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 2

Enrichment of GvH compared with HvG clones in graft and absence of Class I DSAs in circulation are associated with donor T cell macrochimerism.

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Enrichment of GvH compared with HvG clones in graft and absence of Class...
Cumulative frequency of GvH (pink) and HvG (blue) clones among ileum biopsies at indicated time points (A–D). Patients were categorized into 4 groups (I, II, III, IV) based on the presence (+) or absence (–) of donor T cell macrochimerism in blood, de novo Class I and Class II DSAs in serum, and donor age listed in E. (A) Group I patients (Pt7, Pt13, Pt15, Pt16’’, Pt17, and Pt22) had macrochimerism, were de novo Class I DSA–, de novo Class II DSA+/–, and had donor age of 1 year or older. Pt16’ and Pt16’’ represent the first (LITx), and second (MVTx) transplant in this patient, respectively. (B) Group II patients (Pt18, Pt19, Pt21, and Pt23) had macrochimerism, were de novo Class I DSA–, de novo Class II DSA+/–, and had donor age younger than 1 year. (C) Group III patients (Pt4, Pt9, and Pt24) did not have macrochimerism, developed de novo Class I and Class II DSAs, and had donor age of 1 year or older. (D) Group IV patients (Pt14 and Pt20) did not have macrochimerism, developed de novo Class I and Class II DSAs, and had donor age younger than 1 year. (E) Difference of the areas under the GvH and HvG curves (AUCGvH–AUCHvG) was normalized by days of measurement (PODlast–PODfirst) of individual patients in groups I to IV and shown by floating bars plots, which include 3 key values: upper extreme, median, and lower extreme. Normalized AUC >0, =0, and <0 indicate greater, equal, and lower GvH over HvG responses in the allograft, respectively. Kruskal-Wallis test was performed for multiple comparisons between each pair of groups. Significant difference was seen when comparing group I to group III. **P < 0.01.