Fealy M J, Most D, Huie P, Wolf M, Sibley R K, Morris R E, Press B H
Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, California, USA.
Transplantation. 1995 May 27;59(10):1475-80. doi: 10.1097/00007890-199505270-00020.
Cytokines are short-acting protein modulators of many physiologic processes including graft rejection. An understanding of the production, action, and interaction of cytokines may lead to better appreciation of the complex mechanism of graft rejection. The potential would then exist for more selective and less-toxic means of modulating the immune response. A rat hind limb allograft model with major immunohistoincompatibility was used to study the local mRNA expression of IL-1 alpha, IL-2, IL-6, gamma interferon (gamma INF), platelet-derived growth factor-alpha (PDGF-alpha), basic fibroblast growth factor (FGF), and transforming growth factor-beta (TGF-beta) during acute allograft rejection. A 14-day postoperative course of immunosuppressive therapy with FK506 or rapamycin was administered. In situ hybridization was performed on serial full-thickness skin punch biopsies of the untreated rejecting limb allograft and compared with tissue from treated allografts, isografts, and to normal limb tissue. A sequential pattern of cytokine mRNA expression was demonstrated which progressed in a time-dependent manner and paralleled observed clinical rejection. Maximal cytokine mRNA expression correlated with peak graft rejection. Cellular expression of IL-1 alpha, IL-2, IL-6, gamma-INF, FGF, and TGF-beta mRNA was suppressed with FK506 to below isograft levels, and clinical rejection was not observed with the doses, routes, and schedules used. Rapamycin was ineffective in suppressing cytokine expression, and allograft rejection was not prevented. Isografts demonstrated no evidence of rejection. The in situ hybridization technique demonstrates a time-dependent, selective expression of cytokines within rejecting allograft tissue, and the modification of this response with immunosuppressive therapy. Down-regulation of cytokine expression is associated with clinical allograft survival.
细胞因子是许多生理过程（包括移植排斥反应）的短效蛋白调节剂。了解细胞因子的产生、作用和相互作用，可能有助于更好地理解移植排斥反应的复杂机制。届时，将有可能采用更具选择性且毒性更小的方法来调节免疫反应。利用具有主要组织免疫不相容性的大鼠后肢同种异体移植模型，研究急性同种异体移植排斥反应期间白细胞介素-1α（IL-1α）、白细胞介素-2（IL-2）、白细胞介素-6（IL-6）、γ干扰素（γINF）、血小板衍生生长因子-α（PDGF-α）、碱性成纤维细胞生长因子（FGF）和转化生长因子-β（TGF-β）的局部mRNA表达。给予为期14天的FK506或雷帕霉素免疫抑制治疗。对未治疗的排斥肢体同种异体移植的连续全层皮肤打孔活检进行原位杂交，并与治疗后的同种异体移植、同基因移植组织以及正常肢体组织进行比较。结果显示细胞因子mRNA表达呈序贯模式，该模式呈时间依赖性进展，与观察到的临床排斥反应平行。细胞因子mRNA的最大表达与移植排斥反应高峰相关。FK506可将IL-1α、IL-2、IL-6、γ-INF、FGF和TGF-β mRNA的细胞表达抑制至同基因移植水平以下，且所使用的剂量、途径和给药方案未观察到临床排斥反应。雷帕霉素在抑制细胞因子表达方面无效，且不能预防同种异体移植排斥反应。同基因移植未显示排斥反应迹象。原位杂交技术显示了排斥同种异体移植组织内细胞因子的时间依赖性、选择性表达，以及免疫抑制治疗对这种反应的改变。细胞因子表达的下调与临床同种异体移植存活相关。
