Improving Ischemia Reperfusion Injury in Vascularized Composite Tissue Allotransplantation Via Histone Deacetylase Modulation
Abstract
Vascularized composite allotransplantation (VCA) has been in clinical use for 15 years, providing major functional restoration with improved quality of life and aesthetic results for a small number of patients with significant tissue loss, with the vast majority comprising upper extremity and face transplants. The clinical need is significant as there are 1.2 million limb amputees alone in the United States, and military Veterans with significant battlefield injuries make up a significant population of potential candidates for this restorative procedure due to the relative young age and lack of comorbid medical conditions in the military Veteran population. Despite the promising early results, only about 70 hand or forearm/hand transplants, and ~150 VCA procedures of any type, have been performed worldwide. The reason for this is clearly multifactorial, with lack of insurance coverage a significant barrier and the need to balance the requirement for longstanding immunosuppression with the benefits of the procedure a second significant factor. Nonetheless, VCA has passed through the proof-of-concept phase of implementation, and the field needs to expand to increase numbers of treated patients to prove clinical efficacy in a larger cohort to justify placing this approach in the standard of care. One of the major barriers to VCA that has been appreciated, particularly for military Veterans, is that combined injuries associated with limb loss in these cases often involve multiple transfusions and exposure in burn patients to allogeneic skin coverage, which can lead to the development of antibodies in the potential recipient that significantly restrict the number of donors to which a particular potential recipient may be immunologically compatible. Also, as opposed to solid organ transplantation, the VCA graft is external, and this requires much more close matching of size, gender, race, and age in addition to the typical matching parameters in transplantation such as blood type and immunological compatibility. What this means is that for many possible recipients, the potential donor pool is small and the time that must elapse to find a compatible graft among all of the listed parameters may be very long, if achievable at all. The radius of donors that can be considered for an individual recipient is limited in large part by the cold ischemia time (CIT), or time that elapses between when the limb is procured in a donor hospital and the time when it is connected to the circulation of the recipient. The functional outcome of the graft is compromised with prolonged CIT and current practice limits this time to ideally less than 6 hours and with an absolute limit of around 10 hours. Due to time required at the donor and recipient hospitals to procure and implant the graft, flight time is limited to approximately 2 hours. Current standard of care in organ transplantation involves using cold preservation storage and minimizing ischemia time. No specific donor or recipient interventions exist to prolong these times. We have recently discovered that by manipulating a number of nuclear proteins that alter the availability of genes to be expressed, we can significantly extend the amount of time that a kidney can be exposed to cold ischemia and be usable with good results in a mouse transplant model. We have seen that by deleting a single member (histone deacetylase 2 or HDAC-2) of this family in the kidney alone that tolerance of warm ischemia is increased by 30% and survival of transplants after 24 hours of cold storage increased from 42% to 92%. These ongoing studies are now attempting to identify the mechanism of this protective effect. We herein propose to translate the approaches that have been very successful in renal injury models to a limb transplant model in mice. We expect that we will see significant improvement in the ability of a VCA limb graft to tolerate ischemia by inhibiting HDACs in general and HDAC-
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610780
Entities
People
- Matthew Levine
Organizations
- United States Army
- University of Pennsylvania