Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn's disease.
Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn's disease.
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DOI：
10.1136/gutjnl-2014-306919
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发表时间：
2016-04
期刊：
影响因子：
24.5
通讯作者：
Lord GM
中科院分区：
文献类型：
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作者：
Canavan JB;Scottà C;Vossenkämper A;Goldberg R;Elder MJ;Shoval I;Marks E;Stolarczyk E;Lo JW;Powell N;Fazekasova H;Irving PM;Sanderson JD;Howard JK;Yagel S;Afzali B;MacDonald TT;Hernandez-Fuentes MP;Shpigel NY;Lombardi G;Lord GM
胸腺源性调节性T细胞（TCRs）介导显性外周耐受并治疗实验性结肠炎。可从患者血液中扩增THBE，并在最近的移植物抗宿主病和1型糖尿病的I期研究中安全使用。Treg细胞疗法在概念上也对克罗恩病（CD）有吸引力。然而，这一做法存在障碍。从克罗恩氏血中扩增的TdR的稳定性尚不清楚。过继性转移的TGFAP表达白细胞介素-17和加剧克罗恩病病变的可能性值得关注。在活动性CD中，粘液T细胞对Treg介导的抑制具有抗性。扩增的TdR归巢肠道和淋巴组织的能力尚不清楚。为了确定CD中Treg细胞治疗的最佳群体，从患者血液中分离出CD4 + CD25 + CD127loCD45RA+和CD4 + CD25 + CD127loCD45RA-Treg亚群，并使用可容易地转移到良好生产实践背景的工作流程进行体外扩增。T细胞可以在22 - 24天内从CD患者的血液中扩增至潜在的目标剂量。 扩增的CD45RA + T细胞具有表观遗传学稳定的FOXP3位点，并且与CD45RA − T细胞相反，在体外不会转化为Th17表型。CD45RA + TcR高表达α 4 β 7整合素、CD62L和CC基序受体7（CCR7）。在C.B-17严重联合免疫缺陷（SCID）异种移植模型中，CD45 RA + T细胞也归巢于人小肠。重要的是，体外扩增增强了CD45RA + TcB的抑制能力。这些细胞还抑制从发炎的克罗恩氏粘膜分离的固有层和肠系膜淋巴结淋巴细胞的活化。CD4 + CD25 + CD127loCD45RA + TcG可能是最适合扩增TcG用于CD自体Treg治疗的人群，为未来的临床试验铺平了道路。
Thymus-derived regulatory T cells (Tregs) mediate dominant peripheral tolerance and treat experimental colitis. Tregs can be expanded from patient blood and were safely used in recent phase 1 studies in graft versus host disease and type 1 diabetes. Treg cell therapy is also conceptually attractive for Crohn's disease (CD). However, barriers exist to this approach. The stability of Tregs expanded from Crohn's blood is unknown. The potential for adoptively transferred Tregs to express interleukin-17 and exacerbate Crohn's lesions is of concern. Mucosal T cells are resistant to Treg-mediated suppression in active CD. The capacity for expanded Tregs to home to gut and lymphoid tissue is unknown. To define the optimum population for Treg cell therapy in CD, CD4+CD25+CD127loCD45RA+ and CD4+CD25+CD127loCD45RA− Treg subsets were isolated from patients’ blood and expanded in vitro using a workflow that can be readily transferred to a good manufacturing practice background. Tregs can be expanded from the blood of patients with CD to potential target dose within 22–24 days. Expanded CD45RA+ Tregs have an epigenetically stable FOXP3 locus and do not convert to a Th17 phenotype in vitro, in contrast to CD45RA− Tregs. CD45RA+ Tregs highly express α4β7 integrin, CD62L and CC motif receptor 7 (CCR7). CD45RA+ Tregs also home to human small bowel in a C.B-17 severe combined immune deficiency (SCID) xenotransplant model. Importantly, in vitro expansion enhances the suppressive ability of CD45RA+ Tregs. These cells also suppress activation of lamina propria and mesenteric lymph node lymphocytes isolated from inflamed Crohn's mucosa. CD4+CD25+CD127loCD45RA+ Tregs may be the most appropriate population from which to expand Tregs for autologous Treg therapy for CD, paving the way for future clinical trials.