Targeting the Natural Immunosuppressive Capabilities of Endogenous Beta-Adrenergic Neural Pathways to Prolong VCA Graft Survival and Reduce Toxicity Risks
Abstract
Today, thanks to advances in emergency care and surgical procedures, military personnel can survive catastrophic limb and facial injuries incurred during combat. Civilians incur similarly devastating losses as the result of accidents or medically necessary surgical procedures. But these individuals then face challenging physical disabilities and psychological disorders that take an incalculable toll not only personally but on families and caregivers as well. Prosthetic devices are useful, particularly for lower limb deficits, but many people find upper limb prostheses unwieldy and lacking in sensitivity. More recently, surgical procedures have been perfected to allow for successful transplantation of faces, upper limbs, and hands from cadaver donors. This type of specialized transplant contains several different tissues (skin, bone, blood vessels, connective tissue, muscles, and nerves) and the procedure is known as vascular composite allotransplantation (VCA). In the best-case scenarios, the blood vessels to these transplants can be surgically connected to the vascular system of the recipient and the nerves regenerate so that the person regains sensation and normal function in the transplant. This is truly life- altering. The problem is that the recipients’ own immune system tries to reject the transplant, so patients must take very high doses of immunosuppressant drugs for the rest of their lives. These drugs have significant side-effects and include increasing susceptibility to life-threatening infections and cancers. To date, over 100 VCAs have been performed, and 85% of these patients experience one or more episode(s) of rejection which begins a vicious cycle in which immunosuppressive drugs must be intermittently discontinued which can lead to rejection of the graft. Since this surgery is performed solely to improve quality of life and is not life-saving, there are ethical issues associated with these risks. The primary research award focus area we are addressing in our proposal is to develop less-toxic regimens to improve VCA survival by dampening immune rejection at the graft site. This proposal leverages extensive work in our lab showing for the first time that the nervous system can be harnessed to modulate immune responses for clinical benefit in cancer and bone marrow transplantation. Our new idea is that we can manipulate the mechanisms by which the nervous system naturally regulates immune responses by repurposing drugs that are commonly prescribed for asthma (beta-agonists). These drugs target mediators that are part of our bodies’ own natural relay system that allows the sympathetic nervous system to activate the fight or flight response and regulate immune responses. Our hypothesis is that we can develop a protocol that combines the immunosuppressive actions of beta-agonists and reduced doses of toxic immunosuppressant drugs currently used to maintain VCA. This is based on our recently published paper showing that we can safely prolong survival of VCA transplants just by adding a beta-agonist to a standard regimen of immunosuppressive drug (Tacrolimus) that, by itself, is not effective. In this proposal we will use our newly established and validated mouse models of VCA to (1) optimize the combination therapy, (2) study how beta-agonists suppress both immediate and long-term vascular damage and graft rejection driven by an over-active immune response, and (3) study details of how beta-agonists impact immune cells. These studies will examine novel immunological endpoints to monitor the effectiveness of the new combination drug regimen that could be useful as new biomarkers in patients who could receive this new therapeutic strategy in the future. Overall, our study addresses several points in the award focus areas, including studying why VCAs induce strong immune responses, improving immune tolerance, determining what special types of immunosuppression are needed to protect VCA, look
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310529
Entities
People
- Elizabeth Repasky
Organizations
- United States Army