Introduction: Coagulation response is an important obstacle for a long-term xenograft survival. Thrombomodulin (TBM) has critical anticoagulant and anti-inflammatory effects as a component of the protein C pathway. Anti-coagulant effects of TBM have been reported in previous studies, but its complement-regulatory effects have not been explored well. Here, we investigated whether TBM can regulate complement activation as well as coagulation in response to xenogeneic stimuli.
Methods & Results: Porcine endothelial cells (MPN-3) were infected with adenovirus vectors containing the hTBM gene (ad-hTBM), or a control gene containing GFP (ad-GFP). The expression levels of ad-hTBM were measured by FACS. To confirm the anti-coagulant effect of TBM, clot time were measured after treatment with re-calcified human plasma in ad-hTBM-infected MPN-3, and thrombin generation assay was performed after treatment with 50% human serum in ad-hTBM-infected MPN-3. Thrombin generation was significantly decreased in a dose-dependent manner in ad-TBM group, and clot time was increased in ad-hTBM group compared to in ad-GFP group. Next, serum toxicity assay was performed after treatment with 20% human serum or heat-inactivated human serum by LDH assay. Complement-dependent toxicity was significantly attenuated in ad-hTBM group, but complement-independent toxicity was not attenuated in ad-hTBM group. These results suggested that hTBM has complement-regulatory effect as well as anti-coagulant effect. In order to investigate mechanisms of complement regulation by hTBM, we modified some of EGF domains or a lectin domain of TBM and the functional tests were assessed with modified forms.
Conclusion: Human TBM has complement-regulatory effects as well as anti-coagulant effects in xenoimmune response, and therefore it is a promising target for attenuating xenograft rejection.
To cite this abstract in AMA style:Kim H, Jeong J, Koo T, Jeon H, Ro H, Kim M, Park J, Yun I, Yang J, Ahn C. Human Thrombomodulin Regulates Complement Activation as Well as Coagulation in Xenoimmune Response [abstract]. Am J Transplant. 2013; 13 (suppl 5). http://atcmeetingabstracts.com/abstract/human-thrombomodulin-regulates-complement-activation-as-well-as-coagulation-in-xenoimmune-response/. Accessed January 16, 2018.
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