Rana A, Gruessner A, Agopian VG, et al

Rana A, Gruessner A, Agopian VG, et al. Since trained macrophages upregulate costimulatory molecules (signal 2) and produce pro\inflammatory cytokines (signal 3), they contribute to potent graft reactive immune responses and organ transplant rejection. In this review, we summarize the detrimental effects Eledoisin Acetate of trained immunity in the context of organ transplantation and describe pathways that induce macrophage training associated with graft rejection. tuberculosis), but also against other infections (and at the time of transplantation prevents the induction of skin allograft acceptance induced by costimulatory blockade.47 Rejection was dependent on innate immune recognition and IL\6 signaling, since MyD88\, RAG\, or IL\6\deficient recipients prolonged their skin allograft survival despite infection. Interestingly, T cellCdirected therapy with either cyclosporine or sirolimus was unable to prevent graft loss, suggesting a critical role for the innate immune system in response to bacterial infection in transplant recipients. Previous work exhibited that trained macrophages produce large amounts of pro\inflammatory cytokines upon restimulation with NOD2 is also involved in sensing intracellular at the time of transplantation prevented both skin and heart allograft tolerance induced by costimulatory blockade.51 As mentioned above, heterologous immunity refers to the immunity that can develop to one antigen after the host has had exposure to a different antigen through cross\reactivity. Heterologous immunity has been well described as a potent barrier to transplantation tolerance regimens in animal models, since viral\specific T cells are cross\reactive with alloantigen.46 There are few murine models of human chronic viral infections. Of the few existing models, the murine cytomegalovirus chronic contamination model (mCMV) provides an excellent platform for trying to understand the pathology and graft loss associated with viral infections, which are manifested mainly in immunosuppressed hosts.52 Given that CMV activates NOD253 and that mCMV DNA is present only in cells of the myeloid lineage of latently infected mice,54 we hypothesize that mCMV contamination may induce cytokine production by trained macrophages, such as IL\6, which participate in the stimulation of viral\specific T cells and/or antibody\mediated responses that may cross\react with the allograft in transplant recipients.55, 56, 57 Supporting this hypothesis, latent contamination with mCMV prior to transplantation prevented the induction of prolonged allograft survival in heart transplant recipients.58 We argue that infectious brokers represent FTI 277 a risk factor in organ transplant rejection due to the mechanisms associated with trained immunity\mediated immune responses. 1.3. Oxidized low\density lipoprotein and the NLRP3\inflammasome Monocytes primed with OxLDL switch to glycolysis and exhibit increased pro\inflammatory cytokine production upon restimulation.59 OxLDL is DAMP that binds to the receptor CD36 expressed in myeloid cells and induces trained immunity.60 This represents a risk in organ transplantation because OxLDL present in transplant recipients is associated with an increased probability of graft rejection.61 A vast majority of transplant patients (40%\80%) are reported to have hyperlipidemia.62 Circulating low\density lipoprotein (LDL) is enhanced in transplant patients and high LDL content is associated with increased susceptibility to LDL oxidation.63, 64 Consequently, kidney transplant recipients exhibit increased levels of OxLDL after transplantation.65 OxLDL has been associated with development of chronic rejection in transplant recipients66 and represents a prognostic marker of transplant\associated chronic allograft nephropathy and coronary artery disease.67, 68 Mechanistically, OxLDL promotes transplant interstitial fibrosis and arteriosclerosis through the stimulation of collagen production69, 70 and the development of autoantibodies.71, 72 This has a critical impact on the management of FTI 277 transplant patients because cyclosporin A is one of the most widely used immunosuppressive brokers in organ transplantation, but at blood levels 100?ng/mL it is associated with increased OxLDL levels in kidney transplant recipients.73 FTI 277 This argues for the use of alternative immunosuppressive brokers, such as tacrolimus or azathioprine, to reduce FTI 277 the OxLDL levels in these patients.74, 75 Additionally, inhibitors of the hydroxy\methyl\glutaryl coenzyme A (HMG\CoA) reductase, the rate\limiting step in cholesterol biosynthesis, are used to lower the serum levels of LDL and reduce the damage caused by OxLDL, such as transplant atherosclerosis.76, 77 Interestingly, inhibitors of HMG\CoA have been shown to prevent trained immunity by epigenetic reprograming of macrophages through downregulation of H3K4me378 and to reduce vessel wall inflammation in atherosclerotic mice.79 However, in a therapeutic setting, statins are not able to reverse induction of trained immunity.80 This suggests that OxLDL induces trained macrophages that secrete pro\inflammatory cytokines60 that may be involved in the development of atherosclerosis during chronic rejection.81 The dual effect of OxLDL may be explained by the NOD\like receptor pyrin domain\containing\3 (NLRP3), which plays a pivotal function in distinct immunological scenarios. On the one hand, a Western\type diet increases the OxLDL levels that favor the formation.