Extensive cellular rejection (CR) episodes, promotes coronary vascular injury and may lead to coronary vasculopathy (CV) that hinders long-term survival of the allograft. One approach to prevent the incidence of rejection might be through the initial inflammatory process. In cardiac transplantation settings, the initial myocardial ischemia/reperfusion may cause myocyte tissue injury and the release of proinflammatory mediators, leading to rejection episodes. The link between the initial injury and the subsequent rejection might be an innate immunity-derived alloreactivity , interplayed by donor-derived allograft inflammatory factor-1 and TLR-mediated recipient-derived cells entering the graft after reperfusion. We have identified AIF-1, IL-18 and TLR-2 and TLR-4 in peripheral blood and biopsy specimen from patients in association with rejection grades and CV. Studies are in place for identification of the role of AIF-1 as an endogenous molecule in association with TLR-2/TLR-4 in pathogenesis of allograft rejection and or CV. Future therapeutic strategies including blockade of innate immunity mediators during reperfusion may help to prevent the incidence of rejections.
This study is design to investigate the impact of combined effects of recipient-derived immunogenetic and pharmacogenetic markers on the outcome of allograft survival. The underlying causes of long-term kidney allograft failure are numerous. Among which, the engagement of TLRs by endogenous ligands, may cause an excessive production of pro-inflammatory cytokines, HLA disparity particularly class II genes may cause immune activation and episodes of rejection, and CYP 3A gene polymorphisms may cause variability in immunosuppression, requiring individualized regimen. We have identified individual gene polymorphisms affecting susceptibility to allograft rejection. Combined measurements of IL-18, IFN-g and IL-10 production levels have been shown to be a useful tool associated with early episodes of rejections.
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