When rubber meets the road: how innate features of adaptive immune cells play critical roles in transplant alloimmunity Purpose of review Studies on adaptive cells have largely focused on features that are specific to adaptive immunity. However, adaptive cells utilize innate cell features to modulate their responses, and this area of T and B-cell biology is understudied. This review will highlight recent work done to understand how innate features of adaptive immune cells modulate alloimmunity. Recent findings Over the past year, research has shown that T-cell-expressed danger-associated molecular patterns, Toll-like receptors, complement receptors, and Fc receptors regulate T-cell alloimmunity in a cell-intrinsic manner. Further, IL-17 and p40 of IL-12 have been implicated in the migration of T cells into allografts. Lastly, innate B cells, specifically B1 cells, have been shown to produce clinically relevant autoantibody associated with poor graft outcome. Summary These data provide evidence that innate features are utilized by adaptive immune cells to control adaptive alloimmunity.

Adaptive features of innate immune cells and their relevance to graft rejection Purpose of review Allograft rejection involves both innate and adaptive immune cells, and the adaptive immune cells have dominated transplant studies for decades. Recent studies have identified surprising new features for the innate immune cells, including memory recall responses, which may have significant implications in further improvement of transplant outcomes. Recent findings Transplant survival is excellent in the short-term, but the long-term graft outcomes are not so, and most grafts are continuously lost to chronic rejection in the clinic. In both animal models and clinical settings, graft loss to chronic rejection is often dominated by innate immune cells, especially macrophages and natural killer (NK) cells in the grafts. Recent studies suggest that innate immune cells can acquire features of adaptive cells in that they either directly sense allogeneic nonself or become ‘trained’ in the allogeneic milieu, where they show features of memory recall responses. In certain models, targeting the adaptive features of such innate immune cells can promote long-term allograft survival. These findings may open new therapeutic opportunities in promoting transplant survival in the clinic. Summary The discovery of donor specificity and memory recall responses of certain innate immune cells, which are prominently featured in chronic allograft rejection, may open novel therapeutic opportunities in transplantation, as well as in treatment of cancers and autoimmune diseases.

Impact of extracellular vesicles on innate immunity Purpose of review Extracellular vesicles released by prokaryote or eukaryote cells are emerging as mechanisms of cell-to-cell communication, by either physically interacting with the surface of target cells or transferring proteins/peptides, lipids, carbohydrates, and nuclei acids to acceptor cells. Accumulating evidence indicates that extracellular vesicles, among other functions, regulate innate and adaptive immune responses. We revisit here the effects that extracellular vesicles of various origins have on innate immunity. Recent findings Extracellular vesicles comprise a heterogeneous group of vesicles with different biogenesis, composition and biological properties, which include exosomes, microvesicles, apoptotic cell-derived extracellular vesicles, and other extracellular vesicles still not well characterized. Extracellular vesicles released by pathogens, leukocytes, nonhematopoietic cells, tumor cells, and likely allografts, can either stimulate or suppress innate immunity via multiple mechanisms. These include transfer to target leukocytes of pro-inflammatory or anti-inflammatory mediators, membrane receptors, enzymes, mRNAs, and noncoding RNAs; and interaction of extracellular vesicles with the complement and coagulation systems. As a result, extracellular vesicles affect differentiation, polarization, activation, tissue recruitment, cytokine and chemokine production, cytolytic and phagocytic function, and antigen transfer ability, of different types of innate immune cells. Summary The field of intercellular communication via extracellular vesicles is a rapid evolving area and the effects of pathogen-derived and host-derived extracellular vesicles on innate immunity in particular, have received increasing attention during the past decade. Future studies will be necessary to assess the full potential of the crosstalk between extracellular vesicles and the innate immune system and its use for therapeutic applications to treat chronic inflammation-based diseases and cancer growth and dissemination, among the growing list of disorders in which the innate immune system plays a critical role.

Impact of the microbiota on solid organ transplant rejection Purpose of review The microbiota in mammalian hosts can affect maturation and function of the immune system and has been associated with health and disease. We will review new findings on how this dynamic environmental factor impacts alloimmunity and therapy in transplant hosts. Recent findings The microbiota changes after transplantation and immunosuppressive therapy. New data indicate that different microbial community structures have distinct impact on graft outcome, from promoting, to inhibiting or being neutral to transplant survival. In addition, we will address reciprocal interactions between the microbiota and immunosuppressive drugs, as well as the suitability of the microbiota as a predictive biomarker and its utility as adjunct therapy in transplantation. Summary Advances in microbiome sequencing and wider availability of gnotobiotic facilities are enabling mechanistic investigations into the commensal communities and pathways that modulate allograft outcome, responsiveness to immunosuppression and side effects of drugs. A better understanding of the functions of the microbiota may help mitigate drug toxicity, predict drug dosage and dampen alloimmunity in transplant patients.

