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A BSTRACT Background Transplantation of a cardiac allograft from an infected donor risks transmission of disease to the immunocompromised recipient. Such organs are often not utilized despite little supporting evidence. We sought to evaluate outcomes following cardiac transplant with the use of an infected allograft. Methods The UNOS/OPTN database was used to identify first time, adult heart transplant recipients from 1995 to 2009. Patients receiving allografts from blood culture positive donor (CPD) were compared to those who did not (NCPD). Results A total of 26,813 recipients were included. Nine hundred ninety-five (3.7%) received a heart from a CPD. Recipients of hearts from CPDs were more likely to be diabetic (24% vs. 20%, p = 0.01), hypertensive (42% vs. 38%, p = 0.02), status 1 (80% vs. 76%, p = 0.0021), have a BMI > 30 (19% vs. 16%, p = 0.001), on intra-aortic balloon pump (IABP) support (7% vs. 5%, p = 0.017), and worse functional status. Recipients with a CPD were more likely to be treated for a post-transplant infection (28% vs. 23%, p = 0.003) but not for an episode of rejection in the first year after transplantation (39% vs. 40%, p = 0.73). Receipt of a CPD allograft was not a multivariate predictor for mortality. CPD and NCPD survival was similar at one year (86% vs. 87%, p = 0.2585) and 15 years (34% vs. 36%, p = 0.0929). Conclusion Use of allografts from CPD has no influence on survival despite the fact that these recipients tend to have a higher acuity and more comorbidities at the time of transplantation. Utilization of a heart from a donor with a confirmed blood stream infection should be carefully considered. doi: 10.1111/jocs.12509 (J Card Surg 2015;30:288-295) [ABSTRACT FROM AUTHOR]

Ischemia reperfusion injury (IRI) that occurs with solid organ transplantation activates the innate immune system to induce inflammation. This leads to enhanced acute allograft rejection, impaired transplant tolerance and accelerated progression of chronic rejection. In this review, we discuss the innate immune signaling pathways that have been shown to play a role in organ transplantation. In particular, we focus on Toll-like receptor signaling pathways and how they have influenced outcomes after organ transplantation both experimentally and from clinical studies. Furthermore, we describe the substances that trigger the innate immune system after transplantation and several of the key cellular mediators of inflammation. We specifically point out unique aspects of activation of the innate immune system after lung transplantation. Finally, we discuss the areas that should be investigated in the future to more clearly understand the influence of the innate immune system after organ transplantation. [ABSTRACT FROM AUTHOR]

lthough our understanding of the immunological mechanisms of transplant tolerance induction has greatly improved, how the innate immune system impacts transplant tolerance has only been recently appreciated. In this review, the involvement of the innate immune receptors, Toll-like receptors (TLRs), in both experimental models of acute allograft rejection and transplant tolerance induction in addition to clinical studies of organ transplantation are described. Several inflammatory cytokines, including IL-6, TNF-α, and type I interferons, which are induced by TLRs and other activators of innate immunity, prevent transplant tolerance induction. Their induction may be provoked by environmental exposures, such as viral or bacterial infections. Further investigation as to the innate inflammatory basis that controls the balance between immune acceptance and allograft rejection may lead us closer to the elusive goal of transplant tolerance acquisition. [ABSTRACT FROM AUTHOR]

Background: As increasing numbers of older people are listed for solid organ transplantation, there is an urgent need to better understand how aging modifies alloimmune responses. Here, we investigated whether aging impairs the ability of donor dendritic cells or recipient immunity to prime alloimmune responses to organ transplantation. Principal Findings: Using murine experimental models, we found that aging impaired the host environment to expand and activate antigen specific CD8+ T cells. Additionally, aging impaired the ability of polyclonal T cells to induce acute allograft rejection. However, the alloimmune priming capability of donor dendritic cells was preserved with aging. Conclusion: Aging impairs recipient responses, both T cell intrinsic and extrinsic, in response to organ transplantation. [ABSTRACT FROM AUTHOR]

Toll like receptors (TLR) are critical innate immune receptors expressed on a variety of cells including dendritic cells that are activated by the presence of invading pathogens. However, there is emerging evidence that TLR signaling participates in inflammation that may occur in the absence of overt infection. In solid organ transplantation there is increasing evidence, both in experimental and human studies, that TLR activation is involved in the innate immune recognition of allografts. Further investigation of how innate immunity impacts solid organ transplantation may lead to improved therapies for transplant recipients. [ABSTRACT FROM AUTHOR]

