Short-term function and immune-protection of microencapsulated adult porcine islets with alginate incorporating CXCL12 in healthy and diabetic non-human primates without systemic immune suppression: A pilot study.

IF 3.3 4区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Xenotransplantation Pub Date : 2023-11-01 Epub Date: 2023-09-15 DOI:10.1111/xen.12826
Marinko Sremac, Hao Luo, Hongping Deng, Madeline F E Parr, Jessica Hutcheson, Pushkar S Verde, David A Alagpulinsa, Jenna Miner Kitzmann, Klearchos K Papas, Timothy Brauns, James F Markmann, Ji Lei, Mark C Poznansky
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引用次数: 0

Abstract

Replacement of insulin-producing pancreatic beta-cells by islet transplantation offers a functional cure for type-1 diabetes (T1D). We recently demonstrated that a clinical grade alginate micro-encapsulant incorporating the immune-repellent chemokine and pro-survival factor CXCL12 could protect and sustain the integrity and function of autologous islets in healthy non-human primates (NHPs) without systemic immune suppression. In this pilot study, we examined the impact of the CXCL12 micro encapsulant on the function and inflammatory and immune responses of xenogeneic islets transplanted into the omental tissue bilayer sac (OB; n = 4) and diabetic (n = 1) NHPs. Changes in the expression of cytokines after implantation were limited to 2-6-fold changes in blood, most of which did not persist over the first 4 weeks after implantation. Flow cytometry of PBMCs following transplantation showed minimal changes in IFNγ or TNFα expression on xenoantigen-specific CD4+  or CD8+  T cells compared to unstimulated cells, and these occurred mainly in the first 4 weeks. Microbeads were readily retrievable for assessment at day 90 and day 180 and at retrieval were without microscopic signs of degradation or foreign body responses (FBR). In vitro and immunohistochemistry studies of explanted microbeads indicated the presence of functional xenogeneic islets at day 30 post transplantation in all biopsied NHPs. These results from a small pilot study revealed that CXCL12-microencapsulated xenogeneic islets abrogate inflammatory and adaptive immune responses to the xenograft. This work paves the way toward future larger scale studies of the transplantation of alginate microbeads with CXCL12 and porcine or human stem cell-derived beta cells or allogeneic islets into diabetic NHPs without systemic immunosuppression.

含有 CXCL12 的藻酸盐微囊化成年猪胰岛在健康和糖尿病非人灵长类动物中的短期功能和免疫保护,无需全身免疫抑制:试点研究。
通过胰岛移植替代产生胰岛素的胰岛β细胞是治疗 1 型糖尿病(T1D)的一种功能性方法。我们最近证明,一种含有免疫排斥趋化因子和促生存因子 CXCL12 的临床级海藻酸盐微囊剂可以保护和维持健康非人灵长类(NHPs)自体胰岛的完整性和功能,而无需全身免疫抑制。在这项试验性研究中,我们考察了 CXCL12 微囊对移植到网膜组织双层囊(OB;n = 4)和糖尿病(n = 1)NHPs 中的异种胰岛的功能、炎症和免疫反应的影响。移植后细胞因子表达的变化仅限于血液中2-6倍的变化,其中大部分在移植后的前4周内不会持续。移植后 PBMC 的流式细胞术显示,与未受刺激的细胞相比,异抗原特异性 CD4+ 或 CD8+ T 细胞上的 IFNγ 或 TNFα 表达变化极小,而且这些变化主要发生在前 4 周。微珠可在第 90 天和第 180 天取出进行评估,取出时没有降解或异物反应 (FBR) 的显微迹象。对取出的微珠进行的体外和免疫组织化学研究表明,在移植后第 30 天,所有活检的 NHP 中都存在功能性异种胰岛。这项小型试验研究的结果表明,CXCL12微囊化异种胰岛可减轻异种移植的炎症反应和适应性免疫反应。这项工作为今后在不使用全身免疫抑制剂的情况下,将含有CXCL12和猪或人类干细胞衍生β细胞或异体胰岛的藻酸盐微珠移植到糖尿病NHP体内的大规模研究铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Xenotransplantation
Xenotransplantation 医学-医学:研究与实验
CiteScore
6.80
自引率
15.40%
发文量
58
审稿时长
>12 weeks
期刊介绍: Xenotransplantation provides its readership with rapid communication of new findings in the field of organ and tissue transplantation across species barriers.The journal is not only of interest to those whose primary area is xenotransplantation, but also to veterinarians, microbiologists and geneticists. It also investigates and reports on the controversial theological, ethical, legal and psychological implications of xenotransplantation.
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