High-Dose Posttransplantation Cyclophosphamide to Induce Delayed Immune Tolerance After Reconstructive Transplantation
Abstract
Rationale and Objective: Nearly 40% of combat injuries sustained in Operation Iraqi Freedom and Operation Enduring Freedom involved 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). The most commonly known forms of VCA are hand and face transplantation to date. VCA is an approach that provides new, exciting options in particular for wounded Warriors that can 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 as the need for lifelong drug treatment to prevent this rejection is required and comes with significant negative side effects including an increased risk of developing cancer. A great effort in research related to this field is therefore geared towards finding ways to achieve transplant tolerance, i.e., a state in which the recipient does not reject the allograft even without taking anti-rejection drugs. In humans, such a state of transplant tolerance has only been observed in kidney transplantation when the organ was donated by a living relative (e.g., a sibling), a scenario that allows for ample time for preparation and planning of the procedure. Unfortunately, the field of VCA cannot rely on living and related tissue donors. In this study proposal, we aim to apply tolerance promoting/inducing treatment at a later stage after transplantation -- a concept we refer to as “delayed tolerance” -- to allow for transplantation of VCA immediately after the availability of the tissue donor. The overall goal is to minimize or completely avoid the need for anti-rejection drugs in the long term. The combined experience of our group in bone marrow transplantation and in VCA provides a strong background to propose the use of clinically successful therapies in bone marrow transplantation with VCA to induce delayed tolerance to the benefit of VCA recipients. This will be consistent and directly responsive to the Restorative Transplantation Research Investigator-Initiated Research Award Focus Area of Immune system regulation as specifically applied to VCA -- Immunomodulation approaches and mechanisms. Applicability of the Proposed Research: Hand and face transplantations are a clinical reality. However, the necessary use of anti-rejection drugs to guarantee survival of the VCA comes with a considerable toll on human health due to increased risks for cancer and infection as well as significant costs related to those side effects. This research proposal suggests the use of high-dose post-transplantation cyclophosphamide (PT/Cy) treatment to achieve anti-rejection drug free VCA survival. Thereby, this treatment would positively affect the side effect profile and costs associated with conventional treatment. Pioneered at Johns Hopkins University, clinically available PT/Cy-based treatment protocols have revolutionized the treatment of various types of blood cancers (e.g., leukemia) by allowing bone marrow transplantation from non-related donors. In addition, results of animal studies generated by our own laboratory show that PT/Cy-based treatment, if given at the time of transplantation, allows for long-term graft survival without the need for anti-rejection treatment. Taken together, experience in human medicine combined with results from animal studies strongly encourages the use of PT/Cy combined with VCA to establish delayed tolerance to eliminate the long-term need for anti-rejection drugs. Impact on the Field
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710280
Entities
People
- Gerald Brandacher
Organizations
- Johns Hopkins University
- United States Army