Does MHC class II sharing decrease rejection and promote regulatory tolerance in intestinal transplantation

About This Grant

PROJECT SUMMARY Intestinal failure (IF) occurs when patients are not able to maintain sufficient hydration or nutrition through oral intake alone due to either inadequate length of bowel (“short gut syndrome”) or inadequate function of the bowel. Intestinal transplantation (ITx) is the definitive therapy for patients with IF who have no possibility of enteral independence and the only remaining therapy once parenteral nutrition fails, but its use is limited by high rates of rejection that necessitate increased levels of immunosuppression, predisposing patients to infections, malignancy, and graft-versus-host disease. Therefore, identifying strategies to avoid ITx rejection, especially by developing donor-specific tolerance in an otherwise immunocompetent host, would make ITx a more attractive therapeutic option for patients with IF and might also be a useful strategy for other types of transplantation. Based on our pre-clinical studies, matching donor/recipient major histocompatibility complex (MHC) class II appears to be a promising strategy. We developed a swine orthotopic ITx model based on our clinical ITx protocol and found that, unlike fully-MHC-mismatched pairs, sharing only a portion of a single class II allele decreased rejection and promoted the development of regulatory T cells (Tregs) and donor-specific hyporesponsiveness in the graft, while greater MHC sharing extended these findings to the peripheral blood and permitted durable mixed chimerism (donor cells in the recipient’s blood) in a small pilot experiment cohort. We therefore hypothesize that selectively matching donor/recipient MHC class II, which is not currently performed routinely, promotes longer rejection-free survival (RFS) of ITx grafts by minimizing rejection through expansion of Tregs, possibly in a dose-dependent fashion. If our hypothesis is validated, class II sharing could be used to improve ITx outcomes since living donors are usually first-degree relatives and share at least half of their class II alleles with the recipient, and it is also feasible to achieve class II sharing in deceased donor transplantation because some class II alleles exist at high frequency in the general population. Based on our in vitro data, we additionally hypothesize that the mechanism by which class II sharing promotes regulatory tolerance is through linked suppression. If supported by our data, this too would present an opportunity since this immunological principle could be applicable to all forms of transplantation, not just ITx. Therefore, the overall goal of this project is to test our hypothesis regarding the clinical advantages of class II sharing and to evaluate the immunological mechanism by which this occurs. Thousands of patients would benefit from ITx if outcomes were improved, and our prior data have generated a hypothesis for improving immunological outcomes. These data support pursuing further investigation, which we are uniquely poised to perform due to our novel human and large animal models and our ability to perform the proposed mechanistic analysis. Our prior human and swine studies demonstrate the feasibility of our proposed Aims.