Dendritic cells (DCs) rely on glycolysis for their energy needs to induce pro-inflammatory antigen-specific immune responses. Therefore, inhibiting DC glycolysis, while presenting the self-antigen, may prevent pro-inflammatory antigen-specific immune responses. Previously we demonstrated that microparticles with alpha-ketoglutarate (aKG) in the polymer backbone (paKG MPs) were able to generate anti-inflammatory DCs by sustained delivery of the aKG metabolite, and by modulating energy metabolism of DCs. Herein, we demonstrate that paKG MPs-based delivery of a glycolytic inhibitor, PFK15, using paKG MPs induces anti-inflammatory DCs (CD86^LoMHCII⁺) by down-regulating glycolysis, CD86, tnf and IL-6 genes, while upregulating oxidative phosphorylation (OXPHOS) and mitochondrial genes. Furthermore, paKG MPs delivering PFK15 and a self-antigen, collagen type II (bc2), in vivo, in a collagen-induced autoimmune arthritis (CIA) mouse model, normalized paw inflammation and arthritis score, by generating antigen-specific immune responses. Specifically, these formulations were able to reduce activation of DCs in draining lymph nodes and impressively generated proliferating bc2-specific anti-inflammatory regulatory T cells in joint-associated popliteal lymph nodes. These data strongly suggest that sustained glycolytic inhibition of DCs in the presence of an antigen can induce antigen-specific immunosuppressive responses, therefore, generating a technology that can be applicable for treating autoimmune diseases.

树突状细胞 (DC) 依赖糖酵解来满足其能量需求，以诱导促炎性抗原特异性免疫反应。因此，抑制 DC 糖酵解，同时呈递自身抗原，可能会阻止促炎性抗原特异性免疫反应。以前，我们证明了在聚合物骨架 (paKG MP) 中具有 α-酮戊二酸 (aKG) 的微粒能够通过持续递送 aKG 代谢物和调节 DC 的能量代谢来产生抗炎 DC。在这里，我们证明了基于 paKG MPs 的糖酵解抑制剂 PFK15 的递送，使用 paKG MPs通过下调糖酵解、CD86、tnf和IL-6基因来诱导抗炎 DCs (CD86 ^Lo MHCII ^{+ )}，同时上调氧化磷酸化(OXPHOS) 和线粒体基因。此外，在体内传递 PFK15 和自身抗原II 型胶原 (bc2)的 paKG MP，在胶原蛋白诱导的自身免疫性关节炎 (CIA) 小鼠模型中，通过产生抗原特异性免疫反应，使爪子炎症和关节炎评分正常化。具体而言，这些制剂能够减少引流淋巴结中 DC 的活化，并在关节相关的腘窝淋巴结中显着地产生增殖的 bc2 特异性抗炎调节 T 细胞。这些数据强烈表明，在抗原存在的情况下，DCs 的持续糖酵解抑制可以诱导抗原特异性免疫抑制反应，因此，产生了一种可用于治疗自身免疫性疾病的技术。