Immunomodulator is a biological or non-biological substance that directly influences a specific immune function or modifies one or more cells of the immunoregulatory network to perform an indirect effect on a immune function.
It has been known as biological response modifier (BRM) and has been used as a cancer therapy. Among them, lymphokine-activated killer cells with interleukin 2 is most challenging for the treatment of several advansed cancers, particulary metastatic renal cell carcinomas.
However, the use of immunomodulator is not limitted to cancer therapy but can be extended to infectious and autoimmune diseases as well as immunodeficiency states including AIDS.
In this review, anti-proliferative and specific effects on immune function of interferon, interleukin 1 and 2 were discussed.
Finally, several immunomodulators currently being used or tested for the treatment of autoimmune diseases mainly rheumatoid arthritis were introduced.

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Slice tissues of rat lung were preincubated with vitamin A (VA) or vitamin A acid (VAA) and then incubated with endotoxin. After the reaction, the amount of LTC₄, LTB₄ and 6-KPGF_1α in the reactive solution were analysed quantitatively by RIA following the method of Salali or Powell et al. TLC₄ was significantly suppressed by 10^-6M VA. And 10^-8M VA still showed this suppression. The induction of LTB₄ was also suppressed significantly by 10^-7M VA. VAA suppressed the induction of LTC₄ significantly at the concentration from 10^-7M to 10^-9M. And 10^-8M VAA showed the most significant suppression. The induction of LTB⁴ was also suppressed significantly by 10^-9M VAA but was accelated by 10^-7M. However VAA did not interfere the synthesis of 6-KPGF_1α. The values of LTB₄ and LTC₄ determined by RIA were confirmed by the combined method of HPLC and RIA. These suggest that VA and VAA will suppress the synthesis of lipoxygenase products specifically in vitro experiment as well as in vivo experiment already shown in the former report.

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Quantities of prostaglandin E₂ (PGE₂) in carrageenin-induced inflammatory exudate at the rat hind paw were measured by the radioimmunoassay method. PGE₂ level increased rapidly and peaked 3 hours after treatment of carrageenin. Intravenous administration of LM-001, indomethacin (IM) and aspirin DL-lysine (VP), given 1 hour after treatment of carrageenin, significantly lowered the PGE₂ level in the exudate (sampled 3 hours after treatment of carrageenin), dose-dependently. ID₅₀ value (95% confidence limits) of each drug was as follows; LM-001: 1.2 (0.2-6.5) mg/kg, VP: 26.9 (4.5-161.2) mg/kg and IM: 0.2 mg/kg (95% confidence limit was impossible to be calculated) . These drugs very significantly reduced the PGE₂ concentration in exudate, but the edema formation was not always suppressed to the same degree of PGE₂ biosynthesis. These findings suggest that antiinflammatory potencies of these drugs are unable to account for only the inhibitory potencies of PGE₂ biosynthesis in this model.

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The effect of interleukin-1 (IL-1) and tumor necrosis factor (TNF) on the fibrinolytic system of vascular wall was investigated using cultured endothelial cell (EC) . The fibrinolytic potential may depend on the net balance of tissue type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAT) . Both IL-1 and TNF stimulated the PAT production of EC in a dose dependent manner without changing the production of t-PA.
TNF was demonstrated to induce IL-1 production by EC. Since the effect of TNF was not inhibited by neutralization with antibodies to IL-1α and IL-1β, the effect of TNF on PAI production may not have been mediated by the endogenous generation of IL-1.
As we previously reported that IL-1 and TNF additively induced PGI₂ synthesis of EC, the effect of PGI₂ on API production of EC was evaluated. Both PGI₂ and forskolin, an activation of adenylate cyclase, decreased PAI production of EC PGI₂ may compensate the induction of PAT production of EC by IL-1 and TNF.
These data might indicate that cytokines could play an important role on the regulation of fibrinolytic system of vascular endothelial cells.

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Recurrent rheumatoid nodules from the patient with rheumatoid arthritis were investigated. Immunohistochemical analysis of the early rheumatoid nodules suggested that immune responses among CD4 positive T cells and HLA-DR positive mesenchymal cells might be involved in the development of the nodules. Furthermore, interleukin-1 activity were detected in the culture supernatant of the nodules. The role of cytokines in the rheumatoid nodules should be further investigated.

