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We describe our discovery and development of potent and highly selective inhibitors of human constitutive proteasome chymotryptic activity (β5c). Structure-activity relationship studies of the novel class of inhibitors focused on optimization of

Following allogeneic kidney transplantation, a substantial proportion of graft loss is attributed to the formation of donor-specific antibodies and antibody-mediated rejection. B cells infiltrate kidney grafts during antibody-mediated rejection; however, the origins, repertoires, and functions of these intrarenal B cells remain elusive.Here, we use murine allogeneic kidney transplant models to study the origins, transcriptional programming and B cell receptor repertoire of intragraft B cells, and in vitro stimulation assays to evaluate the ability of intragraft B cells to promote CD4+ T cell expansion.B cells infiltrate kidney grafts in settings of allogeneic, but not syngeneic, transplantation. Intragraft B cells have characteristics of activation but are transcriptionally distinct from germinal center B cells and resemble innate-like B cells. B cell receptor sequencing demonstrates that the majority of intragraft B cells do not originate from lymph node germinal center B cells and are largely germline. Class-switched intragraft B cells are rare but can be donor-specific and produce IgG capable of binding to the kidney allograft. Lastly, intrarenal B cells are capable of stimulating naive T cells but have an altered ability to promote T follicular helper cell expansion.Together, these data demonstrate that intrarenal B cells during transplant rejection are transcriptionally distinct from lymph node B cells.

Supplementary Figure 1. In-vivo mouse model's schema; Supplementary Figure 2. Total BLI Flux of SCID.beige myeloma xenograft model and Kaplan-Meier survival analysis of the NSG xenograft model; Supplementary Figure 3. Elotuzumab does not affect myeloma cell proliferation and homing to the bone marrow.

Elotuzumab, a recently approved antibody for the treatment of multiple myeloma, has been shown to stimulate Fcγ receptor (FcγR)-mediated antibody-dependent cellular cytotoxicity by natural killer (NK) cells toward myeloma cells. The modulatory effects of elotuzumab on other effector cells in the tumor microenvironment, however, has not been fully explored. Antibody-dependent cellular phagocytosis (ADCP) is a mechanism by which macrophages contribute to antitumor potency of monoclonal antibodies. Herein, we studied the NK cell independent effect of elotuzumab on tumor-associated macrophages using a xenograft tumor model deficient in NK and adaptive immune cells. We demonstrate significant antitumor efficacy of single-agent elotuzumab in immunocompromised xenograft models of multiple myeloma, which is in part mediated by Fc–FcγR interaction of elotuzumab with macrophages. Elotuzumab is shown in this study to induce phenotypic activation of macrophages in vivo and mediates ADCP of myeloma cells though a FcγR-dependent manner in vitro. Together, these findings propose a novel immune-mediated mechanism by which elotuzumab exerts anti-myeloma activity and helps to provide rationale for combination therapies that can enhance macrophage activity. Mol Cancer Ther; 17(7); 1454–63. ©2018 AACR.

A novel coronavirus has had global impact on individual health and health care delivery. In this C4 article, contributors discuss various aspects of transplantation including donor and recipient screening, management of infected patients, and prevention of coronavirus disease (COVID). Donor screening with SARS-CoV-2 nucleic acid testing (NAT) close to the time of procurement is recommended. Many programs are also screening all potential recipients at the time of admission. The management of COVID has evolved with remdesivir emerging as a new potential option for transplant recipients. Dexamethasone has also shown promise and convalescent plasma is under study. Prevention strategies for transplant candidates and recipients are paramount. Pediatric-specific issues are also discussed. Strategies for the psychological well-being of patients and providers are also imperative, in addition to future research priorities for transplantation.

Background Developing a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells' proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection. Methods Using 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets. Results An exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature's negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell-mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature's negative predictive value was 90.6% and its positive predictive value was 77.8%. Conclusions Our findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.

