Therapeutic strategies directed toward establishing allograft-specific tolerance has long been a goal of transplant immunology. The rhesus monkey renal allograft model ahs been proven to be very useful for examining such strategies. We have shown in this model that a toxin-conjugated anti-CD3 antibody (IT) substantially promotes allograft survival. Unfortunately, most recipients develop chronic rejection with characteristics of immune- mediated injury. This may be due to the fact that significant T cell depletion to the IT is achieved only after 48 hours of treatment, a period that may be sufficient for T cells to activate B cells. Collaborative work between our laboratory and the NMRI has shown that costimulation blockade of CD40L-CD40 and CD28-B7 interactions prolongs allograft survival, albeit not indefinitely. Because the costimulation blockade impedes interactions that are crucial for T and B cell activation, we intend to examine in IT- treated monkeys whether the co-stimulation blockade regimen would prevent immune-mediated chronic allograft rejection.
Our specific aims are: 1. We will determine whether anti-CD40 ligand and/or CTLA4-Ig are capable of preventing chronic rejection of IT-treated non-human primate renal allografts. 2. We will evaluate whether the combination of the IT and the costimulation blockade regimen or the latter by itself has undermined the ability of the immune system to mount an immune response to allograft- unrelated antigens. 3. We will evaluate whether a rhesus monkey renal allograft which survives for a prolonged (>50 day) period on the basis of costimulation blockade but subsequently develops acute rejection can be rescued safely.
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