Targeted Modulation of Inflammation to Improve Immune Tolerance
Abstract
There have been nearly 7,000 U.S. military fatalities and over 52,000 injuries resulting from the wars in Iraq and Afghanistan. Because of improvements in body armor and battlefield practices, many Soldiers who would have died in previous conflicts now survive. Explosive devices and blast trauma account for the majority of combat-related injuries, and Soldiers who survive often have debilitating injuries to unprotected areas such as the face and limbs. These kinds of injury affect not only physical form and function, but they also represent a significant mental health issue due to their psychological impact. Transplantation has now become an accepted surgical approach for facial and limb replacement, and transplantation of multiple tissues (known as vascularized composite allografts or VCA) is required. Because VCA generate a strong immunological response, transplant recipients require aggressive and life-long immunosuppression. Since VCA is usually performed in the context of non-life threatening defects, a major concern is the toxicity of immunosuppressive drugs that can cause organ damage, metabolic disorders, cancer, and an increase in susceptibility to infection. Thus, a necessary long-term research goal is the development of novel strategies that minimize the levels of immunosuppression required to prevent VCA rejection. The long-term goal of this project is to develop a therapeutic strategy that will reduce the level of immunosuppression required and potentially eliminate the need for toxic immunosuppression. Our hypothesis, supported by published and preliminary data, is that by limiting early injury to the graft that occurs immediately after transplantation, the subsequent intensity of the immune response against the transplanted graft will be significantly reduced, thus allowing for reduction or elimination of long-term immunosuppressive treatments. A necessary procedure during all transplantation surgeries is stopping the blood flow in the donor organ/tissue (ischemia) and then restoring the blood flow after the organ/tissue has been transplanted into the recipient (reperfusion). This ischemia and reperfusion results in inflammation and causes a significant amount of early injury to the graft and is known as ischemia reperfusion injury (IRI). A major contributor to IRI is a component of the immune system known as complement. The complement system is a collection of blood proteins that can be activated, as occurs after ischemia and reperfusion, to produce molecules that are highly inflammatory and can be lethal to our own cells. In this project, we will investigate the role of the complement system in causing IRI to VCA. Another necessary component of VCA is a period of cold storage before the graft is transplanted. Longer periods of cold storage are associated with increased IRI, and we will further investigate how complement contributes to this increased injury and whether complement inhibition can ameliorate the injury associated with extended cold storage. We will next determine how complement inhibition early after transplantation (and reduction of IRI) impacts the development of a subsequent immune response against the graft that is ultimately responsible for rejection. We will also investigate what impact early complement inhibition has on the dose of immunosuppressive drugs needed to prevent graft rejection. In this work, we will investigate an immunosuppressive drug that is currently used in the clinic. Our goal is to be able to lower the dose of immunosuppression required with our therapeutic strategy, which would reduce serious and life threatening side effects associated with current immunosuppression. In this work, we are using a model of limb transplantation, and a critical outcome after transplantation is functional recovery of the transplanted limb. Therefore, in this work we also investigate how our novel therapeutic approach, together with different doses of immunosuppression
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010743
Entities
People
- Stephen Tomlinson
Organizations
- Medical University of South Carolina
- United States Army