PURPOSE: The development of novel drugs to hinder transplant rejection is expensive, time consuming and inevitably exposes the subject to lifelong immunosuppression. In contrast, modifying in vitro the donor transplant antigens on donor cells/organ/tissues prior to surgery is an attractive way to thwart host recognition. The purpose of this study was to investigate a simple, in vitro, enzyme-based method to cleave off donor MHC/HLA class I proteins, the dominant trigger of graft rejection, from donor cells to inhibit the host rejection response.

METHODS: Papain in modified physiological pH buffers was used to temporarily ablate MHC class I antigens on murine cells in culture. Ablation of class I structures was confirmed by flow cytometry prior to transplantation of the modified allografts in chemically induced diabetic mice and in a mouse model of liver transplantation. Untreated, secondary allogeneic transplants were later performed in the same host.

RESULTS: At the end of a brief treatment period, all cells remained fully viable and were void of class I surface structures. Transient removal of class I with papain prolonged graft survival. Re-synthesis of MHC class I induced graft-specific tolerance also allowed unprotected, fully allogeneic secondary transplants to be successfully performed in the same host, with prolonged transplant survival in the form of insulin secreting islets or liver cells.

CONCLUSIONS: The enzyme papain is able to rapidly cleave diverse MHC class I alleles from the surface of animal and human cells. Transient or even partial ablation of donor MHC class I using enzymes was sufficient for long-term survival of transplanted cells. An enzyme-based, in vitro donor antigen modification technique may be a new approach to inducing transplant tolerance. Indeed, such simple approaches of donor antigen modification could expand the use of diverse cell transplantation therapies into diseases where high dose immunosuppressive regimens may not be justified.

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