Therapy for collagen diseases by using chemokine antagonists

趋化因子受体拮抗剂的使用是阻断趋化因子作用的另一种方法，有可能为自身免疫性疾病提供新的治疗方法。将NH_2末端截短的MCP-1或Fractalkine类似物转化为分泌型，插入到pCXN2表达载体中，并转入非转移性成纤维细胞样细胞TIN。MRL/N-1。将MCP-1拮抗剂或Fractalkine拮抗剂转基因的MRL/N-1细胞分别注射于7周龄(狼疮性肾炎前)和12周龄(狼疮性肾炎早期)的MRL/LPR小鼠，8周后，MCP-1拮抗剂和Fractalkine拮抗剂组小鼠巨噬细胞和T细胞的浸润明显减少，肾小球细胞增多、肾小球硬化、新月体形成和血管炎也明显减少。此外，与对照组相比，携带MCP-1拮抗剂的小鼠改善了涎腺炎的进展。为探讨SLC拮抗剂对慢性移植物抗宿主病(GVHD)的抑制作用，将DBA/2脾细胞注射于(C57BL/6 X DBA/2)F1小鼠体内，建立慢性GVHD模型。SLC拮抗剂处理的GVHD小鼠脾细胞总数、宿主B细胞总数、血清IgE水平以及抗DNA抗体的总Ig G和Ig G1水平均显著低于PBS对照组。提示SLC拮抗剂对慢性移植物抗宿主病有一定的预防作用。

The use of receptor antagonists for chemokines is an alternative approach to blocking cnemokine actions and has the potential to provide novel therapeutics for autoimmune diseases. The NH_2-terminally truncated MCP-1 or fractalkine analogues were converted to secreting forms, inserted into the pCXN2 expression vector and transfected into a non-metastatic fibroblastoid cell tin. MRL/N-1. MCP-1-antagonist-or fractalkine-antagonist-transfected MRL/N-1 cells were injected subcutaneously into MRL/lpr mice aged 7 wk (before the initiation of lupus nephritis) and 12 wk (at the early stage of the disease) After 8 weeks, MCP-1-antagonist-and fractalkine-antagonist-bearing mice showed markedly diminished infiltration of macrophages and T cells, glomerular hypercellularity, glomerulosclerosis, crescent formation and also vasculitis compared with control mice. In addition, MCP-1-antagonist-bearing mice ameliorated the progression of sialadenitis compared with control mice. To determine whether SLC antagonist inhibits the development of chronic GVHD, chronic GVHD was induced by injecting DBA/2 spleen cells into (C57BL/6 X DBA/2) F1 mice. Total numbers of spleen cells and host B cells, serum levels of IgE, and of total IgG and IgG1 of anti-DNA antibodies in SLC antagonist-treated GVHD mice were significantly lower than those in control PBS-treated GVHD mice. This result suggests that SLC antagonist has beneficial effects for the prevention of chronic GVIHD.