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 Transplantation

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 4

LGVHR migrates to the bone marrow, making space for engraftment of HPCs from the graft.

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LGVHR migrates to the bone marrow, making space for engraftment of HPCs ...
(A) Flow cytometric analysis of a MVTx recipient (Pt19) BM on day 105 after Tx, showing the presence of donor-derived T cells and CD45+CD34+ HSPCs. Similar gating in Pt19 POD105 PBMCs is shown as a control. Fluorescence minus one (FMO) controls for donor HLA (HLA-A3) and CD34 are shown for Pt19 POD105 BM. HLA-A2 is expressed by both the donor and recipient cells of Pt19 (HLA-D+R). (B) Donor CD3+ T cells and CD34+ HSPCs were simultaneously detected in the BM of 4 of 6 transplants receiving composite grafts (LITx: Pt16’; MVTx: Pt16’’, Pt18, and Pt19) and of 1 of 4 iITx (Pt20 POD125). Pt16 was retransplanted on POD786 following the first Tx. Pt16’ (LITx: first Tx) POD912 was the same day as Pt16’’ (MVTx: second Tx) POD126, when we collected the BM aspirate and detected cells from both donors. (C) Cumulative frequencies of alloreactive clones detectable in the BM of patients receiving MVTx (Pt19, Pt18, Pt16’’, Pt23), LITx (Pt16’), and iITx (Pt20, Pt24) are shown in pie charts, including GvH CD4 among donor-mappable CD4 sequences, GvH CD8 among donor-mappable CD8 sequences, HvG CD4 among recipient-mappable CD4 sequences, and HvG CD8 among recipient-mappable CD8 sequences. The counts of mappable unique sequences are annotated in each pie chart and summarized in Supplemental Table 5. (D) CD4 and CD8 GvH clones were detected in either the ileum biopsy or PBMCs in addition to recipient BM in Pt19, Pt16’, and Pt16’’.