*Purpose: Transplantation tolerance is a highly sought and rarely achieved state in clinical medicine. Defined as long-term stable and acceptable graft tolerance without immunosuppression and with an otherwise competent immune system, tolerance maximizes graft survival and function and decreases organ demand without the negative side effects of immunosuppression. While there have been prior reports of tolerance after liver and kidney transplantation, we herein report and mechanistically characterize the first case of tolerance after intestinal transplantation.

*Methods: Intestinal transplantation was performed using our standard method. Immunosuppression for induction was thymoglobulin and steroids and for maintenance was tacrolimus. Graft and blood lymphocytes from the patient, 8 stable intestinal recipients, and 8 healthy controls (blood only) were analyzed using flow cytometry. Recipient T cell responses to donor and third party antigens were assessed by Pleximmune (proprietary).

*Results: We performed intestinal transplantation on a 14-year old male for severe pseudo-obstruction. Course was notable for grade 3 graft-versus-host disease (GVHD) at 7 months treated with thymoglobulin and steroids. Subsequently lost to follow up, he presented 7 years post-transplant and 3.5 years after stopping all immunosuppression with no graft problems. Biopsy showed pristine allograft histology. Given his history of GVHD, we hypothesized that central tolerance was mediated by chimerism. However, serial peripheral chimerism studies did not show donor chimerism. Thus, we speculated that he had peripheral tolerance mediated by regulatory T cells (Treg). This was confirmed by flow cytometric analysis showing that, compared to both sets of controls, the patient’s blood had similar CD4/CD8 proportions but higher levels of naïve and lower levels of effector memory CD4/CD8 as well as higher Treg percentages. Within the graft, we similarly showed lower levels of CD4/CD8 effector memory cells and higher levels of Foxp3 expression when compared to controls. Demonstrating immunocompetence, recipient T cells robustly produced IL-17, TNF-α, and IFN-γ when stimulated by PMA/IO and highly upregulated antigen-specific CD154 expression in response to CMV and EBV antigen stimulation ex vivo. Critically, donor-specific hyporesponsiveness was confirmed by 2-fold higher CD8+CD154+ T cell response to 3rd party vs. donor lymphocytes in mixed lymphocyte reaction.

*Conclusions: This represents the first report of tolerance after intestinal transplantation. Mechanistic analysis demonstrates that peripheral tolerance mediated by increased Tregs and decreased effector memory cells in both graft and blood appears to play a role.

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