ADJUVANT THERAPIES IMPROVING ANTI-REJECTION EFFECTS OF COSTIMULATION BLOCKADE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have obtained 20 specific pathogen free rhesus macaques for renal transplantation. These animals have completed the mandatory three-month quarantine period at the Yerkes Primate Research Center. In preparation for renal transplantation, we have determined the ABO blood types on the animals, performed specific MHC allele typing, performed pre-transplant mixed lymphocyte reactions to verify donor-specific alloreactivity, and determined donor and recipient pairs. Initial donor nephrectomies are scheduled in early January and initial renal transplants will begin in early February. The effects of alefacept with or without abatacept or belatacept have been evaluated in vitro. We found that primate effector memory T cells are characterized by high CD2 and low CD28 expression that increases with each cell division following allo-stimulation. We have performed intracellular cytokine staining and shown that CD8+CD2hiCD28- cells exhibit the highest proportion of both triple cytokine producers (IFN¿, TNF¿, IL-2) and dual expressers of cytotoxic effector molecules (CD107a and granzyme B). In one-way mixed lymphocyte reactions, proliferating cells are phenotypically CD8+CD2hiCD28-. Addition of belatacept or abatacept in vitro inhibited proliferation (1.9- to 5-fold), and addition of alefacept inhibited aba- and belatacept-resistant proliferation. Taken together, these results suggest that the most alloreactive T cells, as measured by both proliferation and effector molecule expression, are overwhelmingly CD28-and represent a population of armed effectors that are able to evade costimulation blockade. The coincident high CD2 expression of this costimulation blockade-resistant population heightens its susceptibility to alefacept.