The neutralizing monoclonal antibody combination of tixagevimab/cilgavimab has been shown to reduce the risk of SARS-CoV-2 infection in unvaccinated individuals during the Alpha (B.1.1.7) and Delta (B.1.617.2) waves. However, data on the efficacy and safety of tixagevimab/cilgavimab in vaccinated solid organ transplant recipients during the Omicron wave is limited. To address this, we conducted a retrospective cohort study comparing 222 solid organ transplant recipients (SOTRs) who received tixagevimab/cilgavimab for pre-exposure prophylaxis and 222 vaccine-matched solid organ transplant recipients who did not receive tixagevimab/cilgavimab. Breakthrough SARS-CoV-2 infections occurred in 11 (5%) of SOTRs who received tixagevimab/cilgavimab and in 32 (14%) of SOTRs in the control group (p .001). In the tixagevimab/cilgavimab group, SOTRs who received the 150-150 mg dose had a higher incidence of breakthrough infections compared to those who received the 300-300 mg dose (p = .025). Adverse events were uncommon, occurring in 4% of our cohort and most were mild. There was no significant change in serum creatinine or liver chemistries in kidney and liver transplant recipients, respectively. In conclusion, we found that tixagevimab/cilgavimab use is safe and associated with a lower risk of breakthrough SARS-CoV-2 infection in vaccinated solid organ transplant recipients during the Omicron wave.

Soon after their discovery in 1972, regulatory T cells (Tregs) appeared as nature’s gift to induce tolerance in auto- and alloimmune settings. We review here the barriers to the use of these bona fide cells and the strategies implanted to overcome them. Tregs are extremely rare and heterogenous, rendering them difficult to isolate and expand in vitro. Furthermore, their adoptive transfer was hurdled by their phenotypic instability and lack of intrinsic survival signals. Most studies in the field have focused on identifying distinctive Tregs markers for their pure isolation. This has also led to the discovery of different subtypes within this regulatory population, such as TR1 cells and CD8 + Tregs. In parallel, a myriad of techniques has been implanted for the targeted delivery of IL-2 as well as the bioengineering of Tregs with antigen-specific chimeric antigen receptors. Despite the drawbacks of the use of Tregs, strategies based on targeted delivery of IL-2 and hijacking conventional CD4 cells into suppressive cells are emerging as a promising tool in the field of transplantation. However, more studies are still required, as the long-term safety and stability of these bioengineered cells remain under investigation.

Induction of longstanding immunologic tolerance is essential for survival of transplanted organs and tissues. Despite recent advances in immunosuppression protocols, allograft damage inflicted by antibody specific for donor organs continues to represent a major obstacle to graft survival. Here we report that activation of regulatory CD8 T cells (CD8 Treg) that recognize the Qa-1 class Ib major histocompatibility complex (MHC), a mouse homolog of human leukocyte antigen-E (HLA-E), inhibits antibody-mediated immune rejection of heart allografts. We analyzed this response using a mouse model that harbors a point mutation in the class Ib MHC molecule Qa-1, which disrupts Qa-1 binding to the T cell receptor (TCR)-CD8 complex and impairs the CD8 Treg response. Despite administration of cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig), Qa-1 mutant mice developed robust donor-specific antibody responses and accelerated heart graft rejection. We show that these allo-antibody responses reflect diminished Qa-1-restricted CD8 Treg-mediated suppression of host follicular helper T cell-dependent antibody production. These findings underscore the critical contribution of this Qa-1/HLA-E-dependent regulatory pathway to maintenance of transplanted organs and suggest therapeutic approaches to ameliorate allograft rejection.

The programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway is a potent inhibitory pathway involved in immune regulation and is a potential therapeutic target in transplantation. In this study, we show that overexpression of PD-1 on T cells (PD-1 Tg) promotes allograft tolerance in a fully MHC-mismatched cardiac transplant model when combined with costimulation blockade with CTLA-4-Ig. PD-1 overexpression on T cells also protected against chronic rejection in a single MHC II-mismatched cardiac transplant model, whereas the overexpression still allowed the generation of an effective immune response against an influenza A virus. Notably, Tregs from PD-1 Tg mice were required for tolerance induction and presented greater ICOS expression than those from WT mice. The survival benefit of PD-1 Tg recipients required ICOS signaling and donor PD-L1 expression. These results indicate that modulation of PD-1 expression, in combination with a costimulation blockade, is a promising therapeutic target to promote transplant tolerance.

Renal transplantation is the preferred therapy for patients with end-stage kidney disease, leading to increased life expectancy, improved quality of life, and reduced health care resource use. Owing to their preexisting burden of disease, caring for renal transplant recipients is complex. Patient management following successful renal transplantation involves a multifactorial approach to cardiovascular risk factor management, along with titration of immunosuppression, management of complications related to immunosuppression, and active monitoring of allograft function. Recent advances in immunosuppressive management hold promise for improved long-term allograft survival. Finally, immune monitoring of transplant recipients is an area of considerable research, with the ultimate aim of individualized management of immunosuppression and the ability to induce transplant-specific tolerance. This review contains 7 figures, 11 tables, and 119 references. Key words: cardiovascular disease, drug interactions, immunosuppression, infection, interstitial fibrosis and tubular atrophy, malignancy, rejection, tolerance

Heart transplantation is the optimal therapy for patients with end-stage heart disease, but its long-term outcome remains inadequate. Recent studies have highlighted the importance of the melanocortin receptors (MCRs) in inflammation, but how MCRs regulate the balance between alloreactive T cells and Tregs, and whether they impact chronic heart transplant rejection, is unknown. Here, we found that Tregs express MC2R, and MC2R expression was highest among all MCRs by Tregs. Our data indicate that adrenocorticotropic hormone (ACTH), the sole ligand for MC2R, promoted the formation of Tregs by increasing the expression of IL-2Rα (CD25) in CD4+ T cells and activation of STAT5 in CD4+CD25+ T cells. ACTH treatment also improved the survival of heart allografts and increased the formation of Tregs in CD28KO mice. ACTH treatment synergized with the tolerogenic effect of CTLA-4-Ig, resulting in long-term survival of heart allografts and an increase in intragraft Tregs. ACTH administration also demonstrated higher prolongation of heart allograft survival in transgenic mouse recipients with both complete KO and conditional KO of PI3Kγ in T cells. Finally, ACTH treatment reduced chronic rejection markedly. These data demonstrate that ACTH treatment improved heart transplant outcomes, and this effect correlated with an increase in Tregs.

Background: Transplantation is the treatment of choice for many patients with end-stage organ disease. Despite advances in immunosuppression, long-term outcomes remain suboptimal, hampered by drug toxicity and immune-mediated injury, the leading cause of late graft loss. The development of therapies that promote regulation while suppressing effector immunity is imperative to improve graft survival and minimize conventional immunosuppression. Notch signaling is a highly conserved pathway pivotal to T-cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell–mediated immunity. Methods: We investigated the pattern of Notch-1 expression in effector and regulatory T cells (Tregs) in both murine and human recipients of a solid-organ transplant. Using a selective human anti-Notch-1 antibody (aNotch-1), we examined the effect of Notch-1 receptor inhibition in full major histocompatibility complex–mismatch murine cardiac and lung transplant models, and in a humanized skin transplant model. On the basis of our findings, we further used a genetic approach to investigate the effect of selective Notch-1 inhibition in Tregs. Results: We observed an increased proportion of Tregs expressing surface and intracellular (activated) Notch-1 in comparison with conventional T cells, both in mice with transplants and in the peripheral blood of patients with transplants. In the murine cardiac transplant model, peritransplant administration of aNotch-1 (days 0, 2, 4, 6, 8, and 10) significantly prolonged allograft survival in comparison with immunoglobulin G–treated controls. Similarly, aNotch-1 treatment improved both histological and functional outcomes in the murine lung transplant model. The use of aNotch-1 resulted in a reduced proportion of both splenic and intragraft conventional T cells, while increasing the proportion of Tregs. Furthermore, Tregs isolated from aNotch-1–treated mice showed enhanced suppressive function on a per-cell basis, confirmed with selective Notch-1 deletion in Tregs (Foxp3 EGFPCre Notch1 fl/fl ). Notch-1 blockade inhibited the mammalian target of rapamycin pathway and increased the phosphorylation of STAT5 (signal transducer and activator of transcription 5) in murine Tregs. Notch-1 low Tregs isolated from human peripheral blood exhibited more potent suppressive capacity than Notch-1 high Tregs. Last, the combination of aNotch-1 with costimulation blockade induced long-term tolerance in a cardiac transplant model, and this tolerance was dependent on CTLA-4 (cytotoxic T-lymphocyte–associated antigen-4) signaling. Conclusions: Our data reveal a promising, clinically relevant approach for immune modulation in transplantation by selectively targeting Notch-1.

