Multivisceral transplantation (MVTx) is associated with a lower rate of severe graft rejection than isolated intestinal transplantation (iITx). We recently demonstrated that mixed T cell chimerism (>3% donor cells) often appears in blood (7/12) usually without graft-versus-host disease (GVHD) following ITx, and was greatest in MVTx recipients. The donor T cells among 6 patients without GVHD were markedly enriched for the naïve recent thymic emigrant (RTE) phenotype (%CD45RA⁺CD45RO^–CD31⁺/CD4⁺) and for T-cell receptor excision circles (TRECs) compared with recipient cells and could last > 1 year. We utilized CFSE-MLR and TCRβ CDR3 deep sequencing to identify and track the GVH alloreactive repertoire in ITx recipients. Expanded GVH clones were detected early in intestinal biopsies in association with rapid myeloid antigen presenting cell replacement in the graft by the recipient. GVH-reactive clones were enriched early, but not late in recipient blood, in the absence of GVHD. GVH clones represented 35-65% of donor CD8 cells in early PBMCs (POD<50). GVH clones were later absent in circulating naïve donor-derived T cells (POD>100), consistent with their de novo generation from progenitors. Donor chimerism was identified in circulating T-cell progenitors in 3 MVTx patients. We also detected donor-derived hematopoietic stem cells (HSCs) and/or multiple types of progenitors, including multipotent progenitors (MPP), lymphoid-primed multipotent progenitors (LMPP), common lymphoid progenitors (CLP), and mixed myeloid progenitors (MPs) in liver and ileum of organ donors, and in perfusates from donor liver, small intestine, and transplanted multivisceral organ blocks. Our findings suggest that GVH-reactive donor T cells expand initially within the graft. These then enter the recipient circulation and may attack host hematopoietic cells, usually without causing GVHD. This lymphohematopoietic GVH response might allow the survival and expansion of donor hematopoietic progenitors from the graft to enter the peripheral blood and then the thymus, resulting in de novo T cell generation, and thereby promote sustained T cell chimerism. This pathway may help to reduce graft rejection after intestinal transplantation.

CITATION INFORMATION: Fu J, Zuber J, Shonts B, Lau S, Obradovic A, Savage T, Simpson M, Yang S, Shen Y, Martinez M, Griesemer A, Kato T, Sykes M. Generation of Naïve Donor-Derived Lymphocytes from Graft-Resident Lymphoid Progenitors After Human Intestinal Transplantation. Am J Transplant. 2016;16 (suppl 3).

« Back to 2016 American Transplant Congress