| Autor: |
Fu J; Columbia Center for Translational Immunology, Department of Medicine and., Zuber J; Columbia Center for Translational Immunology, Department of Medicine and., Shonts B; Columbia Center for Translational Immunology, Department of Medicine and., Obradovic A; Columbia Center for Translational Immunology, Department of Medicine and., Wang Z; Center for Computational Biology and Bioinformatics, Department of Systems Biology, Columbia University, New York, New York, USA., Frangaj K; Columbia Center for Translational Immunology, Department of Medicine and., Meng W; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Rosenfeld AM; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Waffarn EE; Columbia Center for Translational Immunology, Department of Medicine and., Liou P; Department of Surgery., Lau SP; Columbia Center for Translational Immunology, Department of Medicine and., Savage TM; Columbia Center for Translational Immunology, Department of Medicine and., Yang S; Columbia Center for Translational Immunology, Department of Medicine and., Rogers K; Columbia Center for Translational Immunology, Department of Medicine and., Danzl NM; Columbia Center for Translational Immunology, Department of Medicine and., Ravella S; Division of Digestive and Liver Diseases, Department of Medicine., Satwani P; Department of Pediatrics., Iuga A; Department of Pathology and Cell Biology, and., Ho SH; Columbia Center for Translational Immunology, Department of Medicine and., Griesemer A; Columbia Center for Translational Immunology, Department of Medicine and.; Department of Surgery., Shen Y; Center for Computational Biology and Bioinformatics, Department of Systems Biology, Columbia University, New York, New York, USA., Prak ETL; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Martinez M; Department of Pediatrics., Kato T; Department of Surgery., Sykes M; Columbia Center for Translational Immunology, Department of Medicine and.; Department of Surgery.; Department of Microbiology and Immunology, Columbia University, New York, New York, USA. |
| Abstrakt: |
In humans receiving intestinal transplantation (ITx), long-term multilineage blood chimerism often develops. Donor T cell macrochimerism (≥4%) frequently occurs without graft-versus-host disease (GVHD) and is associated with reduced rejection. Here we demonstrate that patients with macrochimerism had high graft-versus-host (GvH) to host-versus-graft (HvG) T cell clonal ratios in their allografts. These GvH clones entered the circulation, where their peak levels were associated with declines in HvG clones early after transplant, suggesting that GvH reactions may contribute to chimerism and control HvG responses without causing GVHD. Consistently, donor-derived T cells, including GvH clones, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were simultaneously detected in the recipients' BM more than 100 days after transplant. Individual GvH clones appeared in ileal mucosa or PBMCs before detection in recipient BM, consistent with an intestinal mucosal origin, where donor GvH-reactive T cells expanded early upon entry of recipient APCs into the graft. These results, combined with cytotoxic single-cell transcriptional profiles of donor T cells in recipient BM, suggest that tissue-resident GvH-reactive donor T cells migrated into the recipient circulation and BM, where they destroyed recipient hematopoietic cells through cytolytic effector functions and promoted engraftment of graft-derived HSPCs that maintain chimerism. These mechanisms suggest an approach to achieving intestinal allograft tolerance. |
