Optimization of Delayed Tolerance Induction in Swine: A Clinically Relevant Protocol for Immunosuppression-Free Vascularized Composite Allotransplantation
Abstract
The proposed research project addresses the Fiscal Year 2015 Restorative Transplantation Research Focus Areas of Understanding mechanisms of immune rejection and Immunomodulation approaches and mechanisms (e.g., tolerance induction, chimerism). Hand and face transplants (i.e., vascularized composite allografts, VCAs) provide a remarkable and revolutionary way to restore function and allow return to independent living following extremity amputations or severe facial injuries. Over 100 hand and 20 face transplants have been performed worldwide so far, with highly promising outcomes such as regaining hand function, sense of smell, and the ability to eat. However, a major limitation to the field of VCA is the requirement for lifelong immunosuppression to prevent the patient from "rejecting" the transplant, similar to patients who have undergone kidney, liver, and lung transplantation. Currently, prevention of transplant rejection is accomplished using medications with side effects that include developing diabetes, kidney failure, and even cancer, while also becoming more susceptible to life-threatening infections. In fact, such complications have already been reported in human VCA patients. A young, healthy individual, such as a Wounded Warrior, would therefore be faced with a lifetime of these risks should he decide to undergo VCA. In turn, this would limit the extent of his return to active duty and most would therefore opt not to undergo VCA despite the significant improvement in quality of life that can be achieved. One potential solution to this dilemma is to promote tolerance of the VCA, which would eliminate the need for lifelong immunosuppression. Various methods of achieving tolerance have been developed in animal models but only mixed chimerism, where both the donor and recipient s cells co-exist without mounting destructive responses against each other, has been successfully applied in human kidney transplantation. Briefly, a patient receives a kidney from a living, related donor (i.e., parent, sibling) and takes standard immunosuppression drugs before stem cell transplantation using bone marrow from the original kidney donor at a later date to generate chimerism to allow complete withdrawal of immunosuppression therapy. Recent attempts using this delayed approach to induce mixed chimerism for immunosuppression-free tolerance in more challenging transplants such as lungs and combined heart and kidney have also proven successful in large animal models. We have previously achieved indefinite immunosuppression-free VCA survival in pig studies at our laboratory. This model, however, required pre-VCA treatment of both the donor and recipient, which would not be realistic clinically because faces and hands, like hearts and lungs, have to be taken from patients who have already passed away and it is also logistically impossible to predict when such matching donors will become available. The delayed approach towards tolerance induction will therefore enable us to overcome the lack of pre-VCA conditioning of both the donor and recipient by allowing VCA to be performed first using immunosuppression drugs to prevent rejection and loss in the interim period before subsequent stem cell transplantation to generate chimerism. This delay period would also allow adequate recovery from the original VCA surgery before attempting chimerism because it is believed that incomplete resolution of the inflammation associated with the initial surgery can affect the outcome of stem cell transplantation negatively. Based on the success of our institution with other types of transplantation using this delayed approach, we anticipate similar success in our VCA studies for immunosuppression-free survival. Building on this, we will use the same delayed approach to perform VCA across various genetic barriers to mirror the challenges of finding matching donors in the clinic. This will enable us to determine the extent of gen
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610702
Entities
People
- Curtis L. Cetrulo, Jr
Organizations
- Massachusetts General Hospital
- United States Army