Despite the 'relative' ease of inducing transplant tolerance in some rodent models, the same approacheshave often proven difficult to translate into larger animals and patients. One reason is that small animalmodels often fail to account for the barrier of memory. In addition to this known hurdle, increasing evidenceindicates that inflammation (which may occur as a result of rejection, ischemia-reperfusion injury, infectionetc.) can also inhibit tolerance induction. The central tenet of this project is that two events occurring very early during the process of engraftment,inflammation and antigen encounter, can determine graft outcome and tolerance susceptibility by modulatingthe balance between regulatory cells and effector/memory cells. Our theoretical framework is thatengraftment initiates a 'race' or 'competition' between regulation and effector/memory development, and theresult of this is crucial to the outcome of the graft.
Our aims will test the hypotheses that: inflammationpromotes the development of donor specific memory, while at the same time inhibiting the development ofregulation (aim #1); that antigen encounter, in addition to its known effects on effector/memory developmentalso shapes Treg development (aim #2), and that regulation which is 'dysfunctional' in the context ofmemory, can nonetheless be harnessed to block memory responses if adjunctive approaches are use (aim#3). This work will be important for the studies in project #1, in particular those that focus on how theTIM1:TIM4 pathway effects Treg generation and conversion. .There will also be close interactions withproject #3, particularly in the area of how cytokines and inflammation interact to affect memory andregulation, and how costimulatory blockade affects these processes. We bring a number of important tools that will be critical to.these studies. Through our ongoinginteractions with Terry Strom and Mo Sayegh as part of the PPG, we have obtained foxp3-GFP knock-inmice. These valuable animals can be used to separately study the stability, expansion and function ofnaturally arising Tregs, and the conversion, expansion and function of antigen/cytokine-induced Tregs. Inaddition to these animals, other resources include MHC class II alloreactive TCR transgenic mice, MyD88-deficient mice, and crosses amongst all of these strains. Collectively, these studies will provide important new insights into the differentiation and fate ofalloreactive T cells in vivo, define how these events are modulated by inflammation and antigen encounter,and explore approaches that will allow for the control of memory T cell responses by regulatory T cells.
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