Study on the Rationale of Prevention of chronic allograft rejection explored by Inhibitory compound of macrophage-effector generation

目的：慢性同种异体移植排斥反应是长期接受同种异体移植的主要障碍。虽然T细胞和巨噬细胞（Mf）被认为参与了CA排斥反应，但这些免疫细胞介导的CA排斥反应机制尚不清楚。我们开发了新的抑制化合物，γ内酯，mf效应代。Gammalactone抑制mf效应的产生，称为自发性斑块形成细胞（SPFC），其中SPFC是由CD11/CD18 β2整合素介导的。在本研究中，我们探讨了在mf效应上表达的哪些分子参与了人肾移植CA排斥反应和实验性进展性肾病大鼠肾纤维化。结果与讨论在CA排斥反应的人肾移植活检标本中，CD11b阳性细胞（表达于Mf细胞、CD5+B细胞或NK细胞上）明显多于CD5阳性细胞。SD大鼠单侧输尿管梗阻改良模型，释放7d后持续14天，在整个研究过程中给予gammalactone 21天。伽玛内酯治疗的动物的肾小球和小管间质病变比未治疗的对照动物得到更显著的改善。cd11b阳性细胞在对照动物中显著浸润，CCR2、CCR5、CXCR2、CXCR4和CX3Crl mRNA水平在对照动物中升高。我们对β2-整合素抗CD11b单克隆抗体作用的研究表明，该抗体可调节CD11b分子，预防轻度而非重度缺血性肾损伤。综上所述，CD11b分子可能参与肾脏疾病的进展。目前的临床和实验研究表明，β2整合素的CD11b可能在进行性肾脏疾病和CA排斥反应中表达。

PURPOSE The main obstacle of long -term acceptance of transplanted allograft is chronic allograft (CA) rejection. Although T cells and macrophages (Mf) are suggested to be involved in, the mechanism of CA rejection mediated by those immune cells is obscure. We developed the new inhibitory compound, gammalactone, of Mf-effector generation. Gammalactone inhibits the generation of Mf-effector, designated as Spontaneous Plaque-Forming Cell(SPFC) , in which SPFC is mediated by CD11/CD18 β2-integrin. In the present study, we investigated which kinds of molecules expressed on Mf-effector are involved in CA rejection of human renal transplant and in renal fibrosis of experimental progressive renal disease in rats. RESULTS & Discussion In biopsy specimen of human renal allograft of CA rejection, CD11b positive cells , which are expressed on Mf, CD5+B cells or NK cells, were detected more significantly than CD5-positive cells. Using the modified model of unilateral ureteral obstruction for 14 days following release for 7days in SD rats, gammalactone was administered for 21 days throughout the study. The glomerular and tubulointerstitial lesions in animals treated with gammalactone were ameliorated more significantly than the untreated control animals. The CD11b-positive cells were significantly infiltrated in control animals, and the mRNA level of CCR2, CCR5, CXCR2, CXCR4, and CX3Crl were augmented in the control animals. Our studies of the effect of monoclonal antibody against CD11b of β2-integrin demonstrated that the antibody modulated the CD11b molecules and prevented the mild, but not severe ischemic renal injury. Together taken in, the molecule of CD11b might be involved in the progression of renal diseases. SUMMARY The present clinical and experimental studies suggested the important role of CD11b of β2-integrin, probably expressed on Mf in progressive renal disease as well as CA rejection.