Reversal of Antilymphocytic Serum-Induced Immunosuppression By Macrophage Administration

Abstract

The key role of the macrophage as the afferent component of the immune reflex arc is well documented (6-8, 10, 11, 19, 22, 31). Furthermore, Frei et al. (9) demonstrated that phagocytosis is an essential step in the development of the primary immune response while others have shown that the transplantation of macrophages into newborn mice ( 1 ) and rabbits (19) will promote the early development of immunocompetence. In view of these findings, it would be expected that the administration of chemotherapeutic agents which alter the normal phagocytic function of the reticuloendothelial system (RES) would induce a corresponding alteration in the immune response. Indeed, Wooles and Di Luzio (31) initially demonstrated that RES depression was associated with a decreased immune response while RES stimulation resulted in an increased antibody titer.Previous studies from this laboratory ( 2 5 ) have shown that a single injection of antilymphocytic serum (ALS) impairs phagocytic activity of the reticuloendothelial system (RES), as reflected by a depressed intravascular clearance rate of gelatinized RE test lipid emulsion. The ALS-induced depression in phagocytosis was associated with a selective decrease in Kupffer cell phagocytosis. In vitro studies which employed both serum and liver slices derived from either normal or ALS-treated animals also indicated the ability of ALS to induce phagocytic impairment, These in vitro studies (25) suggested that the depression of RES activity by ALS could be attributed to an exclusive defect in the cellular compartment of the RES since no Supported, in part, by the U. S. Army Medical Research and Development Command, the Atomic Energy Commission, and the Cancer Association of Greater New Orleans, Inc. alterationin circulating phagocyticpromoting activity was found in ALS-treated animals. Furthermore, a direct injurious effect of ALS on Kupffer cells was demonstrated, not only by ALS-induced impairment of Kupffer cell phagocytic activity, but also by the cytotoxic action of ALS on these macrophages (25). These studies suggested the distinct possibility that ALS-induced immunosuppression may be mediated by an alteration of RES function which results from the antimacrophage activity manifested by ALS (25) Antilymphocytic serum has been shown to be an effective immunosuppressant of both cellular (13, 20, 29) and humoral immune responses (14, 20, 29). Indeed, ALS has been employed extensively in renal transplan tation (23, 28, 31) despite the fact that the mode of action of ALS-induced immunosuppression is as yet unclarified (13, 15, 16, 20, 26). In view of our previous observations of the detrimental effect of ALS on Kupffer cell viability and function (25), studies were undertaken to evaluate the influence of hepatic as well as peritoneal and splenic macrophage transplantation on ALS-induced immunosuppression. Studies were also extended to determine the ability of splenic and thymic lymphocytes to restore the humoral antibody response in ALS-immunosuppressed animals.Materials and Method...

Macrocolony Assays in the Rat of Allogeneic Y-P388 and W-256 Tumour Cells Injected Intravenously: Dependence of Colony Forming Efficiency on Age of Host and Immunity

“…Certain other findings also appear relevant to the mode of action of immunosuppressive agents against growth of syngeneic and allogeneic tumours. Thus Patterson et al, (1970) consider that their experiments point to the macrophage being the primary cellular site of ALS induced immunosuppression. Other workers have provided evidence that ALS destroys or neutralizes the functions of a variety of circulating and fixed tissue cells other than lymphocytes, including other leucocytes, splenic giant cells and even epithelial and connective tissue elements (see Yoffey and Courtice, 1970).…”

“…These cell suspensions were prepared in appropriate dilutions in heparinized ice-cold Tyrode solution in the usual way and were used to treat rats which had been inoculated with tumour cells intravenously. Peritoneal macrophages were harvested from rats 5 days after injecting 5 ml of 6% Na caseinate intraperitoneally (Patterson, Pisano and Di Luzio, 1970). …”

Two Antigenically Different Types of Macrophages

“…Conversely, it is well known that many antilymphocyte antisera show various effects on macrophages (18)(19)(20). This is not surprising, since the cell suspensions used to stimulate antilymphocyte antibody production are seldom purified and often contain significant numbers of macrophages.…”