Innate immunity represents the first line of defense against microbial invasion. Recent studies have determined that a group of germline-encoded receptors, termed Toll-like receptors (TLRs), are critical for recognizing foreign motifs on microbial organisms and initiating innate responses. An exciting area of research has recently linked activation of TLRs on antigen-presenting cells (APCs) to effective antigen presentation and activation of naive T cells. Most studies have shown that TLR-dependent immune function leads to T-helper 1 (TH1) immunity, although evidence also supports that TH2 immune responses may be initiated by TLR signaling in certain contexts. In either case, innate immune signaling via TLRs leads to a productive adaptive immune response. In contrast to studies in purely infectious models, emerging data from experimental and clinical studies have provided evidence that TLR immune function is important in acute allograft rejection. Specifically, MyD88, an important TLR signal adaptor, was found to be critical for the rejection of minor-mismatched skin allografts, and important for alloimmune priming and TH1 immunity against fully allogeneic skin grafts. Furthermore, a clinical study has shown that recipients with TLR 4 polymorphisms associated with endotoxin hyporesponsiveness manifest reduce acute lung allograft rejection. Collectively, these studies demonstrate that innate immunity is important for alloimmunity. Future therapeutic modalities that target innate rather than adaptive immune mechanisms represent a promising avenue for future studies in thoracic organ transplantation. [Copyright &y& Elsevier]

Innate immunity represents the first line of defense against invading pathogens and noxious stimuli. The Toll-like receptors (TLRs) are essential innate immune receptors that alert the immune system to the presence of invading microbes. Emerging evidence shows that TLR signaling is important in allograft rejection. In a murine model, the rejection of minor mismatched allografts cannot occur in the absence of MyD88, an important TLR signal adaptor protein, owing to a defect in dendritic cell maturation, which leads to diminished T-helper cell type 1 immune responses. A recent clinical study also suggests that recipients with a mutant TLR4 genotype manifest reduced lung allograft rejection. Thus, innate immune signaling via TLRs is important for alloimmunity. [Copyright &y& Elsevier]

The Toll-like receptors (TLRs) are recently discovered germline-encoded receptors on APCs that are critically important in innate immune recognition of microbial pathogens. However, their role in solid-organ transplantation is unknown. To explore this role, we employed a skin allograft model using mice with targeted deletion of the universal TLR signal adaptor protein, MyD88. We report that minor antigen-mismatched (HY-mismatched) allograft rejection cannot occur in the absence of MyD88 signaling. Furthermore, we show that the inability to reject these allografts results from a reduced number of mature DCs in draining lymph nodes, leading to impaired generation of anti-graft-reactive T cells and impaired Th1 immunity. Hence, this work demonstrates that TLRs can be activated in a transplant setting and not solely by infections. These results link innate immunity to the initiation of the adaptive alloimmune response. [ABSTRACT FROM AUTHOR]

Invasive graft biopsies assess the efficacy of immunosuppression through lagging indicators of transplant rejection. We report on a microporous scaffold implant as a minimally invasive immunological niche to assay rejection before graft injury. Adoptive transfer of T cells into Rag2-/- mice with mismatched allografts induced acute cellular allograft rejection (ACAR), with subsequent validation in wild-type animals. Following murine heart or skin transplantation, scaffold implants accumulate predominantly innate immune cells. The scaffold enables frequent biopsy, and gene expression analyses identified biomarkers of ACAR before clinical signs of graft injury. This gene signature distinguishes ACAR and immunodeficient respiratory infection before injury onset, indicating the specificity of the biomarkers to differentiate ACAR from other inflammatory insult. Overall, this implantable scaffold enables remote evaluation of the early risk of rejection, which could potentially be used to reduce the frequency of routine graft biopsy, reduce toxicities by personalizing immunosuppression, and prolong transplant life. [ABSTRACT FROM AUTHOR]