After more than 6 decades of clinical practice, the transplant community continues to research noninvasive biomarkers of solid organ injury to help improve patient care. In this review, we discuss the clinical usefulness of selective biomarkers and how they are processed at the laboratory. In addition, we organize these biomarkers based on specific aims and introduce innovative markers currently under investigation.

BackgroundConversion from tacrolimus to belatacept has been shown to be beneficial for an increasing number of kidney transplant (KT) patients. Predicting factors for favorable outcomes are still unknown. We aimed to investigate whether histological vascular lesions at the time of conversion might correlate with greater improvement in renal function post-conversion.MethodsThe study was conducted on a retrospective cohort of 34 KT patients converted from tacrolimus to belatacept. All patients underwent an allograft biopsy prior to conversion. We analyzed the evolution of the estimated glomerular filtration rate (eGFR) at 3 and 12 months after conversion.ResultsMedian time to conversion was 6 (2–37.2) months post-transplant. About 52.9% of patients had moderate-to-severe chronic vascular lesions (cv2–3). We observed an increase in eGFR in the whole cohort from 35.4 to 41 mL/min/1.73 m2 at 3 months (P = 0.032) and 43.7 at 12 months (P = 0.013). Nine patients experienced acute rejection post-conversion, with one graft loss observed beyond the first year after conversion. Patients with cv2–3 had significant improvement in eGFR at 12 months (+8.6 mL/min/1.73 m2; 31.6 to 40.2 mL/min/1.73 m2; P = 0.047) compared with those without these lesions (+6.8 mL/min/1.73 m2; 40.9 to 47.7 mL/min/1.73 m2; P = 0.148).ConclusionsConversion from tacrolimus to belatacept has a beneficial effect in terms of renal function in KT patients. This benefit might be more significant in patients with cv in the biopsy.

New Onset Diabetes After Transplantation (NODAT) is a serious metabolic complication. While β-cell dysfunction is considered the main contributing factor in the development of NODAT, the precise pathogenesis is not well understood. Cytokines are thought to be involved in the inflammation of islet β-cells in diabetes; however, few studies have investigated this hypothesis in NODAT. A total of 309 kidney transplant recipients (KTRs) were included in this study. An association between kidney transplants, and the development of diabetes after transplant (NODAT) was investigated. Comparison was made between KTRs who develop diabetes (NODAT cases) or did not develop diabetes (control), using key cytokines, IL-6 G (− 174)C, macrophage mediator; IL-4 C (− 490)T, T helper (Th)-2 cytokine profile initiator; Th-1 cytokine profile initiator interferon-γ T (+ 874) A gene and TGF β1 C (+ 869) T gene polymorphisms were investigated. The genes were amplified using well-established polymerase chain reaction (PCR) techniques in our laboratory. Compared to the AA and AT genotypes of interferon gamma (IFNG), there was a strong association between the TT genotype of IFNG and NODAT kidney transplant recipients (KTRs) versus non-NODAT KTRs (p = 0.005). The AA genotype of IFNG was found to be predominant in the control group (p = 0.004). Also, significant variations of IL6 G (− 174) C, IL-4 C (− 590) T, interferon-γ T (+ 874) A gene and transforming growth factor β1 C (+ 869) T may contribute to NODAT. Our data is consistent with theTh-1/T-reg pathway of immunity. Further larger pan Arab studies are required to confirm our findings.

