Local Tacrolimus (FK506) Delivery for Prevention of Acute Rejection in the Nonhuman Primate Delayed Mixed Chimerism Vascularized Composite Allograft Tolerance Induction Protocol
Abstract
Hand and face transplants provide a remarkable and revolutionary way to restore function to allow return to independent living following extremity amputations or severe facial injuries. Over 90 hand and 20 face transplants have been performed worldwide, with promising outcomes. A major limitation to this field is the requirement for lifelong immunosuppression to prevent the recipient from "rejecting" the transplant. This is accomplished with medications whose side effects potentially include developing diabetes or cancers and being more susceptible to life-threatening infections. A young, healthy individual, such as a wounded Warrior, is faced with a lifetime of these risks, which limits return to duty, and therefore he/she frequently opts not to undergo such a transplant. One potential solution to this dilemma is the induction of immunologic tolerance of the transplanted tissues. Immunologic tolerance is defined as the acceptance of a transplanted organ without a destructive response from the recipient s immune system in the absence of immunosuppression medications. We have generated an exciting strategy for immunologic tolerance in non-human primates that has been proven successful in preclinical studies in kidney, heart, and lung transplantation and is currently under evaluation in a clinical trial for hand transplantation at our institution. The recipient typically undergoes a conditioning process to mute the immune system before the transplant is performed and receives a bone marrow transplant from the same donor who provided the transplanted hands. The difficulty with current protocols in non-human primates, however, consists of the high immunosuppression levels required to prevent acute rejection episodes (and the resultant complications from these high levels). Cynomolgus macaques have a more complicated immune system than humans in the context of transplantation due to the high level of complexity and diversity of the major histocompatibility complex (MHC). This complexity is best illustrated by the acute rejection and graft loss rates, approaching 50%, observed in some centers when solid organs are transplanted in cynomolgus macaques using clinical induction and maintenance immunosuppression protocols that are greater than 90% effective in humans. Four important disadvantages result from the need for such high immunosuppression levels: (1) Unlike in humans, many acute rejection episodes are irreversible and progress to graft loss. (2) Even when acute rejection episodes can be reversed, when they occur in the context of a delayed mixed chimerism tolerance induction protocol, the potential exists for sensitization to the subsequent donor bone marrow graft thereby resulting in rejection, lack of engraftment, and an inability to obtain mixed chimerism. (3) Severe viral and bacterial infections -- frequently remote from the site of the VCA -- often result in the need for euthanasia of many experimental non-human primates that did not experience rejection episodes of their VCAs. (4) A high frequency of acute rejection episodes has been associated with the initiation of chronic rejection of VCAs in animal models. Our central hypothesis is that the augmented local subcutaneous immunosuppression delivered by the implantable FK506 delivery device will prevent acute rejection episodes and potential sensitization to donor bone marrow, as well as allow reduced levels of systemic immunosuppression during the 4 months that animals are required to remain on immunosuppression until the delayed mixed chimerism donor bone marrow transplantation tolerance induction protocol occurs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1510281
Entities
People
- Curtis L. Cetrulo, Jr
Organizations
- Massachusetts General Hospital
- United States Army