Characterization and Validation of Non-HLA Antibodies as Noninvasive Biomarkers of Rejection in Vascularized Composite Allotransplantation
Abstract
Vascularized composite allotransplantation (VCA) such as face and upper limb transplantation is associated with 6-fold higher rejection rates than in kidney transplantation. Currently, it is not known why these rejection rates are so high. Since the inception of the VCA field 20 years ago, not much has changed in the means of diagnosing rejection. Usually, the physicians recognize rejection by looking at the transplanted face or limb for different sings such as redness or swelling, together with microscopic evaluation of a small skin tissue specimen (skin biopsy). However, the biopsy causes injury to the tissue and represents only a small part of the transplanted organ. Further, the visible signs of rejection might not be present or are non-specific, that said, unrelated to rejection. Therefore, there is an unmet need to improve the diagnosis of rejection, preferably in a way which does not damage the transplanted face or limb (non-invasive monitoring). The transplant rejection is usually attributed to tissue differences between people, specifically to proteins called human leukocyte antigens (HLA). The patients can eventually develop antibodies against a foreign HLA, which was shown to have a negative impact on the survival of the transplanted organ. Furthermore, there is evidence from other transplanted organs such as kidneys that antibodies against tissue factors (non-HLA antibodies) can also lead to damage and worse outcomes. Most of the face or upper limb transplant recipients (e.g., burn survivors) undergo before transplantation a series of reconstructive surgeries such as skin grafting. We think that those events can lead to the production of skin specific non-HLA antibodies. Since skin is the main target of rejection in VCA, we believe that those non-HLA antibodies should be measurable in blood during rejection as markers of the immune system activation. However, in the field of VCA, not much is known about the role of non-HLA antibodies in rejection, primarily due to a lack of tests that could measure these antibodies. Therefore, this study aims to develop a non-invasive test to measure the non-HLA antibodies in the blood. Following that, we want to take advantage of our unique tissue bank containing blood samples from VCA patients and characterize the non-HLA antibody immune system response. To test how unique this immune response is for VCA, we will also include control samples from healthy people, patients that had received a kidney transplant and patients having injuries to the skin which are not related to rejection (autoimmune skin disease patients). Taken together, we hope to provide novel and detailed insights into the VCA immune system response which may guide the management of VCA recipients. An increasing number of American military service members sustain devastating injuries to face or limbs and could profit from both face or limb transplantation. However, the immunosuppressive burden precludes a wider implementation of those procedures that hold great promise to restore recipients’ quality of life. The appropriate intensity of immunosuppressive treatment is crucial in VCA, since both conditions of over- and underimmunosuppression could have unwanted consequences in this non-life-saving transplant. Our study addresses the focus area of “Reduce the risks of VCA-associated immunotherapy (Identify and/or validate new peripheral biomarkers for early acute and chronic rejection).” If successful, this would be a great advancement not only to better diagnose rejection of VCA but also, in doing so, to be able to tailor immunosuppression drug regimens to the patient. More specifically, tissue injuries which are not related to rejection might be treated with less intensive regimens, such as topical therapy or adjustment of maintenance immunosuppression. On the other hand, strong immune system reactions against the transplant could be targeted earlier with more directed therapies, rather than the empirica
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910316
Entities
People
- Leonardo V Riella
Organizations
- Brigham and Women's Hospital
- United States Army