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Schematic illustration of some innate alloimmunity-suppressing strategies : Main aim : to prevent oxidative injury-induced, TLR4triggered, NFkB-mediated maturation of donor-derived and recipient-derived dendritic cells-resulting in insufficient direct and indirect allorecognition/alloactivation. I) minimization of the ROS-mediated oxidative allograft injury via antioxidative therapy of both the donor and the recipient during surgery ( agents such as edaravone, SOD-mimetica) ; II) blockade of TLR4 through TLR4 antagonists (E-5564 ; TAK 242) ; III) generation of immature dendritic cells via siRNA-mediated NFkB-gene silencing followed by their administration to the recipient prior to allografting ( see also ref. 20).
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An emerging body of evidence suggests that the innate immune system plays a critical role in allograft rejection. Any injury to the donor organ, e.g. the reperfusion injury, induces an inflammatory milieu in the allograft which appears to be the initial event for activation of the innate immune system. Injury-induced intragraft damage- associated m...
Context in source publication
Context 1
... (brain dead/living) donor during organ removal, 2) sep- arate in-situ / ex-vivo treatment of the donor organs alone, and 3) treatment of the recipient during allograft reperfusion (+ during the first 2-4 postoperative days). Notably, we are dealing with an a priori time-restricted therapeutic window only. Treatment modalities primari- ly include (Fig. 2) : 1) minimization of the allograft injury -in particular prevention of the oxidative injury in the donor and the recipient with the use of antioxidants ; 2) inhibition of the MBL-dependent activation of the complement cascade that aggravates the ROS-mediated injury ; 3) prevention of the injury-induced, TLR4-trig- gered, and ...
Citations
... It is a real pity that those antioxidants have not been tested in transplant patients, although they were experimentally proven to exert high potency and clinically proven to be safe. Obviously, there was no stringent marketing interest on the Big Pharma's side, pointing to a serious ethical issue in the field of immunosuppression [69]. ...
In parts I and II of this tripartite review, the innate immune system was briefly described, focusing on its emerging role in organ transplantation and by emphasizing the oxidative injury-induced allograft inflammation that promotes the generation of immunostimulatory donor- and recipient-derived dendritic cells (DCs) translating innate immune events into adaptive alloimmunity. This part III of the review discusses the possibility to induce adaptive antigen-specific T regulatory cells (Tregs) in the clinical situation by harnessing donor- and recipient-derived tolerogenic DCs (tolDCs) as inducers for alloantigen-specific adaptive Tregs, an effort that follows current trends to harnessing DCs for immunotherapy. This challenge is based on accumulating evidence from basic immunological work in support of the notion that presentation of antigens, including weak transplantation antigens under subimmunogenic conditions within a noninflammatory microenvironment, promotes generation of tolDCs. With respect to these basic immunological studies, which are expressively reviewed, prevention of oxidative allograft injury can be regarded as an efficient tool in the clinical situation to present alloantigens under subimmunogenic conditions within an intragraft noninflammatory milieu, thereby potentially generating tolDCs able to induce Tregs-mediated innate allotolerance. Various therapeutic strategies to prevent oxidative allograft injury occurring in both the brain-dead donor before/during organ removal and the recipient during/after donor organ reperfusion as well as therapeutic options to inhibit injury-induced molecular and cellular consequences are finally discussed.
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Non‐coding RNA 886 (nc886/VTRNA2‐1) is a Pol III transcript and an atypical imprinted gene. Its exact function as a negative regulator of protein kinase R establishes its connection with innate immunity. Studies have shown that nc886 silencing is closely associated with prostate cancer progression. Previous work has constructed a cell model of stable nc886 overexpression (“mimic” or “nc886⁺”) in PC‐3M‐1E8 cell lines (1E8), which are highly bone‐metastatic human prostate cancer cells with low expression of nc886, and cells expressing the mimic were validated to have lower invasive and metastatic abilities than cells expressing the scramble transcript in vitro and in vivo. In this study, we directly injected mimic or scramble cells into the left ventricle of C57BL/C mice, an immunocompetent animal model, to elucidate the immune mechanisms of tumor‐host interactions. Interestingly, we found that tumor cells induced the inflammation of many important organs due to xenogeneic antigen rejection; this inflammation was ultimately repaired by tissue fibrosis after 28 days, except for in the spleen. The reason is that mimic cells, as heterogeneous antigens, are mostly directly recognized by macrophages or T cells in blood, and few mimic cells enter the spleen compared with scramble cells. The induction of splenic macrophage polarization to M2 macrophages by scramble cells is a critical factor in maintaining chronic splenic inflammation. In addition, we recognize that nc886 broadly decreases the expression of some human leukocyte antigen molecules and antigen transporters. This evidence reveals the interesting role of nc886 in regulating tumor cell antigens.
