Older organs represent an untapped potential to close the gap between demand and supply in organ transplantation but are associated with age-specific responses to injury and increased immunogenicity, thereby aggravating transplant outcomes. Here we show that cellfree mitochondrial DNA (cf-mt-DNA) released by senescent cells accumulates with aging and augments immunogenicity. Ischemia reperfusion injury induces a systemic increase of cfmt-DNA that promotes dendritic cell-mediated, age-specific inflammatory responses. Comparable events are observed clinically, with the levels of cf-mt-DNA elevated in older deceased organ donors, and with the isolated cf-mt-DNA capable of activating human dendritic cells. In experimental models, treatment of old donor animals with senolytics clear senescent cells and diminish cf-mt-DNA release, thereby dampening age-specific immune responses and prolonging the survival of old cardiac allografts comparable to young donor organs. Collectively, we identify accumulating cf-mt-DNA as a key factor in inflamm-aging and present senolytics as a potential approach to improve transplant outcomes and availability.

The advent of more potent immunosuppressants led to the first successful human upper extremity transplantation in 1998. At this time, > than 100 upper extremity transplants, 30 face transplants and a variety of other vascularized composite allotransplantation (VCA) procedures have been performed around the world. VCA recipients present unique challenges for transplantation. The incidence of acute rejection exceeds 80% in hand and face transplantation and is well documented, whereas reports about antibody-mediated rejection and chronic rejection remain scarce. Immunosuppression protocols commonly used at US centers are derived from solid organ transplantation protocols. Novel approaches to minimize rejections in VCA may include improved HLA matching and considerations towards cytomegalovirus infection status. New graft preservation techniques may decrease immunogenicity prior to transplant. Novel monitoring methods such as valid biomarkers, ultrasound biomicroscopy and sentinel flaps may enable earlier diagnosis of rejection. Cell-based therapies are being explored in order to achieve immunosuppressive regimen minimization or even tolerance induction. The efficacy of local immunosuppression in clinical VCA remains controversial. In conclusion, although immunosuppressive strategies adapted from SOT have demonstrated good mid-term results, focusing on the unique features of VCA grafts may enable additional, more specific treatment strategies in the future and improved long-term graft outcomes.

CD4+ CD25+ Foxp3+ Tregs have been shown to play a central role in immune homeostasis while preventing from fatal inflammatory responses, while Th17 cells have traditionally been recognized as pro-inflammatory mediators implicated in a myriad of diseases. Studies have shown the potential of Tregs to convert into Th17 cells, and Th17 cells into Tregs. Increasing evidence have pointed out CD25 as a key molecule during this transdifferentiation process, however molecules that allow such development remain unknown. Here, we investigated the impact of NAD+ on the fate of CD4+ CD25+ Foxp3+ Tregs in-depth, dissected their transcriptional signature profile and explored mechanisms underlying their conversion into IL-17A producing cells. Our results demonstrate that NAD+ promotes Treg conversion into Th17 cells in vitro and in vivo via CD25 cell surface marker. Despite the reduced number of Tregs, known to promote homeostasis, and an increased number of pro-inflammatory Th17 cells, NAD+ was able to promote an impressive allograft survival through a robust systemic IL-10 production that was CD4+ CD25+ Foxp3+ independent. Collectively, our study unravels a novel immunoregulatory mechanism of NAD+ that regulates Tregs fate while promoting allograft survival that may have clinical applications in alloimmunity and in a wide spectrum of inflammatory conditions.

Consequences of aging are gaining clinical relevance. In transplantation, aging and immunosenescence impact treatment and outcomes. The impact of aging, however, will critically depend on distinguishing healthy, chronological aging from biological aging that may result into frailty. Approximately 15% of individuals older than 65 years are frail, and it is expected that this condition will gain more clinical relevance with an expected increase to greater than 20% over the next 5 years. Clearly, frailty impacts various general aspects of health care and organ transplantation in particular including patient selection, waitlist management and treatment after transplantation. In general, frailty has been characterized by a compromised physiological reserve and an augmented vulnerability. In comparison to healthy aging, inflammatory markers and cytokines are increased in frail older adults. Thus, modifications of the immune response, in addition to physical limitations and changes of metabolism, are likely to impact outcomes after transplantation. Here, we provide a risk assessment of frailty at the time of transplant evaluation and review effects on outcomes and recovery after transplantation. Moreover, we summarize our current understanding of the pathophysiology of frailty and consequences on immune responses and metabolism.

NK cell receptors play a critical role in the homeostasis of antigen-experienced T cells. Indeed, prolonged antigen stimulation may induce changes in the receptor repertoire of T cells to a profile that features NK cells receptors (NKRs). Chronic antigen exposure, at the same time, has been shown to trigger the loss of co-stimulatory CD28 molecules with recently reported intensified antigen thresholds of antigen-experienced CD8+ T cells. In transplantation, NKRs have been shown to assist allograft rejection in a CD28-independent fashion. Here, we discuss a role for CD28-negative T cells that have acquired the competency of the NKR machinery, potentially promoting allorecognition either through TCR cross-reactivity or independently from TCR recognition. Collectively, NKRs can bring about innate-like T cells by providing alternative co-stimulatory pathways that gain significance in chronic inflammation, potentially leading to resistance to CD28-targeting immunosuppressants.

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor Tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T-cells. Old recipient mice exhibited prolonged skin graft survival when compared to young animals following TAC administration. More importantly, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce pro-inflammatory IFN-γ cytokine production and promote IL-10 production in old CD4+ T-cells. In addition, TAC administration decreased IL-2 secretion in old CD4+ T-cells more effectively while inhibiting the proliferation of CD4+ T-cells in old mice. Both, TAC treated murine and human CD4+ T-cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+-influx, two critical pathways in T-cell activation. Of note, depletion of CD8+ T-cells did not alter allograft survival outcome in old TAC treated mice, suggesting that TAC age-specific effects were mainly CD4+ T-cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T-cell mediated. The suppression of calcineurin levels and Ca2+-influx in both, old murine and human T-cells emphasizes on the clinical relevance of age-specific effects when utilizing TAC.

Purpose of review With global demographic changes and an overall improved healthcare, more older end-stage-renal-disease (ESRD) patients receive kidney transplants. At the same time, organs from older donors are utilized more frequently. Those developments have and will continue to impact allocation, immunosuppression and efforts improving organ quality. Recent findings Findings mainly outside the field of transplantation have provided insights into mechanisms that drive immunosenescence and immunogenicity, thus providing a rationale for an age-adapted immunosuppression and relevant clinical trials in the elderly. With fewer rejections in the elderly, alloimmune responses appear to be characterized by a decline in effectiveness and an augmented unspecific immune response. Summary Immunosenescence displays broad and ambivalent effects in elderly transplant recipients. Those changes appear to compensate a decline in allospecific effectiveness by a shift towards an augmented unspecific immune response. Immunosuppression needs to target those age-specific changes to optimize outcomes in elderly transplant recipients,

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