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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.

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.

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.

There has been a prolific amount of research dedicated to the T-regulatory cells (Tregs) and their role in achieving immune homeostasis. Here, the authors briefly discuss the known biology, utilization, and potential of Tregs, for current trials and future immunotherapy. Most current trials of Treg therapies include either ex vivo expanded Tregs transferred into the peripheral blood of patients with diseases of immunologic origin or interleukin 2 injected to stimulate Tregs directly. Ongoing trials designed to measure the clinical efficacy and safety profile of these novel therapeutic approaches have resulted in largely favorable outcomes in a variety of autoimmune and alloimmune diseases.