We have long hypothesized that the balance of donor-reactive cytopathic effector T cells to donor reactivegraft protecting cells determines the outcome of the allograft response, namely rejection or tolerance. Newdata and tools have emerged that prompt us'nowto examine the role of pro- and anti-inflammatory cytokinesupon the phenotype and function of antigen activated T cells in the allograft response, and upon graftoutcome itself. Our working model is that the commitment of alloreactive cells to a regulatory or graft-destructive phenotype is governed by the balance of these cytokines. Our test systems will employ isletallografts, a tissue known to be particularly vulnerable in the peri-operative period to toxic and noxiousinsults. We further postulate that blockade of inflammation will provide cytoprotection that will promotesuccessful engraftment and assist in tolerance induction. In particular, we will focus on <xi-anti-trypsin(AAT),an agent which our preliminary data shows to provide potent cytoprotection to islets. To perform this workwe have several lines of genetically manipulated mice, including bicistronic knock-in mice that express foxpSand GFP under control of the foxpS promoter. These mice have been bred to the alloreactive TEa TCRtransgenic line. We also have founders for knock-in mice in which the 1L-17 promoterdrives expression oflL-17 and RFP. These tools will be used as part of adoptive transfer systems along with detailed phenotypic,expression, and functional analyses for the following:
In aim #1, we will test the hypothesis that the Th17subset of cells are uniquely potent in mediating rejection and opposing regulation;
in aim #2, we willdetermine whether AAT can alter the expression of pro- and anti-inflammatory cytokines within the graft andreduce the islet mass needed to achieve euglycemia; and in aim #3, we will test whether the combination ofthe cytoprotective and anti-inflammatory effects of AAT can synergize with costimulatory blockade tosuppress inflammation, promote regulation, and induce tolerance. As these agents are currently clinicallyavailable, we feel that this work, if successful, has the potential for rapid translation into new clinicalapproaches in islet transplantation.
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