Okunuki Yoko, Usui Yoshihiko, Nagai Norihiro, Kezuka Takeshi, Ishida Susumu, Takeuchi Masaru, Goto Hiroshi
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.
Invest Ophthalmol Vis Sci. 2009 May;50(5):2255-61. doi: 10.1167/iovs.08-2649. Epub 2009 Jan 10.
Angiotensin II type 1 receptor (AT1-R) blockers are used widely for the treatment of patients with hypertension. Recent reports have suggested that AT1-R also plays a key role in various inflammatory conditions. The aim of this study was to examine whether blockade of AT1-R is effective in the suppression of murine experimental autoimmune uveoretinitis (EAU).
C57BL/6 mice were immunized with human interphotoreceptor retinoid binding protein-derived peptide 1-20 (hIRBP-p). Telmisartan, an AT1-R blocker, was administrated daily by intraperitoneal injection. On day 21 after immunization, the severity of EAU was assessed clinically and histopathologically. With the use of flow cytometry, the activation of draining lymph node (LN) cells was assessed by cell proliferation response against hIRBP-p and by the number of CD44(high) activated CD4(+) T cells present. In addition, mRNA expression of ICAM-1, MCP-1, and IFN-gamma in the eye was analyzed by reverse-transcriptase PCR, and the number of retinal adherent leukocytes was counted by retinal perfusion labeling.
Telmisartan significantly suppressed EAU clinically and histopathologically. Intraocular mRNA expression of ICAM-1 and MCP-1 was downregulated, and the retinal adherent leukocyte counts were significantly decreased in telmisartan-treated mice compared with vehicle-treated mice. LN cell proliferative responses against hIRBP-p and the number of CD44(high)CD4(+) T cells were remarkably reduced in telmisartan-treated mice.
Systemic administration of telmisartan significantly suppressed EAU by the inhibition of antigen-specific T-cell activation in the LNs and of leukocyte adhesion in the retina. These results indicate that telmisartan may be a novel therapeutic regimen for patients with endogenous uveitis.
血管紧张素II 1型受体（AT1-R）阻滞剂被广泛用于治疗高血压患者。最近的报告表明，AT1-R在各种炎症性疾病中也起关键作用。本研究的目的是检查阻断AT1-R是否能有效抑制小鼠实验性自身免疫性葡萄膜视网膜炎（EAU）。
用人类光感受器间维生素A结合蛋白衍生肽1-20（hIRBP-p）免疫C57BL/6小鼠。AT1-R阻滞剂替米沙坦通过腹腔注射每日给药。免疫后第21天，通过临床和组织病理学评估EAU的严重程度。使用流式细胞术，通过针对hIRBP-p的细胞增殖反应和存在的CD44（高）活化CD4（+）T细胞数量评估引流淋巴结（LN）细胞的活化。此外，通过逆转录聚合酶链反应分析眼中ICAM-1、MCP-1和IFN-γ的mRNA表达，并通过视网膜灌注标记计数视网膜黏附白细胞的数量。
替米沙坦在临床和组织病理学上显著抑制了EAU。与载体处理的小鼠相比，替米沙坦处理的小鼠眼中ICAM-1和MCP-1的眼内mRNA表达下调，视网膜黏附白细胞计数显著降低。替米沙坦处理的小鼠中，LN细胞对hIRBP-p的增殖反应和CD44（高）CD4（+）T细胞的数量显著减少。
替米沙坦的全身给药通过抑制LN中抗原特异性T细胞活化和视网膜中的白细胞黏附，显著抑制了EAU。这些结果表明，替米沙坦可能是内源性葡萄膜炎患者的一种新型治疗方案。
