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

Abstract

Background: Operational tolerance after retransplantation of the intestine has never been reported.

Purpose: To two recently described intestine transplant recipients with operational tolerance, we now add a third.

Methods: Review of case record and immunological testing to confirm donor-specific hyporesponsiveness in multiple immune cell compartments.

Results: Re-transplanted with a multivisceral liver- and kidney-inclusive intestine allograft at age 12 years, this recipient self-discontinued immunosuppression 14 years after the retransplant and has been rejection free for 2 years thereafter. As in the two previous reports, immunological testing demonstrated decreased donor-specific inflammatory response of T-cytotoxic memory cells and B-cells, decreased presentation of donor antigen by B-cells and monocytes, absence of donor-specific anti-HLA antibodies, circulating FOXP3 + T-helper cells, and intact cellular and humoral immunity to cytomegalovirus and Epstein-Barr virus. Additionally, our recipient demonstrated enhanced donor-activation-induced apoptosis of alloreactive T-cytotoxic memory cells.

Conclusions: Despite variable paths to tolerance which include graft versus host disease in two previous cases, and rejection-related loss of the primary isolated intestinal allograft in our recipient, the three cases with operational tolerance are bound by common themes: a relatively large donor antigenic load transmitted during intestine transplantation, and donor-specific hyporesponsiveness. Cell-based assays suggest enhanced donor-induced apoptosis of recipient T-cells and circulating T-regulatory cells as mechanistic links between antigenic load and donor-specific hyporesponsiveness.

Keywords: hyporesponsiveness; intestine; multivisceral; pediatric; re-transplantation; tolerance.