Adult Tissue-Derived Stem Cells and Tolerance Induction in Nonhuman Primates for Vascularized Composite Allograft Transplantation

Hand and face transplants offer a potentially ideal solution to massive tissue loss, amputations, and facial disfigurement secondary to explosive injury experienced by military Service members. The limitation to widespread application of these transplants known as vascularized composite allotransplantation (VCA) is uncertainty over how long these transplants may survive and the potential of serious complications. These VCA grafts demonstrated in a couple select cases that they can survive for over a decade based on daily treatment with potent medications to prevent rejection. The most successful category of these medications is calcineurin inhibitors (CNI). However, a known and predictable complication of these medications is the development of chronic kidney disease in over 40% of patients after 5 years. Patients treated with these medications are also at increased risks for cancer, infections, diabetes, and other medical complications. Thus, with current medications, some VCA patients will develop renal failure requiring hemodialysis or other potentially life-threatening complications.

Therapies that could avoid these complications including renal failure, while still protecting the transplanted tissue, are highly desirable before widespread application of hand and face transplants. Strategies that could eliminate the need for medications and promote permanent graft acceptance would be ideal. The state of permanent transplant acceptance without the need for any medication is termed tolerance. This proposal will study an approach to achieve tolerance that has worked in mouse models of transplantation. Our prior studies support that a combination of medications and cells administered together develop tolerance. This could be applied to hand, face, and all life-saving organ transplants. These methods need to be tested in models that would justify using them in patients.

Our studies will be performed in a preclinical non-human primate model of face VCA for which we have a decade of prior experience. The results from our studies would provide support for a study in patients whom would receive a hand or face transplant. The benefit of a safe and effective tolerance strategy for patients could justify hand and face transplantation as the first option to heal young military patients with devastating tissue injuries. These injured military patients require solutions that will provide multiple decades of success and safety after hand or face transplantation.