Intestinal transplantation (ITx) provides a unique opportunity to address questions of intestinal mucosal lymphocyte (IML) turnover, but these must be interpreted in the context ofthe presence of graft-vs-host (GVH) and host-vs-graft (HvG) alloreactivity. The long-term success of ITx has been limited by graft rejection, with only about 50% graft survival at 5 years. Composite graft (multivisceral graft or liver-intestine graft) transplantation is associated with reduced rejection rates compared to isolated ITx. ITx , with or without other organs, involves removal of varying amounts of recipient lymphoid tissue and delivery of varying amounts of donor lymphoid mass, which we hypothesize determines the balance between GVH and HvG reactivity, which impacts the outcome of ITx and the turnover of graft lymphoid cell populations. We propose to compare the phenotypes, reactivity and repertoire of donor- and recipient-derived T cells and other cell types in the periphery and the allograft before and after transplantation, and compare them to normal human intestinal IML populations defined in Projects 1,2 and 3. These studies will provide novel insights into the turnover of subsets of APCs, B cells, ILCs and T cells in the human intestine and their ability to be replaced during adult life. We also address the hypothesis that, when HvG reactivity is uncontrolled, donor lymphocytes and APCs will be eliminated from the graft and donor-reactive recipient T cells, detected functionally by limiting dilution assay, phenotypically as activated effector/memory-type T cells, and by clonal TCR repertoire analysis, will predominate in the graft, precluding restoration of a normal IML subset distribution and repertoire. Specifically, we aim to: 1) Compare the chimerism, phenotype and turnover of intestinal graft and peripheral blood immune cell populations in relation to the type of allograft (isolated ITx vs MVTx);2) Determine the relationship between allograft lymphoid load and GVH and HvG T cell alloreactivity and function in the peripheral blood and intestinal graft;3) Use high throughput TCR(3 CDR3 sequencing to compare the T cell repertoire in donor and recipient T cells in the peripheral blood with that in intestinal allografts. The proposed studies will provide novel insights into the relationship between GVH and HvG reactivity, an unexplored area that may drive intestinal transplant outcomes. They will provide unique information on the ability of adult hematopoietic cells to repopulate gut resident lymphocyte populations, complementing the """"""""steady state"""""""" data on T cells, B cells and ILCs obtained in Projects 1,2 and 3, respectively. Finally, they will define a novel method of tracking alloreactive T cells in transplant patients.
The proposed studies will provide novel information on the causes of intestinal graft rejection and will lead to the development of markers that predict rejection and acceptance intestinal and ultimately other types of transplants. They will provide unique new information on the origin and turnover of lymphoid cells in the intestine, which drive human immune responses to infections and regulate the immune response. This unique information will be of fundamental importance in understanding human immune health and disease.
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