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Presenter: Jianing, Fu, New York, United States
Authors:
DIFFERING MECHANISMS FOR EARLY VERSUS PERSISTENT DONOR T CELL CHIMERISM IN PERIPHERAL BLOOD OF HUMAN INTESTINAL TRANSPLANT RECIPIENTS
Jianing Fu 0; Julien Zuber 0; Brittnay Shonts 0; Aleksandar Obradovic 0; Sai-Ping Lau 0; Thomas Savage 0; Amy Xia 0; Michael Simpson 0; Suxiao Yang 0; Michelle Miron 0; Yufeng Shen 0; Donna Farber 0; Mercedes Martinez 0; Adam Griesemer 0,0; Tomoaki Kato 0; Megan Sykes 0
0Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, United States; 1Department of Systems Biology, Columbia University, New York, NY, United States; 2Department of Pediatrics, Columbia University, New York, NY, United States; 3Department of Surgery, Columbia University, New York, NY, United StatesDonor T cell macrochimerism (>4%) often appears in blood following intestinal transplantation (ITx), usually without graft-versus-host disease[1]. Patients with donor T cell macrochimerism displayed less graft rejection, slower recipient T cell replacement within the graft and less donor-specific antibody (DSA) production[2]. However, the reasons for the development and persistence of donor T cell chimerism are unknown.
We analyzed the repertoire, phenotype and origin of circulating donor T cells in ITx recipients using flow cytometry, mixed lymphocyte reaction (MLR) and high-throughput TCR sequencing.
Expanded graft-versus-host (GvH) clones triggered by rapidly replaced recipient antigen-presenting cells were detected early in ileum biopsies (Figure 1A). Enrichment of GvH clones in the graft and absence of Class I DSA in the circulation were associated with donor T cell macrochimerism. Cumulative frequencies of GvH clones in blood early post-Tx correlated with the peak level of donor T cell chimerism (Figure 1B). Frequencies of host-versus-graft (HvG) clones subsequently declined in the blood of a patient with a high level of T cell chimerism (>38%), suggesting that lymphohematopoietic GvH responses may attenuate HvG responses (Figure 1C). Long-term donor T cells were markedly enriched for the naïve recent thymic emigrant phenotype compared with recipient cells regardless of donor age (Figure 2A). GvH clones were absent among long-term circulating naïve donor-derived T cells, which were enriched for CD31 expression and T-cell receptor excision circles (TRECs), suggesting they developed de novo in the recipient thymus. Long-lasting (POD>200) circulating donor cells lacked GvH reactivity yet were immunocompetent in MLR, partially due to the presence of recipient-specific Tregs (Figure 2B). We also detected donor-derived hematopoietic stem cells (HSCs) and/or progenitors (HPs) in blood and stoma specimens post-Tx and in donor liver, ileum and perfusates pre-Tx. HSCs/HPs from ileum and bone marrow of each organ donor showed similar properties on CyTOF (mass cytometry) analysis, suggesting they may have similar functional phenotypes.
Together, donor GvH-reactive T cells and HSCs/HPs carried within the graft promote and maintain donor T cell chimerism in blood, which correlates with better clinical outcomes and suggests an approach to reduce graft rejection and achieve tolerance post-ITx. {{AbstractFigure.1}}{{AbstractFigure.2}}
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