Context: Chronic immunosuppression is associated with an increased risk of opportunistic infections. Although kidney transplant recipients with coronavirus disease 2019 (COVID-19) have higher mortality than the general population, data on their risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are unknown. Subject of Review: A recent single-center screening study from the UK (Transplantation. 2021 Jan 1;105(1):151–7) showed that 89 (10.4%) of 855 consecutive kidney transplant recipients tested positive for SARS-CoV-2 antibodies. Risk factors for infection included a nonwhite background, diabetes, and a history of allograft rejection. Risk factors for mortality in individuals who developed COVID-19 were older age and receiving steroids. Second Opinion: This study shows that the rate of SARS-CoV-2 infection in kidney transplant recipients is similar to the one observed in the general population in the same area (13%), indicating that transplant recipients are not at increased risk of COVID-19. However, the investigators raise the interesting point that since transplant individuals were advised to shelter earlier than the general population, they may be in fact more susceptible. This statement is hard to substantiate, but the identification of specific risk factors for infection and poor outcomes is crucial to tailor strategies to prevent spread of the infection. This is particularly important, considering that kidney transplant recipients may be at increased risk of prolonged viral spread and in-host viral mutations, making them not just a particularly fragile population for COVID-19 but also a potentially major source of further contagions.

An unprecedented global pandemic caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) has quickly overwhelmed the health care systems worldwide. While there is an absence of consensus among the community in how to manage solid organ transplant recipients and donors, a platform provided by the American Society of Transplantation online community “Outstanding Questions in Transplantation”, hosted a collaborative multicenter, multinational discussions to share knowledge in a rapidly evolving global situation. Here, we present a summary of the discussion in addition to the latest published literature.

Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. Current immunosuppression protocols are not designed to target antigen-specific alloimmunity and are uncapable of preventing chronic allograft injury. As myeloid-derived suppressor cells (MDSCs) are potent immunoregulatory cells, we tested whether donor-derived MDSCs can protect heart transplant allografts in an antigen-specific manner. C57BL/6 (H2Kb, I-Ab) recipients pre-treated with BALB/c MDSCs were transplanted with either donor-type (BALB/c, H2Kd, I-Ad) or third-party (C3H, H2Kk, I-Ak) cardiac grafts. Spleens and allografts from C57BL/6 recipients were harvested for immune phenotyping, transcriptomic profiling and functional assays. Single injection of donor-derived MDSCs significantly prolonged the fully MHC mismatched allogeneic cardiac graft survival in a donor-specific fashion. Transcriptomic analysis of allografts harvested from donor-derived MDSCs treated recipients showed down-regulated proinflammatory cytokines. Immune phenotyping showed that the donor MDSCs administration suppressed effector T cells in recipients. Interestingly, significant increase in recipient endogenous CD11b+Gr1+ MDSC population was observed in the group treated with donor-derived MDSCs compared to the control groups. Depletion of this endogenous MDSCs with anti-Gr1 antibody reversed donor MDSCs-mediated allograft protection. Furthermore, we observed that the allogeneic mixed lymphocytes reaction was suppressed in the presence of CD11b+Gr1+ MDSCs in a donor-specific manner. Donor-derived MDSCs prolong cardiac allograft survival in a donor-specific manner via induction of recipient’s endogenous MDSCs.

