Session Name: Islet Cell and Cell Transplantation
Session Date & Time: None. Available on demand.
*Purpose: A large portion of grafted islets are lost shortly after infusion due to the instant blood mediated inflammatory reaction (IBMIR). In our previous studies, we have observed increased viability and functionality of transplanted islets as well as decreased inflammatory markers in serum when islets were transplanted into mice following isolation with TAK-242 supplemented solutions. Therefore, we sought to investigate the effects of TAK-242 in an in vitro IBMIR model using human islets.
*Methods: Following isolation of human islets, islets were allowed to recover in culture for 24 hours. Islets were challenged with the administration of whole blood with and without supplemental TAK-242. Serum or supernatant was collected at 0 and 3 hours. These samples were analyzed for damage associated biomarkers hsa-miRNA 375 using RT-qPCR. C-peptide was measured by ELISA. IL-1β, IL-6, and IL-8 in plasma or supernatant were measured by Luminex assay.
*Results: Damage associated hsa-miRNA 375 showed a significant decrease (p<0.005) with the addition of TAK-242 when compared to control after being exposed to blood for 3 hours (Figure 1). C-peptide also showed decreases in TAK-242 samples (p<0.005) following 3 hours of exposure to whole blood further verifying attenuated islet stress and damage with the administration of TAK-242. Inflammatory cytokines IL-1β, IL-6, and IL-8 in TAK-242 treated samples also showed significant decreases compared to control (p<0.05) after 3 hours exposure to blood.
*Conclusions: The results of this study confirm the efficacy of TAK-242 and its ability to attenuate IBMIR in a human in vitro model as all markers measured in this experiment showed decreases in damage and inflammatory biomarkers of islets. This study also implicates the TLR4 signaling pathway as a potential therapeutic target for attenuating IBMIR during islet transplant procedures.
To cite this abstract in AMA style:Mattke J, Vasu S, Kumano K, Liu Y, Darden CM, Lawrence MC, Kane RR, Naziruddin B. A Small Molecule Inhibitor of Toll-like Receptor-4 TAK-242 Attenuates IBMIR Against Human Islets [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/a-small-molecule-inhibitor-of-toll-like-receptor-4-tak-242-attenuates-ibmir-against-human-islets/. Accessed August 4, 2021.
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