We have long hypothesized that the balance of donor-reactive cytopathic effector T cells to donor reactive graft protecting cells determines the outcome of the allograft response, namely rejection or tolerance. New data and tools have emerged that prompt us 'now to examine the role of pro- and anti-inflammatory cytokines upon the phenotype and function of antigen activated T cells in the allograft response, and upon graft outcome itself. Our working model is that the commitment of alloreactive cells to a regulatory or graftdestructive phenotype is governed by the balance of these cytokines. Our test systems will employ islet allografts, a tissue known to be particularly vulnerable in the peri-operative period to toxic and noxious insults. We further postulate that blockade of inflammation will provide cytoprotection that will promote successful 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 work we have several lines of genetically manipulated mice, including bicistronic knock-in mice that express foxpS and GFP under control of the foxpS promoter. These mice have been bred to the alloreactive TEa TCR transgenic line. We also have founders for knock-in mice in which the 1L-17 promoterdrives expression of lL-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 Th17 subset of cells are uniquely potent in mediating rejection and opposing regulation;
in aim #2, we will determine whether AAT can alter the expression of pro- and anti-inflammatory cytokines within the graft and reduce the islet mass needed to achieve euglycemia; and in aim #3, we will test whether the combination of the cytoprotective and anti-inflammatory effects of AAT can synergize with costimulatory blockade to suppress inflammation, promote regulation, and induce tolerance. As these agents are currently clinically available, we feel that this work, if successful, has the potential for rapid translation into new clinical approaches in islet transplantation.
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