Giovannoni Laurianne, Muller Yannick D, Lacotte Stéphanie, Parnaud Géraldine, Borot Sophie, Meier Raphaël P H, Lavallard Vanessa, Bédat Benoît, Toso Christian, Daubeuf Bruno, Elson Greg, Shang Limin, Morel Philippe, Kosco-Vilbois Marie, Bosco Domenico, Berney Thierry
1 Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland. 2 Department of Endocrinology-Metabolisme and Diabetology-Nutrition, Jean Minjoz University Hospital, Besançon, France. 3 Division of Transplantation and Visceral Surgery, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland. 4 NovImmune, Plan-les-Ouates, Switzerland.
Transplantation. 2015 Jan;99(1):29-35. doi: 10.1097/TP.0000000000000468.
Toll-like receptors are key players in sterile inflammation phenomena and can link the innate and adaptive immune systems by enhancing graft immunogenicity. They are also considered mediators of types 1 and 2 diabetes development. The aim of the present study was to assess the role of Toll-like receptor-4 (TLR4) in mediating the inflammatory and immune responses to pancreatic islets, thereby promoting inflammatory destruction and immune rejection of islet grafts.
Experiments were conducted in murine and human in vitro systems and in vivo murine islet transplant models, using species-specific anti-TLR4 monoclonal antibodies. In vitro, mixed lymphocyte-islet reaction experiments were performed to assess T-cell activation and proliferation. In vivo, both a syngeneic (B6-to-B6) marginal mass islet transplant model to assess the impact of TLR4 blockade on islet engraftment and an allogeneic (DBA1-to-B6) model were used.
In vitro TLR4 blockade decreased lipopolysaccharide-mediated β-cell apoptosis and T-cell activation and proliferation against allogeneic islets. In vivo, TLR4 blockade resulted in significantly better syngeneic marginal mass islet engraftment and in indefinite allogeneic islet graft survival. Tolerance was not observed because donor-specific skin graft rechallenge in nonrejecting animals resulted in rejection of both skin and islets, but without accelerated rejection as compared to naive animals.
Taken together, our data indicate that TLR4 blockade leads to a significant improvement of syngeneic islet engraftment and of allogeneic islet graft survival. A mechanism of graft accommodation with concurrent inhibition of donor-specific immune memory is likely to be involved.
Toll样受体是无菌性炎症现象的关键参与者，可通过增强移植物免疫原性连接先天性和适应性免疫系统。它们也被认为是1型和2型糖尿病发展的介质。本研究的目的是评估Toll样受体4（TLR4）在介导对胰岛的炎症和免疫反应中的作用，从而促进胰岛移植物的炎症破坏和免疫排斥。
使用物种特异性抗TLR4单克隆抗体，在小鼠和人类体外系统以及体内小鼠胰岛移植模型中进行实验。在体外，进行混合淋巴细胞-胰岛反应实验以评估T细胞活化和增殖。在体内，使用同基因（B6到B6）边缘质量胰岛移植模型来评估TLR4阻断对胰岛植入的影响，并使用异基因（DBA1到B6）模型。
在体外，TLR4阻断减少了脂多糖介导的β细胞凋亡以及针对异基因胰岛的T细胞活化和增殖。在体内，TLR4阻断导致同基因边缘质量胰岛植入明显改善，异基因胰岛移植物无限期存活。未观察到耐受，因为在未排斥动物中再次挑战供体特异性皮肤移植物会导致皮肤和胰岛均被排斥，但与未处理动物相比，排斥反应没有加速。
综上所述，我们的数据表明，TLR4阻断可显著改善同基因胰岛植入和异基因胰岛移植物存活。可能涉及移植物适应机制并同时抑制供体特异性免疫记忆。
