Operational tolerance in intestinal transplantation

Abstract

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.

Operational tolerance after intestine re‐transplantation in childhood and immunological correlates. Case report and review

“…Previous studies suggest that the relatively larger numbers of donor cells relative to recipient cells may be important contributors to mechanisms underlying donor specific hyporesponsiveness in tolerant IT recipients 10,12,14 . These mechanisms include elimination of donor‐specific cytotoxic T‐cells by alloactivation induced apoptosis, facilitation of this process by rATG as demonstrated by us in in vitro studies, or the induction of T‐regulatory cells which can suppress anti‐donor T‐cells 1,8,14,15 . Significantly, the recipient at our center demonstrated relatively greater apoptosis of T‐cytotoxic memory cells when stimulated with donor cells than with third‐party (Figure 2B).…”

“…Similarly, serologic responses to vaccine targets or EBV and CMV were also intact 2 . Interestingly, DSA, a hallmark of donor‐specific humoral response were present in both previously reported tolerant IT recipients 1,2 . This finding contrasts with previous studies in operationally tolerant liver recipients in whom DSA were absent 13 .…”

“…A second common feature is the presence of donor‐specific immunological hyporesponsiveness in all three patients. This hyporesponsiveness was seen in recipient T‐cytotoxic memory cells in all three, and in impaired donor antigen presentation by B‐cells and monocytes in two of three patients who were tested with these assays 1,5–7 . Cellular immune responses to common post‐transplant infections such as EBV and CMV were intact 1,9 .…”

“…Table 2 summarizes the salient features and the variable path to operational tolerance in the three IT recipients from three centers 1,2 . Immunosuppression withdrawal after primary IT occurred following treatment of severe GVHD despite detectable DSA in both previous reports.…”

Operational tolerance after pediatric composite liver‐pancreas‐intestine transplantation following severe graft‐versus‐host disease

“…While operational tolerance would alleviate these concerns, tolerance has only been well described and investigated in the isolated liver and kidney transplant populations. There is just one other case report of tolerance following ITx 5 and no reports of our knowledge in composite liver‐intestine transplantation. We present not only operational tolerance after composite liver‐pancreas‐intestine transplant but demonstrate immunocompetence and continued graft health for almost a decade after cessation of all IS.…”