Investigating Novel Approaches to Block Inflammation and Prevent Ischemia Reperfusion Injury During VCA Transplantation
Abstract
Over half of all combat-related casualties in the U.S. military since 2006 were sustained in improvised explosive device (IED)-related incidences. Up to 80% of those involved wounds to the hands and or face. Victims of such attacks are often left permanently disfigured and, in some cases, with extremities and/or portions of their face missing. The current technology available to reconstruct the wounded Warrior after severe trauma to the extremity or face consists of taking tissue from non-injured portions of the body to reconstruct what has been lost. The surgical techniques are often inadequate to completely restore the patient to their pre-injury status. In addition, these techniques require multiple revision procedures, prolonged rehabilitation, and complications and functional restrictions that occur because of the need to surgically relocate the patient’s own (autologous) tissue. In those cases where no like tissue exists, such as in the case of a lost hand or leg, the only option for reconstruction is to use a prosthesis. One solution to the overwhelming need for tissue for reconstruction is the use of tissue (such as a hand) taken from deceased donor and transplanted to the living recipient. These organ transplants are called vascularized composite tissue allografts (VCA), as they include multiple tissues types such as bone, tendon, muscle, and skin, together with the vasculature that supplies blood to these tissues. Currently, to prevent rejection and loss of these transplants, patients receive immunosuppression (as is used in kidney and other organ transplants). Despite the use of immunosuppression, all VCA patients have experienced episodes of rejection. In addition, there have been major complications related to the immunosuppression itself. Although clinical VCA transplantation has resulted in successful outcomes, the high rates of acute rejection and increased requirements for immunosuppression have led to significant long-term complications. During transplantation, blood supplying oxygen to tissues of the VCA is necessarily temporarily cut off when the VCA is removed from the donor and before the blood supply is reestablished in the recipient. The resulting inadequate supply of oxygen is known to trigger a robust inflammatory response when the recipients blood supply is reconnected. This inflammatory response causes injury to the transplanted VCA and greatly influences transplant outcome. This is referred to as ischemia reperfusion injury (IRI). The overall scientific goal of this proposal is investigate novel therapeutic approaches to reduce the inflammatory response following transplantation and to avoid IRI. Approaches that reduce inflammation associated with ischemic injury during VCA transplantation may permit reduction in immunosuppression with improved function. Galectin-3 (Gal3), a known inflammatory factor, is actively involved in ischemia-induced inflammation and fibrosis of various organs. This protocol will investigate the role of Gal3 in VCA IRI and determine whether Gal3 can serve as a therapeutic target to prevent or reduce IRI. Results of this study will also determine whether Gal3 levels in the blood can be used as a novel biomarker to predict the degree of tissue damage and graft function following VCA transplantation. Impact and Focus Area(s): Reduce the risks of VCA-associated immunotherapy; define the mechanisms of VCA immunogenicity; and identify and/or validate new peripheral biomarkers for early acute and chronic rejection.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910163
Entities
People
- Christene A Huang
Organizations
- United States Army
- University of Colorado Denver