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Modern treatment strategies for the maintenance of allograft acceptance frequently target ubiquitously‐expressed pathways, leading to significant side‐effects and poor long‐term allograft outcomes. Constitutive proteasome inhibitors, which have recently been introduced for the treatment of antibody‐mediated rejection, target the ubiquitously‐expressed proteasome. To limit off‐target effects and serious mechanism‐based toxicity, however, these inhibitors are administered intermittently and suboptimally. Immunoproteasomes, which are an inducible subset of proteasomes enriched in immune cells, replace constitutive proteasomes after cell exposure to proinflammatory cytokines such as interferon‐γ. While immunoproteasomes were first described as processors of antigen for presentation by major histocompatibility complex molecules, recent findings point to its broader biological roles. These vary from activating different subsets of the immune system, by controlling transcriptional activators and downstream cytokines, to affecting their differentiation and survival. These emerging roles of the immunoproteasome in activated immune cells have made it a rational candidate for the targeted treatment of immune‐mediated diseases. Preclinical studies have established its role in maintaining allograft acceptance without significant short‐ or long‐term toxicity. This review provides a brief background of the immunoproteasome and outlines its role in immunological pathways and its potential in alloimmunity. Eskandari et al summarize the current knowledge of proteasomes, immunoproteasomes, and their potential role in alloimmunity.

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 follow‐up 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‐HLAantibodies, 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‐γ/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 novodonor‐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 novodonor‐specific antibody development. In this study, the authors characterize the immune responses of six patients who underwent face transplantation and find that an increase in both IFN‐γ/IL‐17–producing cells in peripheral blood and in the allograft's skin with a concomitant peak in serum MCP‐1 levels and a reduction in circulating Th2 cells characterizes acute cellular rejection.

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 follow‐up 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‐γ/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 novodonor‐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 novodonor‐specific antibody development.

The clonal expansion of effector T cells and subsequent generation of memory T cells are critical in determining the outcome of transplantation. While cytotoxic T lymphocytes induce direct cytolysis of target cells through secretion of Granzyme-B (GrB), they also express cytoplasmic serine protease inhibitor-6 (Spi6) to protect themselves from GrB that has leaked from granules. Here, we studied the role of GrB/Spi6 axis in determining clonal expansion of alloreactive CD8-T cells and subsequent generation of memory CD8-T cells in transplantation. CD8-T cells from Spi6−/−mice underwent more GrB mediated apoptosis upon alloantigen stimulation in vitroand in vivofollowing adoptive transfer into an allogeneic host. Interestingly, while OT1.Spi6−/−CD8 T cells showed significantly lower clonal expansion following skin transplants from OVA mice, there was no difference in the size of the effector memory CD8-T cells long after transplantation. Furthermore, lack of Spi6 resulted in a decrease of short-lived-effector-CD8-cells but did not impact the pool of memory-precursor-effector-CD8-cells. Similar results were found in heart transplant models. Our findings suggest that the final alloreactive CD8-memory-pool-size is independent from the initial clonal-proliferation as memory precursors express low levels of GrB and therefore are independent of Spi6 for survival. These data advance our understanding of memory T cells generation in transplantation and provide basis for Spi6 based strategies to target effector T cells.

Using in vitroand in vivomurine heart and skin transplant models, this study describes the key role of the serine protease inhibitor‐6 in protecting CD8 alloreactive cytotoxic T cells from granzyme B–mediated self‐inflicted damage. See editorial by Ashton‐Rickardt on page 13.

The PD1:PDL1 pathway is an essential negative costimulatory pathway that plays a key role in regulating the alloimune response. PDL1 is expressed not only on antigen‐presenting cells (APCs) but also cardiac endothelium. In this study, we investigated the importance of PDL1 expression on donor cardiac allograft in acquired transplantation tolerance in a fully MHC‐mismatched model. We generated PDL1 chimeric mice on B6 background that expressed PDL1 on either hematopoietic cells or nonhematopoietic cells of the heart. Sham animals were used as controls. These hearts were then transplanted into BALB/c recipients and treated with CTLA4‐Ig to induce tolerance. Cardiac endothelium showed significant expression of PDL1, which was upregulated upon transplantation. While the absence of PDL1 on hematopoietic cells of the heart resulted in delayed rejection and prevented long‐term tolerance in most but not all recipients, we observed an accelerated and early graft rejection of all donor allografts that lacked PDL1 on the endothelium. Moreover, PDL1‐deficient endothelium hearts had significant higher frequency of IFN‐γ‐producing alloreactive cells as well as higher frequency of CD8+effector T cells. These findings demonstrate that PDL1 expression mainly on donor endothelium is functionally important in a fully allogeneic mismatched model for the induction of cardiac allograft tolerance.

