Targeting Innate Immune Regulators to Reduce Rejection in Vascularized Composite Tissue Transplants
Abstract
Anti-rejection medications are associated with significant complications post-transplant, including a higher rate of infection and cancer. Different than other organ transplants, all face and extremity transplant recipients develop rejection despite the use of available anti-rejection drugs. Therefore, better understanding of how the transplanted extremity or face triggers rejection and the development of novel therapies that minimize rejection and minimize the systemic toxic effects of anti-rejection medications are of paramount importance. The current research proposal has two main objectives: 1. Investigate a promising innate immune receptor that slows down the rejection process. 2. Develop an innovative therapy to prevent rejection that involves treatment of the transplanted organ prior to transplantation, promoting immune regulation and minimizing systemic toxic exposure related to high doses of anti-rejection medications in the organ recipient. This proposal is innovative for three main reasons: (1) We will use animal and human experimental approaches to answer our questions in combination with advanced technological tools such genetic-modified animals and mouse limb transplantation. (2) We have developed a unique drug capable of “educating” the donor immune cells prior to transplantation, permitting the development of a new concept of rejection prevention that lacks systemic toxicity to the recipient. (3) For the past 10 years, we have been collecting samples from patients that have undergone face/extremity transplants in our center (over 350 time-points), which will allow us to correlate our animal findings with the more relevant observations in humans. To our knowledge, this is the largest collection of extremity/face transplant samples in the world and a precious resource that we wish to utilize to help improve the care of current and future extremity/face transplant recipients. Last, we will test our novel drug treatment in a humanized transplant mouse model to better predict its beneficial effect in humans. This proposal addresses three main Focus Areas of this Award (under category: reduce risks of VCA-associated immunosuppression): 1. Define the unique mechanisms of VCA immunogenicity. 2. Develop novel approaches for improving VCA immune tolerance. 3. Identify unique immunosuppression requirements for VCA compared to other solid organ transplants. The results of this study will allow us to better understand the molecular mechanisms of the rejection process by specifically characterizing an anti-rejection receptor present in the transplant organ cells and applying a novel therapeutic molecule that targets the transplanted organ instead of the whole body of the transplant recipient. This approach could be applied to future extremity/face transplants for regulating the immune response and minimizing systemic toxicity of anti-rejection medications, allowing Service members to maintain a better quality of life and prolong their survival post-transplantation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010758
Entities
People
- Leonardo V Riella
Organizations
- Massachusetts General Hospital
- United States Army