Induction of Mixed Chimerism Using Combinatory Cell-Based Immune Modulation with Mesenchymal Stem Cells and Regulatory T Cells for Solid-Organ Transplant Tolerance
Induction of Mixed Chimerism Using Combinatory Cell-Based Immune Modulation with Mesenchymal Stem Cells and Regulatory T Cells for Solid-Organ Transplant Tolerance
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DOI：
10.1089/scd.2013.0617
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发表时间：
2014-10-01
影响因子：
4
通讯作者：
Cho, Seok-Goo
中科院分区：
文献类型：
--
作者：
Im, Keon-Il;Park, Min-Jung;Cho, Seok-Goo
建立混合嵌合体是诱导供体特异性耐受的理想方法，同时扩大其在各种临床环境中的潜力。尽管在部分预处理方案的发展，仍然需要改进，以减少毒性和骨髓移植相关的并发症。最近，基于细胞的疗法，包括间充质干细胞（MSC），已被纳入建立非细胞减少混合嵌合体协议，然而，其疗效只是部分的，并显示出逆转的免疫抑制特性。本研究展示了一种通过MSC和调节性T细胞（TCFs）的组合基于细胞的免疫调节（CCIM）来诱导混合嵌合和耐受的新方法。我们推测这些细胞之间的相互作用可能导致宿主免疫反应的更大抑制。与单细胞疗法相比，CCIM诱导了更高的植入率和强大的供体特异性耐受皮肤同种异体移植物跨越完整的主要组织相容性复合物屏障。这些调节作用与抑制自然杀伤细胞细胞毒活性、CD 4（+）IL-17（+）细胞、记忆B细胞、浆细胞和免疫球蛋白产生水平沿着增加CD 4（+）Foxp 3（+）细胞、产生IL-10的成熟B细胞和髓源性抑制细胞的频率相关。此外，CCIM能够通过相互调节Treg/Th 17来调节移植物抗宿主病模型中的死亡率。综上所述，我们建议CCIM作为促进诱导混合嵌合体和永久耐受的临床适用策略。
Establishment of mixed chimerism is an ideal approach to induce donor-specific tolerance while expanding its potential in various clinical settings. Despite the developments in partial conditioning regimens, improvements are still needed in reducing toxicity and bone marrow transplantation-related complications. Recently, cell-based therapies, including mesenchymal stem cells (MSCs), have been incorporated in establishing noncytoreductive mixed chimerism protocols; however, its efficacy is only partial and shows reversed immunosuppressive properties. This study demonstrates a novel approach to induce mixed chimerism and tolerance through combinatory cell-based immune modulation (CCIM) of MSCs and regulatory T cells (Tregs). We hypothesize that the interaction between these cells may lead to greater inhibition of host immune responses. Compared with single cell therapy, CCIM induced a higher engraftment rate and robust donor-specific tolerance to skin allografts across full major histocompatibility complex barriers. These regulatory effects were associated with inhibition of natural killer cell cytotoxic activity, CD4(+)IL-17(+) cells, memory B cells, plasma cells, and immunoglobulin production levels along with increased frequencies of CD4(+)Foxp3(+) cells, IL-10-producing mature B cells, and myeloid-derived suppressor cells. Furthermore, CCIM was able to regulate mortality in a graft-versus-host disease model through reciprocal regulation of Treg/Th17. Taken together, we suggest CCIM as a clinically applicable strategy for facilitating the induction of mixed chimerism and permanent tolerance.