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

目的慢性排斥反应是同种异体移植物长期接受的主要障碍。尽管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排斥反应的机制尚不清楚。我们开发了新的抑制化合物伽马内酯，以产生MF效应器。伽马内酯抑制MF效应分子的产生，称为自发性空斑形成细胞，其中自发性空斑形成细胞是由CD11/CD18CD18β2-整合素介导的。在本研究中，我们研究了在人肾移植的CA排斥反应和实验性进展性肾病大鼠的肾纤维化过程中，表达在MF-效应分子上的分子。结果与讨论在CA排斥的人移植肾活检标本中，表达于MF、CD5B细胞或NK细胞上的CD11b阳性细胞明显高于CD5阳性细胞。采用改良的SD大鼠单侧输尿管梗阻模型，松解7天后，给予伽玛内酯治疗21天。经伽马内酯治疗的动物的肾小球和肾小管间质病变较未治疗的对照组动物明显改善。对照组CD11b阳性细胞明显渗出，CCR2、CCR5、CXCR2、CXCR4、CX3Cr1等基因表达增强。我们对β-2-整合素CD11b单抗作用的研究表明，该单抗可以调节CD11b分子，预防轻度但不严重的缺血性肾损伤。综上所述，CD11b分子可能参与了肾脏疾病的进展。目前的临床和实验研究提示β-2整合素CD11b可能在进行性肾脏疾病和CA排斥反应中的重要作用。

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.