Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody-Mediated Rejection After Vascularized Composite Allotransplantation
Abstract
Rationale and Objective: Nearly 40% of combat injuries sustained in Operation Iraqi Freedom and Operation Enduring Freedom involve severe trauma to the arms, legs, and/or face. For many devastating injuries where conventional surgical reconstruction is not possible, vascularized composite allotransplantation (VCA) has become a viable alternative. The term VCA describes procedures whereby any section of the body that includes arteries and veins supplying and removing blood from an area (vascularized) along with multiple types of body tissues such as bone, muscle, and skin (composite) is transplanted from one person to another (allotransplantation). VCA is an approach that provides new, exciting options for Wounded Warriors that could restore appearance and function better than other currently available treatments. However, the problem of immunologic rejection of transplanted tissue is a major barrier to this treatment. In particular, the role of donor-specific antibodies (DSA) in VCA has yet to be defined. Therefore, the rationale and objective of the proposed research is to better understand the mechanisms governing VCA rejection and allowing these patients the benefits of reconstructive transplantation. This will be consistent and directly responsive to the Fiscal Year 2015 Restorative Transplantation Research Focus Area: Immune System Regulation - Immunomodulation approaches and mechanisms. Applicability of the Proposed Research: Hand and face transplantations are a clinical reality. However, clinical management of severe injuries to the hands, arms, and face often necessitates that patients receive multiple lifesaving blood transfusions and/or skin grafts in the time immediately following their injury. VCA is attempted only after a patient has stabilized and recovered from these primary lifesaving medical interventions. This is done because the goal of VCA is to restore proper form and function to damaged body parts, and in the grand scheme of medical care, this goal falls secondary to preserving the patient s life. The problem that arises with this sequence of treatments is that an immunologic reaction is initiated by exposing patients to another individual s body fluids or tissues such as blood transfusion or skin grafts prior to VCA. This results in the formation of compounds called donor-specific antibodies (DSA). Antibodies are structures within the blood that are responsible for recognizing and alerting the body to foreign invasion, either by infectious bacteria or another person s blood. DSA are said to "sensitize" the patient to further exposures of blood or tissue from another donor, meaning that if that patient were to receive future transplants, the result could be catastrophic. This reaction has been termed antibody-mediated rejection (AMR). DSA and the subsequent high risk of AMR are thus typically considered exclusion criteria for patients to receive a solid organ transplant. In the United States, about 40% of kidney transplant candidates are currently sensitized or highly sensitized. In a recent study, it was shown that this number is even higher for VCA candidates. In addition, in kidney and heart transplantation, presensitization is known as the greatest risk factor for allograft rejection and long-term graft loss. However, the role of DSA and their contribution to the rejection of transplanted tissue such as hand and face is still largely unknown. To complicate things even more, the fact that VCA can only be performed in a cadaveric/brain dead donor setting in which the time of transplant cannot be predicted does not allow to apply desensitization protocols as currently used in SOT. We will therefore investigate the ability of an entirely novel approach to desensitize VCA candidates by performing a bone marrow transplant using the patient s own stem cells called autologous hematopoietic stem cell transplantation (aHSCT) in a preclinical large animal model. This concept is based
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610664
Entities
People
- Gerald Brandacher
Organizations
- Johns Hopkins University
- United States Army