*Purpose: Long-term multilineage chimerism often appears in blood following intestinal transplantation (ITx), usually without graft-versus-host disease (GVHD). Patients with donor T cell macrochimerism (≥4%) in blood experience less graft rejection, less donor-specific antibody (DSA) development and slower graft mucosal T cell replacement by the recipient. We hypothesize that clinical outcomes are largely determined by the balance of graft-versus-host (GvH) and host-versus-graft (HvG) alloreactivity in the graft.

*Methods: We identified GvH and HvG clones in intestinal allografts and peripheral blood on the basis of TCRβ CDR3 high throughput sequencing following pre-transplant mixed lymphocyte reactions.

*Results: Enrichment of GvH compared to HvG clones in intestinal biopsies and absence of de novo Class I DSA in serum were associated with macrochimerism. Upon entering the circulation, both the peak level and the persistence of GvH clones were significantly greater in patients with macrochimerism than in those without, suggesting that a systemic lymphohematopoietic GvH response (LGVHR) may contribute to macrochimerism. Donor-derived multilineage hematopoiesis might reflect a LGVHR migrating from recipient circulation to the bone marrow (BM), making “space” for engraftment of progenitor cells from the graft. Indeed, donor-derived T cells and CD34⁺ progenitors were simultaneously detected in the BM of 4 recipients. TCR sequencing identified GvH clones among donor-mappable BM T cells. CD8 GvH clones were detected in either the ileum biopsy or PBMCs before detection in recipient BM, suggesting their migration patterns.

*Conclusions: Together, donor GvH-reactive T cells expanding within the graft migrate into the recipient circulation and BM, playing a key role in promoting and maintaining mixed chimerism. LGVHR without GVHD in ITx recipients suggests a novel approach to achieving intestinal allograft tolerance.

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