[Mechanisms of the effect of interleukin-1 inhibitor activators]. / Mehanizam delovanja inhibitora aktivnosti interleukina-1.

Interleukin-1 (IL-1) has a broad range of effects on physiologic processes, including immunologic phenomena. In maintaining the tissue homeostasis the existence of feed-back mechanisms regulating down the IL-1 activity would be beneficial for the host. We and other investigators have provided evidence that such a regulatory circuit exists and may be altered by agents such as glucocorticoids and as well as by the UV irradiation. Here we provide evidence describing the mode of action of an accessory cell derived inhibitor of the IL-1 activity. This inhibitor is a product of radioresistant cells, it does not represent a nonspecific inhibitor of the DNA synthesis and appears to be specific for IL-1 since it does not interfere with the IL-2 dependent T cell proliferation. It affects both the IL-2 production and the induction of IL-2 receptor expression. As indicated in our previous work the immunoinhibitory factors affecting T cell proliferation are present in the sera of patients suffering from chronic renal and hepatic diseases. Further analyses have shown that these serum inhibitors have the same mode of action as macrophagederived glucocorticoid-induced inhibitors. Thus, it appears that the production of an IL-1 receptor antagonist may be enhanced in a pathological condition and during chronic inflammations in particular. Its significance for the disease pathogenesis remains to be elucidated.

[The role of T-lymphocyte subsets in susceptibility and resistance to induction of autoimmunity in the central nervous system]. / Uloga subpopulacija T limfocita u osetljivosti i otpornosti na indukciju autoimunosti u centralnom nervnom sistemu.

The importance of two major subsets of T cells (CD4 and CD8) for the induction of EAE was analysed in two strains of rats differing in susceptibility to EAE and the level of IL 2 production. It was found that CD8 cells do not play a role in the induction or in the inherent resistance to EAE. Additionally, the elimination of CD8 cells does not increase the IL 2 production in lymphoid cell cultures. Based on these and previous results showing that a low dose of cyclophosphamide readily abrogates the resistance to EAE and enhances the IL 2 production. Thus it was concluded that genetically determined differences in susceptibility to EAE are governed by immunoregulatory genes whose effect appears to be mediated at the level of cellular interaction of different subsets of CD4 T cells.

In vitro effects of retinoid RO 10-9359 on lectin-induced activation and proliferation of T-lymphocytes.

RO 10-9359 has been shown to cause a dose-dependent (0.05-50 micrograms/ml) inhibition of proliferation of rat thymocytes after in vitro activation by PHA and Con A. In experiments designed to dissect the effects of the drug on various aspects of proliferation it was demonstrated that RO 10-9359 did not inhibit IL1 production by macrophages, nor the IL1-dependent events of T-cell activation, i.e. the IL2 production and the acquisition of IL2-receptors. However, the capacity of exogenously supplied IL2 to stimulate the proliferation of T-cells that had previously acquired IL2-receptors was suppressed by RO 10-9359 in a dose-dependent manner. Thus, it appears that retinoid RO 10-9359 does not interfere with the early events of T-cell activation, but inhibits lectin-induced proliferation by affecting the later phase of proliferative activity after T-cell triggering.

Inhibitory action of cyclosporin A on the early events of T cell activation: effects on T cell-independent production of IL1 and on IL1-dependent expression of reactivity to IL2.

Cyclosporin A (CsA) has a selective immunosuppressive effect on T cell functions, but its mode of action on IL1 activities and production remain unclear and controversial. While it has been documented that CsA has a profound effect on the ability of IL1 to promote IL2 production, its effects on the ability of IL1 to promote IL2-responsiveness are not known. Macrophage-depleted nylon wool non-adherent thymocytes (NATs) were preincubated for 6 h with or without IL1 in the presence of a wide range of concentrations of CsA (1 ng/ml-1 microgram/ml), washed and then pulsed with Con A. After washings in medium with alpha-MM, the capacity of NATs to proliferate in response to IL2 was determined. Both background and IL1-dependent acquisition of IL2-reactivity were inhibited by concentrations of CsA as low as 5 ng/ml. The effects of CsA (1 ng/ml-1 microgram/ml) on T cell-independent production of IL1 by irradiated, carrageenan-stimulated peritoneal macrophages were also examined. Up to 50 ng/ml CsA had no effect on IL1 production but higher concentrations produced a dose-dependent inhibition that was complete at 1 microgram/ml. These results show that CsA inhibits both T cell-independent production of IL1 and IL1-dependent expression of reactivity to IL2.

