Azuma H, Binder J, Heemann U, Schmid C, Tullius S G, Tilney N L
Surgical Research Laboratory, Harvard Medical School, Boston, Massachusetts.
Transplantation. 1995 Feb 27;59(4):460-6.
No immunosuppression agent is as yet available that prevents the process of chronic allograft rejection, the most critical cause of late organ allograft loss. RS61443 (mycophenolate mofetil) inhibits de novo DNA synthesis as well as diminishes expression of cell surface molecules and antibody production. As these factors seem important in the pathophysiology of the chronic phenomenon, we investigated the effects of the agent in an established model of chronic rejection of kidney allografts in a F344-to-Lewis rat strain combination. All recipients were treated for the first 10 days after engraftment with low-dose cyclosporine (1.5 mg/kg/day) to reverse an initial acute rejection episode. Since functional and morphological changes do not become manifest in this model until after 12 wk, treatment with RS61443 (15 mg/kg/day, p.o.) was either initiated at the day of grafting (Gp 1) or 8 wks thereafter (Gp 2), and continued throughout the follow-up period. Non-RS61443-treated allografted rats receiving vehicle only (Gp 3) developed progressive proteinuria after 12 wk. Peak cellular infiltration (particularly macrophages in glomeruli and perivascular areas) at 16 wk was associated with densely expressed adhesion molecules (ICAM-1 on endothelium), cytokines and growth factors (TNF-alpha and TGF-beta in glomeruli and PDGF on arterial smooth muscle cells). Interstitial fibrosis, with tubular atrophy, glomerulosclerosis, and varying degrees of intimal proliferation and luminal obliteration of vessels, progressed thereafter. In vitro binding of MNC from naive animals to chronically rejecting allografted kidneys generally confirmed the immunohistological observations, peaking at 12 wk; this binding was significantly inhibited by mAbs against specific adhesion molecules (CD11a, CD18, and ICAM-1). Serum-allospecific IgG and IgM peaked at 1-2 wk after engraftment in the control recipients, decreasing thereafter. Although IgM declined to baseline after 12 wk, low levels of allospecific IgG persisted throughout the follow-up period. In contrast, recipient treatment with RS61443 (both Gp 1 and Gp 2) allowed the allografts to function normally throughout follow-up period. Proteinuria was virtually absent, and morphological and immunohistological manifestations of the chronic process were markedly diminished. In addition, treated recipients developed no significant side effects, including leukopenia, anemia, thrombopenia, nephrotoxicity, and hepatotoxicity. It appears that this agent can safely prevent the changes of chronic rejection of kidney allografts in this rat model.
目前尚无能够阻止慢性同种异体移植排斥反应进程的免疫抑制药物，而慢性同种异体移植排斥反应是晚期器官移植失败的最关键原因。RS61443（霉酚酸酯）可抑制从头DNA合成，并减少细胞表面分子的表达及抗体产生。由于这些因素在慢性排斥反应的病理生理过程中似乎很重要，我们在F344到Lewis大鼠品系组合的已建立的肾移植慢性排斥反应模型中研究了该药物的作用。所有受体在植入后第1天开始的前10天用低剂量环孢素（1.5mg/kg/天）治疗，以逆转最初的急性排斥反应。由于在该模型中直到12周后功能和形态学变化才会显现，因此RS61443（15mg/kg/天，口服）的治疗要么在移植当天开始（第1组），要么在8周后开始（第2组），并在整个随访期持续。仅接受赋形剂的未用RS61443治疗的同种异体移植大鼠（第3组）在12周后出现进行性蛋白尿。16周时的细胞浸润高峰（特别是肾小球和血管周围区域的巨噬细胞）与粘附分子（内皮细胞上的ICAM-1）、细胞因子和生长因子（肾小球中的TNF-α和TGF-β以及动脉平滑肌细胞上的PDGF）的高表达相关。此后出现间质纤维化，并伴有肾小管萎缩、肾小球硬化以及不同程度的血管内膜增生和管腔闭塞。来自未接触过抗原动物的单核细胞与慢性排斥的同种异体移植肾的体外结合通常证实了免疫组织学观察结果，在12周时达到高峰；这种结合被针对特定粘附分子（CD11a、CD18和ICAM-1）的单克隆抗体显著抑制。血清同种异体特异性IgG和IgM在对照受体植入后1-2周达到高峰，此后下降。虽然IgM在12周后降至基线，但同种异体特异性IgG的低水平在整个随访期持续存在。相比之下，用RS61443治疗的受体（第1组和第2组）在整个随访期内同种异体移植肾功能正常。几乎没有蛋白尿，慢性排斥反应的形态学和免疫组织学表现明显减轻。此外，接受治疗的受体未出现明显的副作用，包括白细胞减少、贫血、血小板减少、肾毒性和肝毒性。看来该药物可以安全地预防该大鼠模型中肾移植慢性排斥反应的变化。
