T Cell Receptor Repertoire Analysis as a Biomarker for Predicting Graft Rejection in Transplant Recipients
Abstract
Vascularized composite allotransplantation (VCA) from a deceased donor has emerged as effective treatment to correct injuries that result in loss of limb and/or disfigurement sustained by both Armed Service personnel and civilians. However, a major drawback of VCA is the need for lifelong treatment with anti-rejection drugs, commonly called immunosuppressive drugs (IS). This makes VCA less attractive to the majority of eligible patients. Also, despite taking IS drugs correctly, rapid rejection can occur in a high proportion of patients. At present, rejection can be diagnosed early only by obtaining a biopsy and checking for cellular infiltration into the graft. This also can be tricky as one site may show rejection while another does not. More importantly, getting biopsy causes damage to the sensitive transplanted tissue. Therefore, less damaging means for the diagnosis of rejection is desirable. So, our objective is to develop a new technology that can diagnose transplant rejection easily and reliably. Our approach is to find out the particular identity of the immune cells that are causing rejection of the transplanted graft and track them (these particular immune cell identities are like the first names of individuals in a related clan). These individual immune cells are called T cell clones. (Their normal function is to protect against diseases; but the immune system considers the transplant as a major “infection” and tries to get rid of it.) What we plan to do is to identify before transplant all the T cell clones that can react against the donor by purifying them and assessing their genetic make-up. Then, after the transplant, we will check if and how many of those particular T cell clones are present. If large numbers of them are present in a rejecting biopsy, our approach and hypothesis is proven correct. If they can be detected in the blood during rejection, we can do the diagnosis in a non-damaging manner. More importantly, if we can detect them before a rejection event occurs, then we can predict rejection and possibly save the transplant. Identifying these different scenarios will help the physician to start treatment in a timely manner and prevent the graft loss. The purpose of this proposal is to test if tracking of particular T cell clones first in the biopsy and non-damagingly in the blood can diagnose rejection or even predict rejection. If we can prove our hypothesis through this proposal, we will then conduct a larger study that will also involve other centers. Success in these stages and our present industry partnership are anticipated to lead to widespread routine use of this technology in all transplant patients. About 7 years are required for the completion of these stages and full global application of this technology. Reduced complications by careful management or prevention of rejection by diagnosing it would make VCA more attractive to patients with severe injuries. This would also improve the quality of life for the patients. Thus, this new technology will benefit Service members, Veterans, and/or their family members, caregivers, or clinicians, as well as the general public and the payers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710679
Entities
People
- Joseph Leventhal
Organizations
- Northwestern University
- United States Army