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. Correspondence to Maria-Luisa Alegre, MD, PhD, Department of Medicine, University of Chicago, 924 E. 57th Street, JFK-R312, Chicago, IL 60637, USA. Tel: +1 773 834 4317; e-mail: malegre@midway.uchicago.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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. Correspondence to Macey L. Henderson, JD, PhD, Assistant Professor of Surgery, Johns Hopkins School of Medicine, Director of Policy and External Affairs, The Epidemiology Research Group in Organ Transplantation, 2000 E Monument Street, Baltimore, MD 21205, USA. Tel: +1 443 287 6649; fax: +1 410 630 7217; e-mail: macey@jhmi.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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. Correspondence to Jerzy W. Kupiec-Weglinski, MD, PhD, The Dumont-UCLA Transplantation Research Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, CHS 47-200H, Los Angeles, CA 90095, USA. Tel: +1 310 825 4196; e-mail: jkupiec@mednet.ucla.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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. Correspondence to Mandy L. Ford, PhD, Emory University School of Medicine, Atlanta, Georgia, USA. Tel: +1 404 727 2900; e-mail: Mandy.ford@emory.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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. Correspondence to Xian C. Li, MD, PhD, Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, R7-211, Houston, TX 77030, USA. E-mail: xcli@houstonmethodist.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.