Although innate lymphoid cells (ILCs) play fundamental roles in mucosal barrier functionality and tissue homeostasis, ILC‐related mechanisms underlying intestinal barrier function, homeostatic regulation, and graft rejection in intestinal transplantation (ITx) patients have yet to be thoroughly defined. We found protective type 3 NKp44+ILCs (ILC3s) to be significantly diminished in newly transplanted allografts, compared to allografts at 6 months, whereas proinflammatory type 1 NKp44−ILCs (ILC1s) were higher. Moreover, serial immunomonitoring revealed that in healthy allografts, protective ILC3s repopulate by 2‐4 weeks postoperatively, but in rejecting allografts they remain diminished. Intracellular cytokine staining confirmed that NKp44+ILC3 produced protective interleukin‐22 (IL‐22), whereas ILC1s produced proinflammatory interferon‐gamma (IFN‐γ) and tumor necrosis factor‐alpha (TNF‐α). Our findings about the paucity of protective ILC3s immediately following transplant and their repopulation in healthy allografts during the first month following transplant were confirmed by RNA‐sequencing analyses of serial ITx biopsies. Overall, our findings show that ILCs may play a key role in regulating ITx graft homeostasis and could serve as sentinels for early recognition of allograft rejection and be targets for future therapies.
By presenting the first case report of true operational tolerance in an intestinal transplant patient, we aim to demonstrate that tolerance is possible in a field that has been hampered by suboptimal outcomes. Although operational tolerance has been achieved in liver and kidney transplantation, and some intestinal transplant patients have been able to decrease immunosuppression, this is the first instance of true operational tolerance after complete cessation of immunosuppression. A patient received a deceased‐donor small intestinal and colon allograft with standard immunosuppressive treatment, achieving excellent graft function after overcoming a graft‐versus‐host‐disease episode 5 months posttransplant. Four years later, against medical advice, the patient discontinued all immunosuppression. During follow‐up visits 2 and 3 years after cessation of immunosuppression, the patient exhibited normal graft function with full enteral autonomy and without histological or endoscopic signs of rejection. Mechanistic analysis demonstrated immune competence against third party antigen, with in vitro evidence of donor‐specific hyporesponsiveness in the absence of donor macrochimerism. This proof of principle case can stimulate future mechanistic studies on diagnostic and therapeutic strategies, for example, cellular therapy trials, that can lead to minimization or elimination of immunosuppression and, it is hoped, help revitalize the field of intestinal transplantation.
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