The PD1:PDL1 pathway is an essential negative costimulatory pathway that plays a key role in regulating the alloimune response. PDL1 is expressed not only on antigen-presenting cells (APCs) but also cardiac endothelium. In this study, we investigated the importance of PDL1 expression on donor cardiac allograft in acquired transplantation tolerance in a fully MHC-mismatched model. We generated PDL1 chimeric mice on B6 background that expressed PDL1 on either hematopoietic cells or nonhematopoietic cells of the heart. Sham animals were used as controls. These hearts were then transplanted into BALB/c recipients and treated with CTLA4-Ig to induce tolerance. Cardiac endothelium showed significant expression of PDL1, which was upregulated upon transplantation. While the absence of PDL1 on hematopoietic cells of the heart resulted in delayed rejection and prevented long-term tolerance in most but not all recipients, we observed an accelerated and early graft rejection of all donor allografts that lacked PDL1 on the endothelium. Moreover, PDL1-deficient endothelium hearts had significant higher frequency of IFN-γ-producing alloreactive cells as well as higher frequency of CD8+effector T cells. These findings demonstrate that PDL1 expression mainly on donor endothelium is functionally important in a fully allogeneic mismatched model for the induction of cardiac allograft tolerance.

Ischemic reperfusion injury (IRI) enhances allograft immunogenicity, worsens transplantation outcome, and is the primary cause of activation of the recipient innate immune response, resulting in subsequent amplification of the alloimmune adaptive response. Here, we aimed at demonstrating that the link between innate injury and alloimmunity occurs predominantly through activation of allograft‐derived dendritic cells (ADDC). Perfusion of MCI‐186, a free radical scavenger, into donor cardiac allografts prior to transplantation resulted in prolongation of complete MHC‐mismatched allograft survival in the absence of immunosuppression (MST of 8 vs. 26 days). This prolongation was associated with a reduction in trafficking of ADDC to recipient lymphoid tissue as well as a reduction in T cell priming. Depleting ADDC with diphtheria toxin (using DTR‐GFP‐DC mice as donors) 24 h prior to transplant resulted in abrogation of the prolongation observed with MCI‐186 treatment, demonstrating that the beneficial effect of MCI‐186 is mediated by ADDC. This donor‐specific anti‐ischemic regimen was also shown to reduce chronic rejection, which represents the primary obstacle to long‐term allograft acceptance. These data for the first time establish a basis for donor anti‐ischemic strategies, which in the ever‐expanding marginal donor pools, can be instituted to promote engraftment.

Ischemic reperfusion injury (IRI) enhances allograft immunogenicity, worsens transplantation outcome, and is the primary cause of activation of the recipient innate immune response, resulting in subsequent amplification of the alloimmune adaptive response. Here, we aimed at demonstrating that the link between innate injury and alloimmunity occurs predominantly through activation of allograft-derived dendritic cells (ADDC). Perfusion of MCI-186, a free radical scavenger, into donor cardiac allografts prior to transplantation resulted in prolongation of complete MHC-mismatched allograft survival in the absence of immunosuppression (MST of 8 vs. 26 days). This prolongation was associated with a reduction in trafficking of ADDC to recipient lymphoid tissue as well as a reduction in T cell priming. Depleting ADDC with diphtheria toxin (using DTR-GFP-DC mice as donors) 24 h prior to transplant resulted in abrogation of the prolongation observed with MCI-186 treatment, demonstrating that the beneficial effect of MCI-186 is mediated by ADDC. This donor-specific anti-ischemic regimen was also shown to reduce chronic rejection, which represents the primary obstacle to long-term allograft acceptance. These data for the first time establish a basis for donor anti-ischemic strategies, which in the ever-expanding marginal donor pools, can be instituted to promote engraftment.