Lymphohematopoietic graft-versus-host responses promote mixed chimerism in patients receiving intestinal transplantation
Jianing Fu, … , Tomoaki Kato, Megan Sykes
Jianing Fu, … , Tomoaki Kato, Megan Sykes
Published February 25, 2021
Citation Information: J Clin Invest. 2021;131(8):e141698. https://doi.org/10.1172/JCI141698.
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Research Article Immunology

Lymphohematopoietic graft-versus-host responses promote mixed chimerism in patients receiving intestinal transplantation

Abstract

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.

Authors

Jianing Fu, Julien Zuber, Brittany Shonts, Aleksandar Obradovic, Zicheng Wang, Kristjana Frangaj, Wenzhao Meng, Aaron M. Rosenfeld, Elizabeth E. Waffarn, Peter Liou, Sai-ping Lau, Thomas M. Savage, Suxiao Yang, Kortney Rogers, Nichole M. Danzl, Shilpa Ravella, Prakash Satwani, Alina Iuga, Siu-hong Ho, Adam Griesemer, Yufeng Shen, Eline T. Luning Prak, Mercedes Martinez, Tomoaki Kato, Megan Sykes

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Figure 3

Lymphohematopoietic GvH responses contribute to donor T cell macrochimerism in blood.

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Lymphohematopoietic GvH responses contribute to donor T cell macrochimer...
(A) Kinetics of cumulative frequency of GvH clones in the circulation of patients with (+) or without (–) donor T cell macrochimerism in recipients of MVTx (circles), LITx (squares), or iITx (triangles). (B) Peak cumulative frequency of GvH clones in blood in patients with or without macrochimerism. **P < 0.01, Mann-Whitney U test. (C) Kinetics of cumulative frequency of GvH clones (left y axis: colored curve, solid symbols) and donor T cell chimerism (right y axis: black curve, open symbols) in circulation of representative patients with (+: Pt19, Pt16’’, and Pt15) or without (–: Pt20, Pt14, and Pt16’) T cell macrochimerism. Additional patients are shown in Supplemental Figure 4. Patients with at least one time point of TCR-seq data and 2 time points of FCM chimerism data within 40 days after Tx were included in this analysis. Colored dotted vertical line indicates the POD of peak cumulative frequency of circulating GvH clones and black dotted vertical line indicates the POD of peak donor T cell chimerism in blood. (D) Kinetics of cumulative frequency of HvG clones in the circulation of patients with or without donor T cell macrochimerism who were sequenced on at least 2 time points within 40 days after Tx. (E) Correlation of peak cumulative frequency of GvH (x axis) and HvG clones (y axis) in blood within 40 days after Tx in patients with or without macrochimerism. (F) Association of peak cumulative frequency of GvH clones in blood and slope of linear regression plot of cumulative frequency of HvG clones in blood within 40 days after Tx in patients with or without macrochimerism. Increased slope absolute value indicates increased rate of change in cumulative frequency of circulating HvG clones.