Codominant Role of Interferon‐γ– and Interleukin‐17–Producing T Cells During Rejection in Full Facial Transplant Recipients

Abstract

Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean followup of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti-HLA antibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon-c/interleukin-17–producing cells in peripheral blood and in the allograft’s skin. Serum monocyte chemotactic protein-1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novo donor-specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon-γ/interleukin-17–mediated acute cellular rejection process. Despite that, medium-term outcomes are promising with no evidence of de novo donor-specific antibody development.

Immunological Characteristics of a Patient With Belatacept-Resistant Acute Rejection After Face Transplantation

“…We see a potentially deleterious effect of belatacept on Tregs upon conversion as indicated by others (2) but at the same time, belatacept seems to effectively suppress Tfh cells, which may reduce the risk of antibody-mediated rejection (3). The increase in Th17 and Th1 subsets upon rejection episodes after belatacept conversion ties into other findings regarding BRR (4) and cellular rejections in face transplant recipients (5). Different than kidney transplantation, CD57 + PD1 − subset before transplantation did not predict belatacept-resistant rejection in face transplantation.…”

Adipose-derived stromal cell therapy combined with a short course nonmyeloablative conditioning promotes long-term graft tolerance in vascularized composite allotransplantation

“…Different cytokines have potential as markers for acute rejection . We observed increased values for several cytokines (IL‐1β, IL‐2, TNF‐α, IP‐10, and MCP‐1) at 3 weeks in animals rejecting early.…”

Longitudinal immunological characterization of the first presensitized recipient of a face transplant

“…Surprisingly, even though antithymocyte globulin targets multiple T cell markers, including CD3, circulating Tfh cells were preserved and an expansion of memory B cells was observed, potentially contributing to the antibody response, although the definitive role of circulating Tfh cells in DSA generation is unclear (29,30). Interestingly, the lack of Tfh cell depletion was also present in other face transplant recipients treated with antithymocyte globulin at the first week after transplant (23). A possible explanation for the absence of DSAs during follow-up is related to the multiple (repeated) rejection treatments the patient received for AMR initially and then TCMRs.…”

“…This is in agreement with our hypothesis that cellular and molecular mechanisms underlying AMR and TCMR are different. Indeed, despite complete depletion of T effector cells after antithymocyte globulin in face transplant recipients early after transplant (23), AMR still occurred due to the presence of DSAs, likely triggering injury through complement activation and/or Fc-mediated cytotoxicity (8). Surprisingly, even though antithymocyte globulin targets multiple T cell markers, including CD3, circulating Tfh cells were preserved and an expansion of memory B cells was observed, potentially contributing to the antibody response, although the definitive role of circulating Tfh cells in DSA generation is unclear (29,30).…”