Macrochimerism in Intestinal Transplantation: Association With Lower Rejection Rates and Multivisceral Transplants, Without GVHD

Abstract

Blood chimerism has been reported sporadically among visceral transplant recipients, mostly in association with graft-vs-host disease (GVHD). We hypothesized that a higher degree of mixed chimerism would be observed in multivisceral (MVTx) than in isolated intestinal (iITx) and isolated liver transplant (iLTx) recipients, regardless of GVHD. We performed a longitudinal prospective study investigating multilineage blood chimerism with flow cytometry in 5 iITx and 4 MVTx recipients up to one year post-transplant. Although only one iITx patient experienced GVHD, T-cell mixed chimerism was detected in 8 out of 9 iITx/MVTx recipients. Chimerism was significantly lower in the four subjects who displayed early moderate to severe rejection. Pre-formed high titer donor-specific antibodies, bound in vivo to the circulating donor cells, were associated with an accelerated decline in chimerism. Blood chimerism was also studied in 10 iLTx controls. Among non-sensitized patients, MVTx recipients exhibited greater T and B-cell chimerism than either iITx and iLTx recipients. Myeloid lineage chimerism was present exclusively among iLTx and MVTx (6/13) recipients, suggesting that its presence required the hepatic allograft. Our study demonstrates, for the first time, frequent T cell chimerism without GVHD following visceral transplantation and a possible relationship with reduced rejection rate in MVTx recipients.

Myeloid-derived suppressor cells increase and inhibit donor-reactive T cell responses to graft intestinal epithelium in intestinal transplant patients

“…7,27–30 The MDSCs may have an almost entirely recipient-derived origin, as macrochimerism of myeloid cells is hard to detect in intestinal transplantation, 31, 32 which we also confirmed in some of the recipients (data not shown). In this study, we demonstrated that MP expand MDSCs from human bone marrow cells, but not from PBMCs.…”

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

“…In line with this hypothesis, immunosuppression withdrawal in a liver transplant recipient induced the conversion of mixed to full donor chimerism, despite the lack of GVHD [19]. This case report underscores the role of graft-borne GvH-reactive T cells in neutralizing HvG-reactive T cells and in promoting transplant tolerance [19, 20]. Furthermore, we found in intestinal transplant recipients that expanded intra-graft GVH-reactive T cells may have attenuated the HvG response locally, as high GvH/HvG clonal ratios in the graft were associated with slower replacement of graft T cells by the recipient and less rejection [7].…”

Long-term Persistence of Innate Lymphoid Cells in the Gut After Intestinal Transplantation

“…This has been done previously for investigation of chimerism in peripheral blood after transplantation by our group (28), but previous investigation of chimerism in transplanted intestinal tissue has instead relied on genetic analysis via fluorescent in situ hybridization (FISH), polymerase chain reaction (PCR), or immunohistochemistry (3, 4, 29, 30). Our method allows dynamic and in depth analysis of ILC chimerism and phenotyping.…”