Effect of Peritransplant C3d Blockade and Ischemia on Chronic Rejection and Vasculopathy in an Experimental OMC Flap Model of VCA
Abstract
Objectives and Rationale: This proposal is taking advantage of a recent observation by our collaborators, Dr. Platt and Dr. Cascalho. While researching the immune response of mice injected with a tumor, they found that C3d, a product of the body’s response to damage such as lack of oxygen or invasion by bacteria or virus, actually invigorated part of the mice’s immune system, and the mice easily cleared the tumors. It was not previously known that this complement molecule (C3d) could have this effect. In addition, they found that, by giving a molecule that binds up and removes this agent (C2R), they could inhibit the immune system, and the mice no longer aggressively destroyed the tumor. What we propose to do in this study is determine (for the first time) whether C3d, or the agent that binds it (the CR2 receptor), can be used to control the immune system in the recipient of a VCA graft. We hypothesize that the free C3d will activate the immune system in response to injury. So for VCA recipients, we want to remove or inhibit the free C3d. We are using a rat model of VCA transplantation. The graft we are using is part of a leg from the donor animal that contains skin, muscle, bone, and vessels. We will implant this in the groin of the recipient animal. The benefit of this model is that the recipient is able to walk right away and doesn’t have some of the complications associated with a complete leg transplant. However, we can ask all the immunologic questions we like. It is a good model to study VCA transplantation. We have considerable experience with this model, and we know how much immunosuppressive drug to use to achieve a little rejection, a lot of rejection, or the slow burn type of rejection that is seen in some VCA recipients. Another significant problem in hand and face transplantation is the role of ischemia, or lack of oxygen, that all VCA grafts are subjected to at the time of transplant. Because of this lack of oxygen, the donor graft suffers while it is transplanted activates complement; it makes sense that more of this free C3d will be around and will further activate the immune system. We propose to determine whether that is the case and whether, by mopping up the free C3d, we can reduce the harmful effects of ischemia. As outlined in the project narrative, we will transplant rats with donor grafts and compare the effect of soaking up all the C3d at the time of transplant on the incidence and severity of graft rejection, as outlined in tables I, II, and III. We expect to see rejection less often and with a lower grade of rejection in animals treated with C3d blockade. We also expect that C3d blockade will reduce the tissue damage of grafts exposed to longer periods without oxygen (ischemia). The proposed research addresses all three of the FY19 RTRP focus areas. We will reduce the risks of VCA-associated immunosuppression by “developing a novel approach for improving VCA tolerance and, identify unique immunosuppression requirements for VCA compared to other solid organ transplants.” In addition, detection of free C3d has the potential to provide “a new peripheral biomarker for acute and chronic rejection.” Finally, we will analyze the effect of increased ischemia time in the presence or absence of C3d blockade and the incidence and severity of acute and chronic rejection, directly addressing “determine the extent to which VCA tissue preservation technology impacts VCA immunogenicity.” We expect to determine whether C3d blockade plays an immunomodulatory role for both IRI and graft rejection. In the long term, we hope that this therapy may be used to reduce the incidence and severity of graft rejection. Lessons learned would also be potentially useful, not only for solid organ transplant recipients, but for patients with autoimmune disease and patients with cancer who are seeking ways to target the immune response to attack a malignant growth. In summary, this project combine
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010943
Entities
People
- Christina Kaufman
Organizations
- United States Army
- University of Louisville