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The biochemical properties of KME-4, α- (3, 5-di-tert-butyl-4-hydroxybenzylidene) -γ-butyrolactone, were evaluated in vitro. Unlike other NSAIDs such as indomethacin and diclofenac, KME-4 or BW-755C significantly inhibited active oxygen productions from plymorphonuclear leukocytes (PMN) stimulated with opsonized zymosan, without change of viabilities. [³H] f-Met-Leu-Phe binding to the PMN membrane was not affected by either KME-4 or BW-755C but inhibited by indomethacin.
KME-4 and BW-755C also clearly inhibited an active oxygen generation in a cellfree hypoxanthine-xanthine oxidase system. KME-4 and BW-755C were more potent than indomethacin and diclofenac in inhibiting the secondary aggregation of human platelet induced by platelet activating factor. These results suggest that KME-4, a dual inhibitor of arachidonic acid metabolism, like BW-755C affects the functions of leukocytes and platelets on different mechanisms from those of typical known NSAIDs.

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One of five compounds, AC-5-1, strongly inhibits 5-lipoxygenase with a half-inhibition dose of 5±0.12×10^-8M. However, prostaglandin synthesizing activity is not inhibited until 10^-5M. AC-5-1 is a highly selective inhibitor for 5-lipoxygenase. The AC-5-1 at 10^-5M inhibits 96% of leukotriene C₄ synthesis of mouse peritoneal cells facilitated by calcium-ionophore. Arachidonic acid induced ear edema of mice, an in vivo inflammatory model, involving leukotriene induction, is strongly inhibited by AC-5-1 in a dose-dependent manner. The inhibition is the strongest of any inhibitors of 5-lipoxygenase reported previously. Since the natural compound AC-5-1 can selectively inhibit 5-lipoxygenase and affect in vivo inflammation, it will be interesting to investigate the role of leukotrienes on inflammation and other physiological processes.

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TNF (tumor necrosis factor) modulates various cell functions directly or indirectly and has an autocrine, paracrine and endocrine regulatory function. TNF often induces various cytokines which regulate inflammation and immunity. Here we demonstrated that TNF was chemotactic for neutrophils and a good trigger for TNF production.
We also demonstrated that physiological concentrations of glucocorticoids inhibited non-competitively the cytotoxic activity of TNF.
These findings suggest that an inflammatory reaction by TNF may be regulated by glucocorticoids through some mechanism involving de novo transcription and translation. Finally, these and other's results indicate that TNF play an important role in host defense mechanisms including inflammation and immunity.

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We studied on effectiveness of sulphasalazine (SASP) in rheumatoid arthritis. SASP was compared with other oral remission-inducing drugs, D-penicillamine (D-P), auranofin (Aur), robenzarit (CCA) and methotrexate (MTX), for 6 months. In addition, we studied on cessation of treatment of each drug.
After treatment of 6 months effectiveness of SASP turned out to be just the same with that of D-P and Aur. As for frequency of treatment cessation during 6 months MTX was the lowest among other drugs, being followed by D-P, SASP, Aur and CCA in order. As for achievement of continual administration of drug in each month MTX, D-P and SASP were significantly greater than Aur and CCA. The cessation of treatment due to side effect was more frequently seen in MTX and D-P. On the other hand in Aur and CCA the cessation of treatment was almost due to ineffectiveness.
Many serious side effects were experienced in MTX and D-P, but not in SASP, Aur and CCA.
In conclusion sulphasalazine turned out to be effective drug and tolerable over long periods in rheumatoid arthritis.

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To determine if rheumatoid arthritis patients on gold sodium thiomalate (GST) can be maintained on auranofin (AF), we examined a group 111 patients, who had been stable on GST.
The patients were randomized to receive either AF 6 mg daily, or continued GST. Patients eligible for study showed no difference in clinical outcome after 6 months of treatment.
On-therapy conditions in the 2 groups were similar, with the exception of diarrhoea in 29.8% of the AF-treated group.
And there were no correlation between blood gold concentration and safety & efficiency.
This study shows that AF may be substituted for GST during rheumatoid arthritis therapy.

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