Peroxisome proliferator-activated receptor-γ agonists prevent in vivo remodeling of human artery induced by alloreactive T cells.
Peroxisome proliferator-activated receptor-γ agonists prevent in vivo remodeling of human artery induced by alloreactive T cells.
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DOI：
10.1161/circulationaha.110.015396
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发表时间：
2011-07-12
期刊：
影响因子：
37.8
通讯作者：
Bothwell AL
中科院分区：
文献类型：
--
作者：
Tobiasova Z;Zhang L;Yi T;Qin L;Manes TD;Kulkarni S;Lorber MI;Rodriguez FC;Choi JM;Tellides G;Pober JS;Kawikova I;Bothwell AL
激活转录因子过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ）的配体具有抑制作用。同种异体T细胞诱导的血管排斥反应可导致急性和慢性移植物丢失。啮齿类动物研究表明，PPARγ激动剂可能抑制移植血管排斥反应，但人类T细胞对同种异体血管细胞的反应与啮齿类动物不同，PPARγ在人类移植中的作用尚不清楚。我们使用一种模型测试了PPARγ激动剂对人血管移植物排斥反应的影响，在该模型中，将人动脉插入免疫缺陷小鼠的腹主动脉，随后过继转移同种异体（动脉供体）人外周血单核细胞。4周内出现干扰素-γ依赖性排斥反应，特征为内膜增厚、T细胞浸润和血管细胞活化，类似临床内膜动脉炎的反应。PPARγ激动剂15-脱氧-前列腺素-J2、环格列酮和吡格列酮可减少内膜扩张、CD 45 RO+记忆T细胞的内膜浸润和炎性细胞因子的血浆水平。PPARγ拮抗剂GW 9662逆转了PPARγ激动剂的保护作用，证实了PPARγ介导的通路的参与。在体外，吡格列酮抑制同种抗原诱导的记忆T细胞增殖和超抗原诱导的记忆T细胞跨内皮迁移，表明了PPARγ效应的潜在机制。我们的研究结果表明，过氧化物酶体增殖物激活受体γ激动剂抑制同种异体人类记忆T细胞反应，并可能是有用的治疗血管移植排斥反应。
Ligands activating the transcription factor peroxisome proliferator–activated receptor-γ (PPARγ) have antiinflammatory effects. Vascular rejection induced by allogeneic T cells can be responsible for acute and chronic graft loss. Studies in rodents suggest that PPARγ agonists may inhibit graft vascular rejection, but human T-cell responses to allogeneic vascular cells differ from those in rodents, and the effects of PPARγ in human transplantation are unknown. We tested the effects of PPARγ agonists on human vascular graft rejection using a model in which human artery is interposed into the abdominal aorta of immunodeficient mice, followed by adoptive transfer of allogeneic (to the artery donor) human peripheral blood mononuclear cells. Interferon-γ–dependent rejection ensues within 4 weeks, characterized by intimal thickening, T-cell infiltrates, and vascular cell activation, a response resembling clinical intimal arteritis. The PPARγ agonists 15-deoxy-prostaglandin-J2, ciglitazone, and pioglitazone reduced intimal expansion, intimal infiltration of CD45RO+ memory T cells, and plasma levels of inflammatory cytokines. The PPARγ antagonist GW9662 reversed the protective effects of PPARγ agonists, confirming the involvement of PPARγ-mediated pathways. In vitro, pioglitazone inhibited both alloantigen-induced proliferation and superantigen-induced transendothelial migration of memory T cells, indicating the potential mechanisms of PPARγ effects. Our results suggest that PPARγ agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection.