Department of Pediatrics and Department of Molecular Microbiology and Immunology, NextGen Precision Health Institute, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO.
J Immunol. 2024 Jun 15;212(12):1971-1980. doi: 10.4049/jimmunol.2300743.
Most pancreatic islets are destroyed immediately after intraportal transplantation by an instant blood-mediated inflammatory reaction (IBMIR) generated through activation of coagulation, complement, and proinflammatory pathways. Thus, effective mitigation of IBMIR may be contingent on the combined use of agents targeting these pathways for modulation. CD47 and thrombomodulin (TM) are two molecules with distinct functions in regulating coagulation and proinflammatory responses. We previously reported that the islet surface can be modified with biotin for transient display of novel forms of these two molecules chimeric with streptavidin (SA), that is, thrombomodulin chimeric with SA (SA-TM) and CD47 chimeric with SA (SA-CD47), as single agents with improved engraftment following intraportal transplantation. This study aimed to test whether islets can be coengineered with SA-TM and SA-CD47 molecules as a combinatorial approach to improve engraftment by inhibiting IBMIR. Mouse islets were effectively coengineered with both molecules without a detectable negative impact on their viability and metabolic function. Coengineered islets were refractory to destruction by IBMIR ex vivo and showed enhanced engraftment and sustained function in a marginal mass syngeneic intraportal transplantation model. Improved engraftment correlated with a reduction in intragraft innate immune infiltrates, particularly neutrophils and M1 macrophages. Moreover, transcripts for various intragraft procoagulatory and proinflammatory agents, including tissue factor, HMGB1 (high-mobility group box-1), IL-1β, IL-6, TNF-α, IFN-γ, and MIP-1α, were significantly reduced in coengineered islets. These data demonstrate that the transient codisplay of SA-TM and SA-CD47 proteins on the islet surface is a facile and effective platform to modulate procoagulatory and inflammatory responses with implications for both autologous and allogeneic islet transplantation.
大多数胰岛在门静脉移植后立即被即时的血液介导的炎症反应（IBMIR）破坏，这种反应是通过凝血、补体和促炎途径的激活产生的。因此，有效缓解 IBMIR 可能取决于联合使用针对这些途径的调节剂。CD47 和血栓调节蛋白（TM）是两种在调节凝血和促炎反应方面具有不同功能的分子。我们之前报道过，胰岛表面可以用生物素修饰，以短暂显示这两种与链霉亲和素（SA）融合的新型分子，即 TM 与 SA 的融合（SA-TM）和 CD47 与 SA 的融合（SA-CD47），作为一种单一的药物，在门静脉内移植后改善了植入。本研究旨在测试胰岛是否可以与 SA-TM 和 SA-CD47 分子共工程化，作为一种抑制 IBMIR 改善植入的组合方法。小鼠胰岛可以有效地与这两种分子共工程化，而其活力和代谢功能没有可检测到的负面影响。共工程化的胰岛对 IBMIR 具有抗破坏性，在边缘质量同基因门静脉移植模型中显示出增强的植入和持续的功能。改善的植入与移植内固有免疫浸润物（特别是中性粒细胞和 M1 巨噬细胞）的减少相关。此外，共工程化胰岛中各种移植内促凝和促炎剂的转录物，包括组织因子、HMGB1（高迁移率族蛋白 1）、IL-1β、IL-6、TNF-α、IFN-γ 和 MIP-1α，显著减少。这些数据表明，SA-TM 和 SA-CD47 蛋白在胰岛表面的瞬时共展示是一种简单有效的调节促凝和炎症反应的平台，对自体和同种异体胰岛移植都有意义。