Innate immunity in ischemia-reperfusion injury and graft rejection Purpose of review Although organ transplantation has become the standard life-saving strategy for patients with end-stage organ failure and those with malignancies, effective and safe therapeutic strategies to combat allograft loss remain to be established. With the emerging evidence suggesting the critical role of innate immunity in the mechanism of allograft injury, we summarize the latest understanding of macrophage-neutrophil cross-communication and discuss therapeutic prospects of their targeting in transplant recipients. Recent findings Macrophages and neutrophils contribute to the pathogenesis of early peritransplant ischemia-reperfusion injury and subsequent allograft rejection immune cascade, primarily by exacerbating inflammatory response and tissue damage. Noteworthy, recent advances enabled to elucidate multifaceted functions of innate immune cells, which are not only deleterious but may also prove graft-protective. Indeed, the efficacy of macrophage polarizing regimens or macrophage-targeted migration have been recognized to create graft-protective local environment. Moreover, novel molecular mechanisms in the neutrophil function have been identified, such as neutrophil extracellular traps, tissue-repairing capability, crosstalk with macrophages and T cells as well as reverse migration into the circulation. Summary As efficient strategies to manage allograft rejection and improve transplant outcomes are lacking, newly discovered, and therapeutically attractive innate immune cell functions warrant comprehensive preclinical and clinical attention.

Linking innate immunity and chronic antibody-mediated allograft rejection Purpose of review To summarize recent findings linking donor-specific antibodies with innate immunity resulting in chronic allograft rejection. Recent findings Studies in recent years highlight the significance of donor-specific antibodies (DSA) in both acute and chronic allograft rejection. Since chronic rejection is the leading cause of graft failure, this review centers on the contribution of three areas of innate immunity of particular recent focus: complement, NK cells, and macrophages. Recent advances indicate the diverse roles that complement components play both in directly initiating allograft injury and indirectly by contributing to enhanced alloreactivity. NK cells also have emerged as an additional innate response that directly links DSA with chronic graft injury. Finally, recent studies identify alternatively activated macrophages as an additional arm of innate immunity contributing to chronic allograft rejection. Summary Chronic allograft rejection involves a significant contribution of DSA and differing pathways of the innate immune system. However, key issues remain unresolved. First, it is not always clear which of these varied sources of innate immunity contributing to chronic rejection may be antibody dependent. Moreover, it is not yet clear if these innate pathways represent independent routes that contribute to chronic rejection or rather act in concert to mediate allograft injury.

The landscape of vascularized composite allograft donation in the United States Purpose of review Vascularized composite allograft (VCA) donation and transplantation has now demonstrated feasibility and impact to the lives of patients suffering from devastating and traumatic injury. This review summarizes the current landscape of VCA donation in the United States. Recent findings VCA donations are nonlife-saving allografts, for nonlife-saving transplants – and therefore, conservative donor selection focused on the optimization of donors for the lowest risk to transplant recipients is paramount. VCA donors in the United States are a demographically and clinically diverse group that largely reflects the characteristics of the VCA candidates waiting for transplants. Public opinion about VCA donation is generally supportive, but has lower support for VCA transplants than for solid organ transplants. Summary As an emerging area of transplantation, VCA donation is evolving in the United States with growing interest by the public, and those suffering from catastrophic injury for which reconstructive transplantation may offer excellent outcomes and a high quality of life.

Psychosocial dimensions of hand transplantation: lessons learned from solid organ transplantation Purpose of review The present review examines psychosocial factors emerging as predictive of clinical outcomes among solid organ transplant (SOT) recipients, with possible extensions to vascular composite allograft (VCA) and hand transplantation, in particular. The Chauvet Workgroup report and International Society of Heart and Lung Transplantation consensus guidelines are used to delineate areas of commonality between SOT and VCA, as well as unique features contributing to post-VCA psychosocial risk. Recent findings Increasing evidence suggests that depression, cognitive function, and other posttransplant psychosocial factors consistently associate with clinical risk in SOT. However, the mechanisms precipitating these psychosocial risk factors are likely diverse in their cause, with large individual differences across SOT and VCA. Transdiagnostic dimensions may serve as mechanistic factors, increasing the risk of adverse clinical outcomes and suggesting potential treatment strategies for risk mitigation. Psychosocial dimensions including psychological flexibility, self-efficacy, and posttraumatic growth are discussed as potential contributory factors. Summary Psychosocial factors hold importance in predicting posttransplant clinical outcomes. Emerging transdiagnostic factors may provide insight into mechanisms and potential treatments.

Vascularized composite allotransplantation versus solid organ transplantation: innate-adaptive immune interphase Purpose of review Vascularized composite allotransplantation (VCA), a life-enhancing treatment for patients with complex tissue defects, trauma or illness, expounds upon the foundation of solid organ transplantation (SOT), the gold standard in end-stage organ failure. As innate and adaptive immunity remain the fundamental concern, this review highlights divergent immunobiology responses in VCA and SOT recipients. Recent findings Host innate immune activation drives peritransplant tissue ischemia–reperfusion injury (IRI). Despite the direct relationship between ischemia–reperfusion (IR)-stress and cell-mediated acute rejection, the mechanism of how IRI may affect VCA loss needs investigation. With skin grafts being highly immunogenic, the incidence of cell-mediated rejection is higher in VCA than SOT; whereas ex-vivo perfusion may exert cytoprotection against IRI in VCA and SOT. New treatment concepts, such as topical immunosuppression or cell-based tolerogenic therapies, may avoid systemic immunosuppression in VCA. Although antibody-mediated rejection is relatively rare in VCA and its disease seems to be distinct from that in SOT, little is known as to whether and how IRI may influence humoral immune rejection cascade in VCA or SOT. Summary Further understanding of the innate-adaptive immune crosstalk should contribute to much needed development of novel therapies to improve VCA outcomes, based on strategies established in SOT.