Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance.
Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance.
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工程人类干细胞衍生的胰岛逃避免疫排斥并促进局部免疫耐受性。
DOI：
10.1016/j.xcrm.2022.100879
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发表时间：
2023-01-17
影响因子：
14.3
通讯作者：
Melton, Douglas A.
中科院分区：
文献类型：
--
作者：
Gerace, Dario;Zhou, Qua;Kenty, Jennifer Hyoje-Ryu;Veres, Adrian;Sintov, Elad;Wang, Xi;Boulanger, Kyle R.;Li, Hongfei;Melton, Douglas A.
移植的干细胞来源的胰岛（SC-胰岛）细胞的免疫保护尚未实现无慢性免疫抑制或封装。现有的基因工程方法，以产生免疫逃避SC胰岛细胞迄今已显示出不同的结果。在这里，我们表明，靶向人类白细胞抗原（HLA）和PD-L1单独不足以保护SC-胰岛细胞从异种移植（异种）或同种异体移植（同种）排斥反应。作为这些方法的补充，我们对SC-胰岛细胞进行基因工程改造，使其分泌细胞因子白细胞介素-10（IL-10）、转化生长因子β（TGF-β）和修饰的IL-2，从而通过向胰岛移植物募集调节性T细胞（T细胞）来促进致耐受性局部微环境。分泌细胞因子的人SC-β细胞在非肥胖糖尿病（NOD）小鼠中移植后抵抗异种排斥并纠正糖尿病长达8周。因此，基因工程改造人胚胎干细胞（hESC）诱导耐受性局部微环境代表了一种有前途的方法，提供SC-胰岛细胞作为糖尿病的细胞替代疗法，而不需要封装或免疫抑制。干细胞衍生的胰岛（SC-胰岛）具有抑制性NK细胞配体特征免疫逃避性SC-胰岛在异种移植时被迅速排斥免疫逃避性SC-胰岛逆转糖尿病并在人源化小鼠中被缓慢排斥免疫耐受性SC-胰岛逆转NOD小鼠的糖尿病并抵抗异种排斥目前，1型糖尿病的细胞替代疗法受到终身免疫抑制要求的限制。杰雷斯等人表明工程干细胞衍生的胰岛作为局部免疫耐受的载体可能是解决这一尚未解决的挑战的一种方法。
Immunological protection of transplanted stem cell-derived islet (SC-islet) cells is yet to be achieved without chronic immunosuppression or encapsulation. Existing genetic engineering approaches to produce immune-evasive SC-islet cells have so far shown variable results. Here, we show that targeting human leukocyte antigens (HLAs) and PD-L1 alone does not sufficiently protect SC-islet cells from xenograft (xeno)- or allograft (allo)-rejection. As an addition to these approaches, we genetically engineer SC-islet cells to secrete the cytokines interleukin-10 (IL-10), transforming growth factor β (TGF-β), and modified IL-2 such that they promote a tolerogenic local microenvironment by recruiting regulatory T cells (Tregs) to the islet grafts. Cytokine-secreting human SC-β cells resist xeno-rejection and correct diabetes for up to 8 weeks post-transplantation in non-obese diabetic (NOD) mice. Thus, genetically engineering human embryonic SCs (hESCs) to induce a tolerogenic local microenvironment represents a promising approach to provide SC-islet cells as a cell replacement therapy for diabetes without the requirement for encapsulation or immunosuppression. Stem cell-derived islets (SC-islets) possess an inhibitory NK cell ligand profile Immune-evasive SC-islets are rapidly rejected upon xeno-transplantation Immune-evasive SC-islets reverse diabetes and are slowly rejected in humanized mice Immune-tolerizing SC-islets reverse diabetes and resist xeno-rejection in NOD mice Currently, cell replacement therapy for type 1 diabetes is limited by the requirement for lifelong immunosuppression. Gerace et al. show that engineering stem cell-derived islets as vehicles of localized immune tolerance may be an approach to address this yet unanswered challenge.
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影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
影响因子：
24.8
作者：
Abou-Daya KI;Tieu R;Zhao D;Rammal R;Sacirbegovic F;Williams AL;Shlomchik WD;Oberbarnscheidt MH;Lakkis FG
通讯作者：
Lakkis FG
T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
9.3
作者：
Baron M;Veres A;Wolock SL;Faust AL;Gaujoux R;Vetere A;Ryu JH;Wagner BK;Shen-Orr SS;Klein AM;Melton DA;Yanai I
通讯作者：
Yanai I
DOI：
10.1073/pnas.1705301114
发表时间：
2017-11-07
影响因子：
11.1
作者：
Herndler-Brandstetter, Dietmar;Shan, Liang;Flavell, Richard A.
通讯作者：
Flavell, Richard A.