Toll-like Receptor 4 (TLR4) is the canonical receptor for lipopolysaccharide (LPS), however recent evidence reveals that TLR4 also plays an important role in ischemia-reperfusion injury (IRI). TLR4 is suggested to play a key role in acute graft failure. Here, we demonstrate that treatment with a clinically-tested, small molecule TLR4 antagonist (TAK-242) protects transplanted islets from the inflammatory effects of DAMPs and IRI. To do this, we challenged mouse islets in vitro with LPS or whole blood +/- TAK-242 to demonstrate both the sensitivity of islets to TLR4 stimulation as well as the efficacy of TAK-242 as a TLR4 antagonist. Then we transplant a marginal dose of islets +/- TAK-242 treatment into a diabetic mouse model to show both the safety and efficacy of TAK-242 in protecting islet grafts (Fig1).

To localize and prolong the protective effects of TLR4 inhibition, we developed a linkable variant of TAK-242. To test this compound, islets modified with this compound were both tested in vivo (Fig1) and challenged in vitro 24hrs after modification and compared to non-treated and islets treated previously (Fig2). In vivo TAK-linker modified islets effectively restored normoglycemia and significantly blocked IL6 secretion from LPS-stimulated islets in vitro.

The results from these experiments demonstrate that TLR4-blockade improves islet graft function and this novel chemistry has the potential for application in islet as well as whole organ transplant.

CITATION INFORMATION: Chang C, Yoshimatsu G, Akinbobuyi B, Lawrence M, Kane R, Naziruddin B. The Role of Toll-Like Receptor 4 in Islet Transplantation and a Novel Method of Protection Using Chemical Surface Modification. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress