Hancock W H, Whitley W D, Tullius S G, Heemann U W, Wasowska B, Baldwin W M, Tilney N L
Surgical Research Laboratory, Harvard Medical School, Boston, Massachusetts.
Transplantation. 1993 Sep;56(3):643-50. doi: 10.1097/00007890-199309000-00028.
Little is known of the host immune mechanisms responsible for initiation and progression of chronic rejection. We describe immunopathologic features associated with progressively deteriorating function of kidney allografts in the F344-to-Lewis rat strain combination, which differ at MHC and non-MHC loci. Initial rejection in untreated recipients was controlled by a brief course of CsA (5 mg/kg/day, for 10 days), resulting in > 80% of recipients surviving up to a year despite declining renal function. In contrast to controls (isografts placed in untreated or CsA-treated Lewis rats), allografts from 12-16 weeks post-Tx showed segmental or global glomerulosclerosis, increasing tubular atrophy, interstitial fibrosis, and intimal proliferation leading ultimately to vascular occlusion. By flow cytometry, IgM and IgG alloantibodies peaked at 2-4 weeks, with a gradual decline to baseline thereafter. Immunohistology showed early and progressive deposition of IgM, IgG, C3, and fibrin in vessel walls and glomeruli. In addition, by 12 weeks, extensive infiltration by activated (IL-2R+) macrophages and CD4+ T cells were noted in glomeruli and blood vessels, in conjunction with staining for the cytokines TNF-alpha, IL-1, and IL-6. The persistent and dense intraglomerular expression of IL-6 was of particular interest, given its potent mitogenic effects for mesangial cells in vitro, and suggests a role for this cytokine as a mediator of mesangial expansion, advanced glomerular injury, and glomerulosclerosis in chronic rejection. Parallel timing of IL-6 and TNF-alpha expression was shown in serum samples by ELISA and bioassays. In vitro binding studies showed increased binding of naive host lymphocytes to allograft versus isografts, correlating with upregulation (peaking at week 16) of intercellular adhesion molecule-1 expression by graft endothelium. We conclude that cytokine production and upregulation of adhesion molecules occurring as part of a cellular immune response may be as important to the etiology of chronic rejection as the hitherto widely emphasized antibody-mediated host responses.
关于负责慢性排斥反应起始和进展的宿主免疫机制，人们了解甚少。我们描述了F344到Lewis大鼠品系组合中与同种异体肾移植功能逐渐恶化相关的免疫病理特征，这两个品系在主要组织相容性复合体（MHC）和非MHC位点存在差异。未治疗受体的初始排斥反应通过短期使用环孢素A（CsA，5毫克/千克/天，持续10天）得到控制，尽管肾功能下降，但仍有超过80%的受体存活长达一年。与对照组（植入未治疗或经CsA治疗的Lewis大鼠的同基因移植）相比，移植后12 - 16周的同种异体移植显示节段性或全球性肾小球硬化、肾小管萎缩增加、间质纤维化以及内膜增生，最终导致血管闭塞。通过流式细胞术检测，IgM和IgG同种异体抗体在2 - 4周达到峰值，此后逐渐下降至基线水平。免疫组织学显示IgM、IgG、C3和纤维蛋白在血管壁和肾小球中早期且逐渐沉积。此外，到12周时，在肾小球和血管中观察到活化的（IL - 2R +）巨噬细胞和CD4 + T细胞广泛浸润，同时伴有细胞因子肿瘤坏死因子 - α（TNF - α）、白细胞介素 - 1（IL - 1）和白细胞介素 - 6（IL - 6）的染色。鉴于IL - 6在体外对系膜细胞具有强大的促有丝分裂作用，其在肾小球内持续且密集的表达尤为引人关注，这表明该细胞因子在慢性排斥反应中作为系膜扩张、晚期肾小球损伤和肾小球硬化的介质发挥作用。通过酶联免疫吸附测定（ELISA）和生物测定法在血清样本中显示了IL - 6和TNF - α表达的平行时间关系。体外结合研究表明，未致敏宿主淋巴细胞与同种异体移植的结合增加，相对于同基因移植而言，这与移植内皮细胞上细胞间黏附分子 - 1表达上调（在第16周达到峰值）相关。我们得出结论，作为细胞免疫反应一部分而发生的细胞因子产生和黏附分子上调，对于慢性排斥反应的病因学可能与迄今广泛强调的抗体介导的宿主反应同样重要。
