Postdoctoral Research Scientist Columbia University Center for Translational Immunology New York, New York, United States
Abstract Text: Background. Intestinal transplantation is the only remaining treatment for patients with intestinal failure who failed parenteral nutrition. Unfortunately, it carries the highest rate among solid organ grafts of immunologic complications, including rejection and graft-vs-host disease. We developed a porcine intestinal transplant model across a full-MHC-mismatch to evaluate chimerism and cellular immune responses associated with rejection.
Methods. The recipient was T-cell depleted using CD3-immunotoxin and anti-CD8-antibody. The recipient's intestine was removed and replaced by a full-MHC-mismatched graft. Immunosuppression, mimicking our clinical protocol, consisted of tacrolimus (goal: 16-18ng/ml) and 1mg/kg prednisone for 90 days and was subsequently weaned over 30 days to assess immune responses. Peripheral and mucosal chimerism were tracked weekly and biweekly, respectively. Mixed lymphocyte assays (MLR) with and without CD25-depletion were done monthly using peripheral and mucosal lymphoid cells.
Findings. The recipient was successfully weaned from immunosuppression without clinical or pathological signs of rejection. Peripheral blood chimerism was lost 10 days after transplantation. Recipient chimerism in the graft mucosa peaked at 80% and stabilized at 60%. Peripheral blood lymphocytes in MLRs maintained a robust response against the donor, while the mucosal lymphocytes showed donor-specific unresponsiveness that was abrogated when T-regs were depleted.
Conclusion. We unexpectedly achieved tolerance to a full-MHC-mismatched intestinal graft in our pig model, which appears to have been locally mediated by T-regs within the graft but not the peripheral blood. We intend to repeat this experiment to see if the findings are reproducible and if the mechanisms favoring tolerance can be applied to our clinical regimen.
