CD154 Blockade for Induction of Mixed Chimerism and Prolonged Renal Allograft Survival in Nonhuman Primates

Abstract

Costimulatory blockade with anti-CD154 monoclonal antibody (aCD154) prolongs allograft survival in nonhuman primates, but has not reliably induced tolerance when used alone. In the current studies, we evaluated the effect of adding CD154 blockade to a chimerism inducing nonmyeloablative regimen in primates. We observed a significant improvement of donor bone marrow (DBM) engraftment, which has been associated with a lower incidence of acute rejection and long-term survival of renal allografts without the need for previously required splenectomy. Among the long-term survivors, four never showed evidence of rejection, with the longest survival exceeding 1700 days following discontinuation of immunosuppression. Nevertheless, late chronic rejection was observed in three of eight recipients, indicating the necessity of further modifications of the regimen. Control recipients receiving no DBM or donor splenocytes in place of DBM rejected their allografts. Thus, DBM engraftment with, at least, transient mixed chimerism appears essential for induction of allograft tolerance using this conditioning regimen. Modification of the original mixed chimerism approach, by the addition of costimulatory blockade, has been shown to enhance mixed chimerism and induce renal allograft tolerance with less morbidity in nonhuman primates.

Frontiers in Nephrology

“…97 It has also been used as a means to facilitate chimerism. 98,99 Although many co-stimulatory molecules have been identified and tested experimentally, only one, CD28, is targeted by a clinically available agent. CD28 is the most studied T cell co-stimulatory receptor, and its inhibition has been shown to mediate the classic effects of costimulation blockade (reviewed by Salomon and Bluestone 100 ).…”

Preserving the B-Cell Compartment Favors Operational Tolerance in Human Renal Transplantation

“…In recent years, researchers succeeded in inducing allograft tolerance in several experimental models (1,(9)(10)(11); however, little has been translated in benefits to transplanted patients. Therefore, the development of new approaches to translate basic research in tolerance to the clinic is required.…”

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

“…A better understanding of basic tolerogenic mechanisms (clonal exhaustion, deletion, and immune ignorance) as well as the capital role that T cells play during transplant rejection has resulted in different strategies trying to induce tolerance (1)(2)(3)(4)(5)(6); namely, T cell costimulation blockade, mixed chimerism induction, T cell depletion, and tolerance mediated by regulatory T cells (Tregs). 3 It is to note that some of these approaches have been already successfully proven in murine and in nonhuman primate models (7)(8)(9)(10)(11)(12). In the clinical setting, tolerance or "prope" tolerance has been defined as evidence of donor-specific un/hyporesponsiveness with recovered third party response in functional in vitro assays, lack of circulating donor-specific alloantibodies and absence of destructive lymphocyte infiltration in allograft biopsies in patients without or with minimal amount of immunosuppression.…”