Preclinical Development of a Novel Small Molecule T Cell Metabolism Inhibitor to Prevent Rejection and Enable Calcineurin Inhibitor-Free Allograft Survival in VCA
Abstract
According to published analyses of the Joint Theater Trauma Registry (JTTR), over half of the combat-related injuries sustained by Service members in Iraq and Afghanistan involved extremities or the face with the vast majority (78%) sustained from explosions. Improved personal protective equipment and injury response protocols have greatly increased the survival rates of Warfighters with even the most complex injuries. Furthermore, approximately 185,000 extremity amputations are performed in civilians in the United States yearly due to traumatic and non-traumatic causes. Currently an estimated two million amputees live in the U.S. However, despite the best surgical techniques using the patient’s own tissue for reconstruction, these injuries are often not only mutilating but frequently result in permanent disfigurement or amputation. Prosthetic devices are currently the only established means of rehabilitation for amputees and Service members surviving devastating extremity injuries. Lower limb prostheses offer excellent functional return and mobility and have even allowed wounded Warriors to return to active duty. In contrast, even the most advanced upper limb prostheses have failed to optimally restore the multiple and complex functions of a human hand in daily activities, social expression, and professional and social interaction. In particular, for such devastating combat and civilian injuries where conventional reconstruction is not achievable, vascularized composite allotransplantation (VCA), most commonly in the form of hand, arm, or face transplantation, has become a viable alternative and exciting new treatment option. However, the toxicities and side effects of multiple, lifelong immunosuppressive medications needed at high doses have limited wider application of VCA. In addition, these types of transplants contain skin -- the tissue thought most likely to cause an immune system response leading to rejection episodes capable of compromising the health and function of the transplant and recipient. Because VCA is not a life-saving procedure, the risks introduced by such immunosuppression must be carefully balanced against all the potential benefits such an improvement in function, independence, and quality of life. Thus, this proposal will address the Fiscal Year 2016 Restorative Transplantation Research Focus Area of Immune system regulation as specifically applied to VCA -- optimizing immunosuppressive drug regimens. The body’s immune system is designed to recognize “foreign” from “self.” This allows the body to fight off an infection when you have a cold, because the cold virus is recognized as “foreign.” When someone has an organ transplant or a VCA, such as a heart, kidney, hand, or face, which is donated from another person, the body recognizes that donated organ as “foreign” and the immune system of the patient fights to reject the transplant. Doctors currently deal with this problem of rejection of the organ by giving the patient multiple types of drugs that suppress, or weaken, the immune system. This allows the transplanted tissue to become part of the patient and not be seen as “foreign.” Currently, most people who have had a transplant have to take multiple immune-suppressing drugs for their entire lives. These drugs, however, have serious side effects and toxicities and, by suppressing the immune system, make the patient more susceptible to other types of infections. Surgeons and Scientists at Johns Hopkins are proposing a solution to this problem by applying a new method to help regulate the immune system in a more natural way that doesn’t rely solely on conventional drugs to keep the person from rejecting the transplant after an extremity transplant. Instead of previously used toxic drugs, this new technique will use specifically designed and highly specific agents (so-called metabolic inhibitors) that by altering the sugar metabolism of the cells that primarily cause rejection
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710521
Entities
People
- Barbara Slusher
Organizations
- Johns Hopkins University
- United States Army