients maintained normoglycemia for >100 days post-transplantation. Only 5 of 50 mice rejected their grafts before 300 days post-transplantation. Intact islets, foxp3+ immune cells, as well as interleukin (IL)-10 and transforming growth factor (TGF)-β regulatory cytokine transcripts were detected in the NPI xenografts from tolerant mice. A higher percentage of CD4+ T-cell population from these mice expressed regulatory markers, suggesting that tolerance to NPI xenografts may be mediated by T regulatory cells. This was confirmed when tolerant mice treated with depleting anti-CD25 mAb became diabetic. Lymphocytes from tolerant mice inhibited the proliferation of lymphocytes from B6 mice immunized with porcine cells and they displayed limited proliferation when adoptively transferred. All protected B6 mice transplanted with a second-party NPI xenograft maintained long-term normoglycemia even after removal of the first NPI graft-bearing kidney.CONCLUSIONSThese results demonstrate that tolerance to NPI xenografts can be achieved by transient administrations of combined anti–LFA-1 and anti-CD154 mAb therapy.

Transient B-Cell Depletion Combined With Apoptotic Donor Splenocytes Induces Xeno-Specific T- and B-Cell Tolerance to Islet Xenografts

“…Consequently, therapies targeting these processes such as costimulation blockade have been shown to provide long-term protection to islet xenografts in mice (27,28). Previous work in our laboratory has shown that donor ECDI-SPs effectively control donor-specific T-cell responses by parallel mechanisms including deletion, anergy, and induction of regulation (24).…”

Xenocorneal transplantation

“…However, it can be assumed that costimulatory pathway modulation may reduce the xenocorneal rejection based on the previous studies of islet xenografts or of corneal allografts [34][35][36][37][38]. Treatment with anti-CD154 antibodies prolonged the survival of islet xenograft, nonvascularizing organ, by inducing tolerance [34][35][36]. Augmented ligation of the PD-1-negative costimulatory molecule significantly prolongs corneal allograft survival [38] and inhibition of CD154-mediated costimulation diminished corneal allograft rejection [37].…”

“…The effect of modulation of costimulatory signals in T cells has not been studied on xenocorneal transplantation. However, it can be assumed that costimulatory pathway modulation may reduce the xenocorneal rejection based on the previous studies of islet xenografts or of corneal allografts [34][35][36][37][38]. Treatment with anti-CD154 antibodies prolonged the survival of islet xenograft, nonvascularizing organ, by inducing tolerance [34][35][36].…”

Integrin Antagonists for Transplant Immunosuppression: Panacea or Peril?

“…To further augment the efficacy of integrin blockade, several investigators coupled it with standard costimulatory blockade drugs such as anti-CD154 or CTLA-4 Ig, achieving prolonged graft survival in a variety of murine transplant systems [10,11]. Dual integrin/costimulatory blockade was even shown to prolong survival of xenografts such as porcine islets in murine recipients [12]. This regimen of dual costimulatory and integrin blockade was also recently utilized successfully in a primate islet transplant system (using belatacept and efalizumab), demonstrating a substantial prolongation in islet graft survival [13].…”