Bio-defense mechanism consists of various factors including antigen-specific immunities and non-specific factors. They express their functions to prevent the invasion of microorganisms or harmful substances into the tissue and to eliminate those in the tissue. Targets of bio-defense include a large number of substances of self- or nonself-origin. Thus, patterns of expression in the bio-defense are too much complex and then we need some new systems to compose such expression in systematized forms. In this paper, fundamental rules for understanding bio-defense and trials for clinical applications will be proposed.

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The respiratory tract is controlled by autonomic nerve systems. Besides cholinergic and adrenergic nerve systems, their is another efferent pathway, so-called non-adrenergic inhibitory nerve system (NAIS), in some species including human beings. Many kinds of neuropeptides, such as vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), substance P (SP), neurokinin A (NKA) and clacitonin gene-related petide (CGRP), are now known to be present in the nerve systems of the respiratory tract. Among these peptides VIP and PHI are suggested to be the neurotransmitters of NAIS. Reversible bronchial obstruction and bronchial hyperreactivity are the outstanding clinical features of asthmatic patients. Neuropeptide may be involved in the process of the bronchial obstruction as follows. It has been reported that NKA may be the most important intrinsic bronchoconstrictor in the process because it effects as a more potent bronchoconstrictor on bronchial smooth muscle than SP in vitro. Axon-reflex might be present in the human respiratory tract as well as the skin and SP is suggested to be involved in this reflex. SP might be released with NKA and CGRP from primary afferent nerve endings and they could cause bronchoconstriction, mucus hypersecretion and inflammatory cells infiltration. On the contrary to the bronchoconstrictive action of these neuropeptides, VIP has been reported that it can dilate bronchial smooth muscle in asthmatics when given by intravenous infusion. Bronchial inflammation and the dysfunction of autonomic nerve systems in the bronchial smooth muscle are considered as the important factors of the pathogenesis of bronchial hyperreactivity. Dysfunction of NAIS caused by VIP and PHI degradation by proteases released from many inflammatory cells could be involved in the bronchial hyperreactivity.

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Tumor necrosis factor (TNF) plays an important role in inflammatory responses other than inducing haemorrhagic necrosis of animal tumors or exibiting cytotoxicity to tumor cells. We prepared five recombinant human TNF muteins (amino acid sequence partly changed by protein engineering techniques) and compared their biological activity in stimulating polymorphonuclear functions by measuring iodination activity. TNF (C-Phe) (leucine changed to phenylalanine in C-terminal) was more potent than the parent TNF in activating polymorphonuclear neutrophils, even though the binding activity of TNF (C-Phe) to neutrophil membrane receptor was less than that of the parent TNF. Other TNF muteins also showed this activiy in parallel with their receptor binding activity to neutrophils. The stimulating activity of TNF muteins on polymorphonuclear function was proportional to the proliferation-enhancing activity on fibroblasts.

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When the peritoneal exudate cells enriched with macrophages were separated from rat and stimulated with calcium ionophore A23187, a significant amount of both leukotriene B₄ and prostaglandin E₂ was produced. The production of these arachidonic acid metabolites was significantly reduced by glycyrrhizin and glycyrrhetinic acid. These results suggested that anti-inflammatory and anti-allergic actions of glycyrrhizin and glycyrretinic acid were attributable to their inhibitory actions on the arachidonic acid metabolism at least partially, and these drugs might exert their inhibitory effect on the phospholipase A₂ activation.

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The mechanism of chemotactic peptide-induced priming of the respiratory burst was explored, by using human granulocytes and peripheral blood granulocytes from the colony-stimulating factor producing tumor-bearing nude mice. N-formyl-methionyl-leucyl-phenylalanine (fMet-Leu-phe) induced the transient increase in cytoplasmic free Ca²⁺, [Ca²⁺] i, whereas fMet-Leu-Phe induced neither superoxide (O^-₂) release nor membrane potential changes (depolarizaion) in mouse granulocytes. On the other hand, phorbol myristate acetate (PMA) induced O^-₂ release and membrane depolarization without inducing an increase in [Ca²⁺] i. The pretreatment of cells with fMet-Leu-Phe for 5 min at 37°C enhanced O^-₂ release and membrane depolarization stimulated by PMA (1-100 ng/ml) . The dose response curves for triggering of an increase in [Ca²⁺] i by fMet-Leu-Phe were identical to those for priming the cells. Similar results were obtained in human granulocytes.
Furthermore, the pretreatment of cells with Ca²⁺ ionophore ionomycin enhanced O^-₂ release and membrane depolarization stimulated by PMA. These findings suggest that an increase in [Ca²⁺] i by itself is not sufficient to trigger the respiratory burst and membrane potential changes, and that fMet-Leu-Phe-induced priming is caused by an increase in [Ca²⁺] i.

