Our group has established that donorspecific tolerance in rodents and functional tolerance in primates can be induced using an epitope specific monoclonal antibody (mAb) that targets the CD45RB isoforms. We have also demonstrated that LF 15-195 (LF), an analogue of 15-deoxyspergualin (DSG), induces donor-specific tolerance in rodents and significantly prolongs renal allograft survival in primates. Recently, we found that combining these two approaches has a synergistic effect on the induction of tolerance in rodents, but this must be confirmed in primates, in which tolerance may be more difficult to establish or less durable. While mosque studies are currently underway in our laboratory to more precisely define the mechanisms by which LF and anti-CD45RB mAb induce tolerance, we believe that concurrent testing of this powerful novel approach in a non-human primate model is warranted to accelerate the development of a clinically useful approach to achieve tolerance in patients. We hypothesize that tolerance established in non-human primates using this strategy requires both 1) generation of regulatory T cells by CD45RB mAb; and 2) generation of a tolerogenic subset of dendritic cells (DC) by LF and that tolerance synergy in combination therapy is mediated by an interaction between these regulatory T cells and tolerogenic DC. The use of primates will also allow us to study, using clinical outcomes and functional genomics with cDNA microarrays, the potential effect of currently available immunosuppressive agents including calcineurin inhibitors cyclosporine (CsA), and non- calcineurin inhibitors such as rapamycine (Ra) on tolerance induced by this therapy.
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