An increasing number of older people receive organ transplants for various end-stage conditions. Although organ transplantation is an effective therapy for older patients (i.e., older than 65 years of age), such as in end-stage renal disease, this therapy has not been optimized for older patients because of our lack of understanding of the effect of aging and the immune response to organ transplantation. Here, we provide an overview of the impact of aging on both the allograft and the recipient and its effect on the immune response to organ transplantation. We describe what has been determined to date, discuss existing gaps in our knowledge, and make suggestions on necessary future studies to optimize organ transplantation for older people. [ABSTRACT FROM AUTHOR]

Graft inflammation impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection. Elucidating the mechanisms by which inflammation is induced after organ transplantation could lead to novel therapeutics to improve transplant outcomes. In this Review we describe endogenous substances--damage-associated molecular patterns (DAMPs)--that are released after allograft reperfusion and induce inflammation. We also describe innate immune signalling pathways that are activated after solid organ transplantation, with a focus on Toll-like receptors (TLRs) and their signal adaptor, MYD88. Experimental and clinical studies have yielded a large body of evidence that TLRs and MYD88 are instrumental in initiating allograft inflammation and promoting the development of acute and chronic rejection. Ongoing clinical studies are testing TLR inhibition strategies in solid organ transplantation, although avoiding compromising host defence to pathogens is a key challenge. Further elucidation of the mechanisms by which sterile inflammation is induced, maintained and amplified within the allograft has the potential to lead to novel anti-inflammatory treatments that could improve outcomes for solid organ transplant recipients. [ABSTRACT FROM AUTHOR]

Age-related decline in immunity can impair cell-mediated responses during an infection, malignancy, and acute allograft rejection. Although much research has been allocated to understand the immune responses that impact the former two conditions, the cellular mechanisms by which aging impacts the immune acceptance of organ allografts are not completely clear. In this study, we examined how recipient age impacts the efficacy of therapies that modulate immune recognition of allografts using an immunogenic murine skin transplant model. We found that costimulatory blockade-based treatment failed to extend allograft survival in older recipients to the same extent as that observed in younger recipients. CD8+ T cells were critical for the inability of aged recipients to achieve maximal allograft survival. Although aged mice displayed a larger number of effector memory T cells prior to transplantation, these cells did not exhibit enhanced alloreactivity compared with young memory T cells. In contrast, naive aged CD8+ T cells exhibited enhanced IFN-γ production to allostimulation compared with young naive T cells. Our results provide evidence that aging enhances CD8+ T cell alloreactivity. This could impair the ability of costimulatory blockade-based therapies to prolong allograft survival. Thus, targeting CD8+ T cells in humans may be a way to improve outcomes in older patients requiring immune modulatory therapy. [ABSTRACT FROM AUTHOR]

Background: Ventricular assist devices (VADs) are increasingly used to support critically ill heart failure patients awaiting transplantation. Previous work has focused on the Thoratec Heartmate VE device, use of which is associated with pre-formed antibody production. We reviewed our cumulative experience with the Worldheart Novacor VAD as a bridge to transplantation (BTT). Methods: From January 1989 through October 2002, 39 patients required a VAD bridge, with 26 of 39 surviving to transplantation. Antibody levels were assessed by complement-dependent cytotoxicity assay at routine intervals and expressed as panel reactive antibody (PRA) levels. Post-transplant allograft rejection, coronary vasculopathy, and survival were compared between Novacor-supported patients and non-VAD transplant recipients. Results: PRA values did not significantly change after VAD implantation (12.4% ± 11.2% vs 14.8% ± 12.3%, p = 0.28). Survival for the BTT patients was 80.4%, 75.7%, 64.0%, 64.0%, and 64.0%, respectively, for 1, 3, 5, 7, and 10 years post-transplant, with similar results for non-BTT patients. The freedom from coronary vasculopathy was 90.2%, 90.2%, 72.2%, and 72.2%, respectively, at 1, 3, 5, and 7 years post-transplant. Conclusions: First, to our knowledge, this study is the first to examine the incidence of allosensitization after Novacor implant in detail. In contrast with previous results of work with other VAD systems, as assessed by PRA levels, Novacor patients did not become sensitized. Second, compared with 220 non-BTT patients who received transplants during a similar time frame, Novacor BTT patients had equivalent rejection profiles and survival. Finally, the incidence of transplant-associated coronary artery disease was lower than in previous reports. [Copyright &y& Elsevier]