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The effect of gold compounds on calcium ionophore A 23187 induced platelet-activating factor (PAF) production by human neutrophilis has been studied. We assumed that PAF might play an important role in the pathogenesis of rheumatoid arthritis (RA) as a potent inflammatory mediator, because PAF has a many biological actions, such as neutrophil activation, platelet activation and increasing vessel permiability.
1×10⁷ human neutrophils produced 20.7±3. 5 unit (ranging 16.8 to 42.5 unit) of PAF production by the stimulation of 10 μg/ml of ionophore. Gold sodium thiomalate (GST) did not have any inhibitory effect on PAF production at the concentrations ranging from 1 ng/ml to 100 μg/ml. In contrast auranofin (AF) dose-dependently inhibited PAF production, 17.9% at 10^-2 μg/ml to 56.1% at 1 μg/ml and 71.2% at 10 μg/ ml. This inhibitory action observed at the therapeutic concentrations reached during AF treatment in RA patients.
The dissimilar action of GST and AF might be attributable to their different biochemical structure, and many previous reports of the inhibitory effect of gold compounds on neutrophil functions support our result.
The effectiveness of AF in the treatment of RA patients is partially due to its antiinflammatory action, because PAF may play an important role in perpetuation and in tissue injury in rheumatoid arthritis.

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Cepharanthin (CR), one of biscoclaurine alkaloids, are utilized for treatment in a wide variety of diseases, and also for the stings of wasps. In order to describe the pharmacological actions of CR, it was determined the effects of CR on leukocyte migration induced by chemotactic peptides isolated from venom sac of Vespinae. Vespid chemotactic peptides were isolated from Vespa tropica (VesCP-T) and Vespa mandarinia (Ves CP-M) . Human polymorphonuclear leukocyte (PMNL) and mononuclear leukocyte (MNL) were separated from peripheral blood, and in vitro chemotaxis assay was performed with membrane filter and multi-well chemotaxis chamber. VesCP-T and VesCP-M showed significant levels of chemotactic activities for PMNL and MNL, and these chemotactic migrations to VesCPs were decreased by addition of CR at a concentration over 10^-5M. However, leukocyte migration induced by formyl peptide, synthetic chemoattractant, and buffer control were also depressed. These results suggest that the depression of leukocyte chemotaxis by CR in vitro was attributed to the direct action of CR to leukocytes.

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The effects of Juzentaihoto (TJ-48) on cellular immunity were investigated by using delayed type hypersensitivity (DTH) reaction, mixed lymphocyte culture response (MLR) and cytotoxic T lymphocyte (CTL) response. Oral administration of TJ-48 was found to induce the augmentation of DTH and CTL responses. TJ-48 tended to enhance the MLR although it was not statistically significant. These results suggest that TJ-48 has an immunopotentiating activity on cellular immunity in addition to humoral immunity which we have reported previcusly.

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Lobenzarit disodium (CCA) is an immunomodulating antirheumatic drug. Its chemical structure is similar to that of mefenamic acid, nonsteroidal anti-inflammatory drug (NSAID) . The mechanism of action of NSAID is the inhibition of fatty acid cyclooxygenase. CCA does not inhibit prostaglandin synthesis and is not effective in preventing acute inflammation. To further discriminate the pharmacological profile of these two drugs, we examined whether they demonstrate differential effects on the immunological abnomralities and the development of autoimmune disease in MRL/Mp-lpr/lpr (MRL/l) mice. Mefenamic acid neither improved the immunological abnormalities nor inhibited the development of autoimmune disease. In sharp contrast, CCA improved the immunological abnormalities and prolonged the life span in MRL/l mice. Although chemical structure of mefenamic acid is similar to that of CCA, two drugs showed different effects on the development of autoimmune disease in MRL/l mice.

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