Selective effects of human cord serum on distinct events of the lectin-induced activation and proliferation of thymic T-cells.

The results of this study demonstrate that human cord serum, but not adult serum, contains a factor(s) which without being by itself mitogenic for unstimulated resting cells, enhances the PHA- and ConA-induced proliferation of rat thymocytes. Dissection of the effects of HCS on the distinct events involved during lectin-induced activation and growth of thymic T cells, revealed the basic mechanisms by which the stimulatory factor(s) exerts its action. HCS does not affect the IL-2-dependent proliferation of ConA-blasts derived from thymocytes. Furthermore, it does not act via macrophages but rather directly on thymic T cells by increasing their capacity to proliferate in response to the activating signals delivered by lectins in conjunction with IL1. Thus, HCS enhances the lectin-induced expression of IL2-receptors as evidenced by both increased responsiveness to IL2 and increased capacity to absorb IL2 of HCS-treated thymocytes. On the other side, HCS also enhances the lectin-induced production of IL2 by thymocytes.

The dual role of interleukin 1 in lectin-induced proliferation of T cells.

Nylon wool non-adherent, thoroughly macrophage-depleted rat thymocytes (NaTs) or lymph node cells (NALs) pulsed with Con A for 20 h did not proliferate and acquired a very low level of IL 2 responsiveness or were completely unresponsive to exogenous IL 2. When supplemented with irradiated resident peritoneal cells used as a source of macrophages during Con A pulsing, NATs/NALs became capable of proliferating and expressing competence to respond to exogenous IL 2. Thus in the experimental system used in this study both IL 2 production and acquisition of IL 2 responsiveness are macrophage-dependent. Semipurified rat IL 1 could efficiently replace the requirement for macrophages in the promotion of proliferation of NATs/NALs both in the presence or absence of exogenous IL 2. Furthermore, NATs/NALs pretreated with IL 1 for 6 h before Con A pulsing were able to acquire reactivity to IL 2. The effect of IL 1 pretreatment in promoting the Con A-induced IL 2 responsiveness of NATs/NALs was dose-dependent. IL 1 by itself did not induce competence to IL 2. IL 1 pretreatment did not alter the overall Con A-binding capacity of NATs nor the ability of Con A to aggregate them. Irradiated IL 1-pretreated NATs could not accomplish the function of "accessory cells" for induction of IL 2 responsiveness of untreated NATs by Con A. Our study indicates that IL 1 exerts two activities in lectin-induced proliferation of at least some resting T cells present both in thymus and lymph nodes. On the one hand, IL 1 promotes IL 2 production and, on the other hand, it promotes expression of IL 2 receptors.

Accessory cell function in immune responses in vivo: enhancing effect of radioresistant spleen cells on antibody response to SRBC in rats.

Spleen cells taken 4 days after lethal irradiation of Lewis rat were used as a source of radioresistant accessory cells. The transfer of 2 x 10(6) cells into syngeneic recipients significantly enhanced the antibody response to an immunogenic dose of SRBC, if given immediately prior to antigen. The enhancing effect was not observed if radioresistant cells were transferred 24 h or later after immunization. Elimination of adherent or phagocytic cells abolished the enhancing capacity of the radioresistant spleen cells. One hour pre-incubation in medium containing 0.4 mg/ml kappa carrageenan potentiated rather than inhibited the enhancing effect of radioresistant spleen cells. IgG PFC response appear to be more sensitive to the effect of the transferred spleen cells as compared with the direct (IgM) PFC response. It is concluded that activated splenic macrophages may enhance antibody response when transferred, at the time of immunization, into an immunocompetent host. Possible mechanisms of action are discussed.