Hancock W W, Lord R H, Colby A J, Diamantstein T, Rickles F R, Dijkstra C, Hogg N, Tilney N L
J Immunol. 1987 Jan 1;138(1):164-70.
Monoclonal antibodies to lymphokine-induced activation antigens of lymphocytes and macrophages were used to analyze the intragraft events occurring during acute rejection of rat heterotopic cardiac allografts. The cells present during untreated rejection were then compared with those present in situ after immunosuppression with the mouse anti-rat IL 2 receptor (anti-IL 2R) monoclonal antibody ART-18 or cyclosporin (CsA). Untreated rats rejected their grafts within 7 days, whereas rats receiving 10 days of i.v. ART-18 antibody therapy showed graft prolongation to more than 21 days, and rats receiving CsA for 7 days maintained their grafts indefinitely. Untreated rejection was associated with an influx of T (W3/13+) cells and macrophages (ED-1+, ED-2+). Activated mononuclear cells (IL 2R+) were identified within rejecting grafts from day 2, and their numbers peaked on days 4 to 6 when 15 to 20% of infiltrating leukocytes were IL 2R+. Double labeling studies of IL 2R+ cells present at day 6 showed surprisingly that both T cells and macrophages expressed IL 2R. In particular, although 55.8 +/- 6.9% (mean +/- SD) of IL 2R+ cells expressed the pan-T cell antigen 3/13, a similar proportion of IL 2R+ cells (49.8 +/- 8.2%) expressed the macrophage antigen ED-2. Conversely, both T cells and macrophage populations showed heterogeneity in their expression of IL 2R, because 39.2 +/- 12.2% of T cells and 31.0 +/- 13.4% of macrophages were IL 2R+. In addition, inflammatory macrophages at day 6 expressed the A1-3 antigen. Expression of this antigen by macrophages has previously been linked with development of macrophage procoagulant activity, and in this model intragraft inflammatory macrophages were closely associated with widespread deposits of fibrin. By comparison with untreated animals, rats treated with either ART-18 or CsA both lacked detectable IL 2R+ cells during the first 14 days post-transplantation (post-Tx), and showed significantly less cellular infiltration. However, although grafts of CsA-treated animals continued to remain IL 2R- and failed to stain with the macrophage activation marker A1-3, ART-18-treated rats showed increasing infiltration by both IL 2R+ mononuclear cells and A1-3+ macrophages, as well as increasing perivascular and interstitial fibrin deposition, prior to rejection by day 22. These studies document the presence of small number of activated intragraft T cells and macrophages during rat cardiac rejection, and show how CsA, and to a lesser extent anti-IL 2R therapy, inhibit this in situ activation and prolong graft survival. (ABSTRACT TRUNCATED AT 400 WORDS)
利用针对淋巴细胞和巨噬细胞的淋巴因子诱导激活抗原的单克隆抗体，分析大鼠异位心脏同种异体移植急性排斥反应期间移植物内发生的事件。然后将未治疗排斥反应期间存在的细胞与用小鼠抗大鼠白细胞介素2受体（抗IL-2R）单克隆抗体ART-18或环孢素（CsA）免疫抑制后原位存在的细胞进行比较。未治疗的大鼠在7天内排斥其移植物，而接受10天静脉注射ART-18抗体治疗的大鼠移植物存活期延长至21天以上，接受CsA治疗7天的大鼠移植物可无限期维持存活。未治疗的排斥反应与T（W3/13+）细胞和巨噬细胞（ED-1+、ED-2+）的流入有关。从第2天起在排斥的移植物中鉴定出活化的单核细胞（IL-2R+），其数量在第4至6天达到峰值，此时浸润的白细胞中有15%至20%为IL-2R+。对第6天存在的IL-2R+细胞进行双重标记研究，结果令人惊讶地发现T细胞和巨噬细胞均表达IL-2R。特别是，虽然55.8±6.9%（平均值±标准差）的IL-2R+细胞表达泛T细胞抗原3/13，但类似比例的IL-2R+细胞（49.8±8.2%）表达巨噬细胞抗原ED-2。相反，T细胞和巨噬细胞群体在IL-2R表达上均表现出异质性，因为39.2±12.2%的T细胞和31.0±13.4%的巨噬细胞为IL-2R+。此外，第6天的炎性巨噬细胞表达A1-3抗原。巨噬细胞对该抗原的表达此前已与巨噬细胞促凝活性的发展相关联，在该模型中，移植物内炎性巨噬细胞与广泛的纤维蛋白沉积密切相关。与未治疗的动物相比，用ART-18或CsA治疗的大鼠在移植后（Tx后）的前14天均未检测到IL-2R+细胞，且细胞浸润明显减少。然而，尽管用CsA治疗的动物的移植物继续保持IL-2R阴性且未用巨噬细胞活化标记A1-3染色，但在第22天排斥之前，用ART-18治疗的大鼠显示IL-2R+单核细胞和A1-3+巨噬细胞浸润增加，以及血管周围和间质纤维蛋白沉积增加。这些研究证明了大鼠心脏排斥反应期间移植物内存在少量活化的T细胞和巨噬细胞，并表明CsA以及程度较轻的抗IL-2R疗法如何抑制这种原位活化并延长移植物存活期。（摘要截断于400字）