Lung allograft rejection results in the accumulation of low-molecular weight hyaluronic acid (LMW-HA), which further propagates inflammation and tissue injury. We have previously shown that therapeutic lymphangiogenesis in a murine model of lung allograft rejection reduced tissue LMW-HA and was associated with improved transplant outcomes. Herein, we investigated the use of 4-Methylumbelliferone (4MU), a known inhibitor of HA synthesis, to alleviate acute allograft rejection in a murine model of lung transplantation. We found that treating mice with 4MU from days 20 to 30 after transplant was sufficient to significantly improve outcomes, characterized by a reduction in T cell-mediated lung inflammation and LMW-HA content and in improved pathology scores. In vitro, 4MU directly attenuated activation, proliferation, and differentiation of naive CD4+ T cells into Th1 cells. As 4MU has already been demonstrated to be safe for human use, we believe examining 4MU for the treatment of acute lung allograft rejection may be of clinical significance.

Precursor states of Multiple Myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, MGUS and smoldering myeloma (SMM), to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find NK cell abundance is frequently increased in early stages, and associated with altered chemokine receptor expression. As early as SMM, we show loss of GrK(+) memory cytotoxic T-cells, and show their critical role in MM immunosurveillance in mouse models. Finally, we report MHC class II dysregulation in CD14(+) monocytes, which results in T cell suppression in vitro. These results provide a comprehensive map of immune changes at play over the evolution of pre-malignant MM, which will help develop strategies for immune-based patient stratification.

Elotuzumab, a recently approved antibody for the treatment of multiple myeloma, has been shown to stimulate Fcγ receptor (FcγR)-mediated antibody-dependent cellular cytotoxicity by natural killer (NK) cells toward myeloma cells. The modulatory effects of elotuzumab on other effector cells in the tumor microenvironment, however, has not been fully explored. Antibody-dependent cellular phagocytosis (ADCP) is a mechanism by which macrophages contribute to antitumor potency of monoclonal antibodies. Herein, we studied the NK cell independent effect of elotuzumab on tumor-associated macrophages using a xenograft tumor model deficient in NK and adaptive immune cells. We demonstrate significant antitumor efficacy of single-agent elotuzumab in immunocompromised xenograft models of multiple myeloma, which is in part mediated by Fc–FcγR interaction of elotuzumab with macrophages. Elotuzumab is shown in this study to induce phenotypic activation of macrophages in vivo and mediates ADCP of myeloma cells though a FcγR-dependent manner in vitro. Together, these findings propose a novel immune-mediated mechanism by which elotuzumab exerts anti-myeloma activity and helps to provide rationale for combination therapies that can enhance macrophage activity. Mol Cancer Ther; 17(7); 1454–63. ©2018 AACR.

PURPOSE OF REVIEW The main objective of this review is to briefly highlight how we gradually came to understand regulatory T cells (Tregs) and forkhead box p3 (FoxP3) biology, including their function and regulation. We will also discuss how this knowledge is being translated into the clinical setting and the significant challenges that need to be overcome. RECENT FINDINGS CD4FoxP3 Tregs are key players in immune regulation. Their deficiency and dysfunction have been implicated in the pathogenesis of many autoimmune diseases. This has led towards extensive work across the years to figure out the biology and suppressive mechanisms of these cells. Furthermore, Tregs' ability to suppress immune responses makes the idea of their utilization in adoptive immunotherapy appealing. Work has been underway to establish ideal methods to integrate Tregs into the management of autoimmune diseases and alloimmunity, either by treatment with IL-2 or infusion of ex-vivo expanded Tregs. Despite Tregs' scarcity and increased tendency for Activation-induced cell death, many groups have developed effective methods to expand them ex vivo. SUMMARY Although clinical trials are ongoing to test the safety and efficacy of regulatory cells in transplant recipients, it is vital to continue exploring the cellular and molecular mechanisms that control their stability and homeostasis.

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.