Identification of IL 2R+ T cells and macrophages within rejecting rat cardiac allografts, and comparison of the effects of treatment with anti-IL 2R monoclonal antibody or cyclosporin.

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)

Detection of lymphokines and lymphokine receptors in pulmonary sarcoidosis. Immunohistologic evidence that inflammatory macrophages express IL-2 receptors.

In an investigation of the immunopathogenesis of sarcoidosis, the authors undertook the tissue localization of those lymphokines and lymphokine receptors which are known to play a central role in T-cell and macrophage activation. Using monoclonal antibodies and an ABC immunoperoxidase technique. They determined the distribution of gamma interferon (IFN-g), interleukin-2 (IL-2), and corresponding IL-2 receptors (IL-2R), plus T cells and T cell subsets, B cells, and macrophages within thoracic lymph nodes and lung specimens of 9 patients with active pulmonary sarcoidosis. Epithelioid and multinucleate giant cells within sarcoid granulomas of all specimens showed membrane labeling for IL-2R and IFN-g, in addition to IL-2, suggesting that these cells indeed express functional IL-2 receptors. Infiltrating T cells, largely T4+, were also IL-2R+, and many showed IL-2 and IFN-g labeling. By comparison, macrophages within sections of normal lung or lymph node failed to stain for IL-2, IL-2R, or IFN-g. These immunohistologic studies extend recent in vitro observations by these authors and others that normal human blood monocytes and alveolar macrophages are induced by IFN-g or IL-2 to express functional membrane-bound IL-2 receptors. The in vivo expression of IL-2R by mononuclear phagocytes in pulmonary sarcoidosis is demonstrated, and a new role is suggested for T-cell-derived lymphokines in macrophage activation.