Basophils and mast cells are important effector cells of inflammation and in particular of acute allergic reactions. Basophils can be activated to release inflammatory mediators by IgE-dependent and IgE-independent stimuli (1-4). The mediator profile produced by basophils strongly depends upon the agonist used to activate the cells (4a) . For example, crosslinking ofhigh-affinity IgE-receptors by an antigen, anti-IgE or anti-receptor antibodies leads to the release of preformed mediators from granule stores, like histamine and proteolytic enzymes, and also results in the activation of enzymes (phospholipase[s] and 5-lipoxygenase) responsible for the generation of leukotriene C4 (LTC 4),' a very potent lipid mediator and smooth muscle contractant (6). Conversely, the anaphylatoxin C5a, which at low concentrations is a potent inducer of basophil degranulation, does not activate basophils to produce bioactive lipids . These observations clearly indicate that degranulation and the generation of the arachidonic acid metabolite LTC4 are dissociated events and therefore controlled by different mechanisms .Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a pluripotent growth factor for myeloid bone marrow precursors (7,8), but more recent studies demonstrated that this cytokine also enhances the function (in particular cytotoxicity and oxygen radical release) of mature inflammatory effector cells, like monocytes, eosinophils, and neutrophils (PMN) (9-13). Studies from our laboratory demonstrated that PMN sequentially exposed to GM-CSF and the chemotactic peptides C5a or FMLP release relatively large amounts of LTB4 and LTB4 metabolites, while neither peptide alone triggers the formation of these lipid mediators (14). Preexposure of PMN to GM-CSF also results in a strong enhancement of chemotactic peptide-dependent generation ofplatelet-activating factor, another potent lipid mediator (15). From these experiments we concluded that GM-CSF not only enhances effector cell functions, but also qualitatively changes in the mediator profile of the neutrophils triggered by diverse agonists .These observations suggested that other growth-promoting cytokines may also modify the mediator profile of mature leukocytes, and we thus studied the effects of IL-3 on blood basophils. IL-3 stimulates the growth of early progenitor cells of

Recent investigations have shown that the hematopoietic growth factor interleukin 3 (IL 3) enhances histamine release of mature human basophils. Furthermore, basophils exposed to IL 3 generate large amounts of leukotriene C4 in response to C5a, a basophil agonist which by itself is unable to promote lipid mediator formation. Also IL 3 renders the cells responsive to factors which do not otherwise induce basophil mediator release. Here we show in more detail how IL 3 affects the release of preformed and newly synthesized inflammatory mediators by basophils in response to antigen, anti-IgE, N-formyl-methionyl-leucyl-phenylalanine (FMLP) and C5a. In cells triggered by maximally effective concentrations of these agonists, IL 3 enhances histamine release, although it more profoundly affects leukotriene generation, in particular in response to stimuli which by themselves are inefficient or poor inducers of lipid mediator formation. This change in the mediator-release reaction occurs at low IL 3 concentrations, over the same concentration range of IL 3 of 0.01-1.0 U/ml regardless of which triggering agent is used as a second signal. Pretreatment of basophils with IL 3 results in a left shift of the dose-response curves for mediator release of both IgE-dependent and IgE-independent agonists by approximately one order of magnitude. IL 3 affects only the extent and not the time course of IgE-independent peptide-induced basophil degranulation. By contrast, histamine and leukotrienes are released more rapidly in response to IgE-dependent stimulation after IL 3 priming. IL 3 also shortens the lag time and increases the rate of leukotriene generation in basophils triggered by FMLP. The priming process induced by IL 3 does not require extracellular calcium. Basophils exposed to IL 3 release significant amount of mediators in response to C5a, even in EDTA buffers without addition of Ca2+/Mg2+, indicating that in the presence of IL 3 the Ca2(+)-dependent mediator release induced by C5a becomes partially Ca2+ independent. Thus, we find that IL 3 strongly affects the mediator profile, the amounts of mediators released, the dose-response curves and the kinetic of the release reaction in basophils stimulated with diverse agonists. The data further support the hypothesis that IL 3 plays an important role in inflammatory processes, in particular in hypersensitivity reactions.

IgE-independent mediator release from basophils is considered an important event in inflammation, particularly in nonallergic immediate hypersensitivity and in allergic late-phase reactions. This study demonstrates that after exposure to IL-3, basophils release histamine and leukotrienes in response to the neutrophil-activating peptide NAF/NAP-1. Thus, the sequential action of two pure cytokines can promote basophils mediator release. In the presence of IL-3, NAF/NAP-1 functions like a "histamine-releasing factor" and may therefore not only induce cellular infiltration but also provoke symptoms of hypersensitivity reactions.

Forssman shock (FS) following the intravenous injection of antisheep erythrocyte antibody into guinea pigs resulted in fatal systemic shock with marked de-, crease in CH50 values of complement, leucocyte, and platelet counts, and a prolongation of blood coagulation time. In addition, there was an increase in lactate dehydrogenase activity, and decreases in both esterase activity and fibrinogen levels were noted. F(ab')2 of antisheep erythrocyte IgG antibody was not capable of eliciting FS. Cobra venom factor showed a fairly potent inhibition of FS. Leukopenia induced by cytosine arabinoside given intraperitoneally for 5 days had no effect on FS. Colchicine, which decreased the leucocyte count, did not inhibit fatal systemic shock. Administration of heparin or trasyrol did not prevent FS. The present findings demonstrate that FS is inhibited by anticomplementary agents but not by drugs which affect leucocyte and platelet counts, the coagulation system or serum proteases.We have already reported that Forssman systemic shock (FS) can be classified as a Type II reaction (11) according to the classification by Coombs and Gell (1). FS is usually observed in guinea pigs given intravenously an antibody against Forssman antigen. Forssman antibody against sheep erythrocyte surface antigen binds to the endothelium of guinea pig capillaries and injures the capillary walls. It may be one of the most useful experimental models for studying injurious mechanisms related to autoimmune diseases. Several reports (2, 4-6, 11, 12, 15) have shown the effectiveness of the anticomplement agent for the inhibition of FS and the important role of complement in the induction of the shock. However, mechanisms regarding shock are not well understood. The present study was an attempt to analyze immunopharmacologically the injurious mechanisms involved in FS. MATERIALS AND METHODSAnimals. Hartley male guinea pigs weighing 280-360 g were used. Antibody. Rabbit antisheep erythrocyte antibody was prepared by the method . previously described (9). In brief, a suspension of 109well-washed sheep erythrocytes in 1.0 ml of phosphate buffered saline (PBS) was injected into the auricular

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Abstract-Effectof Neurotropin on the delayed type hypersensitivity (DTH) response to sheep red blood cells was examined in mice. Neurotropin suppressed the high DTH responses in ddY and BALB/c mice, while it enhanced the low DTH response in C57BL/6 mice when administered after sensitization. In addition, Neurotropin exerted a suppressive effect on the enhanced DTH response by cyclophosphamide pretreatment in C57BL/6 mice, but had a restorative effect on the suppressed DTH response in ddY mice loaded with restraint stress.

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