Activity in saline of phthalylated or succinylated derivatives of mycobacterial water-soluble adjuvant.
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A water-soluble fraction (WSA) of the cell wall can substitute for mycobacterial cells in Freund complete adjuvant. However, when WSA is administered in saline instead of in a water-in-oil emulsion, its adjuvant activity is very weak, and under certain experimental conditions it can even inhibit the humoral immune response. The data reported in the present study show that after treatment by phthalic or succinic anhydride the adjuvant activity of WSA was markedly changed, since high levels of circulating antibodies were produced when these derivatives were administered with an antigen in an aqueous medium. Moreover, the antigenic determinants of WSA were modified and acylated WSA had no tuberculin-like activity. (+info)
N,N'-Diacetyl-L-cystine-the disulfide dimer of N-acetylcysteine-is a potent modulator of contact sensitivity/delayed type hypersensitivity reactions in rodents.
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Oral N-acetyl-L-cysteine (NAC) is used clinically for treatment of chronic obstructive pulmonary disease. NAC is easily oxidized to its disulfide. We show here that N,N'-diacetyl-L-cystine (DiNAC) is a potent modulator of contact sensitivity (CS)/delayed type hypersensitivity (DTH) reactions in rodents. Oral treatment of BALB/c mice with 0.003 to 30 micromol/kg DiNAC leads to enhancement of a CS reaction to oxazolone; DiNAC is 100 to 1000 times more potent than NAC in this respect, indicating that it does not act as a prodrug of NAC. Structure-activity studies suggest that a stereochemically-defined disulfide element is needed for activity. The DiNAC-induced enhancement of the CS reaction is counteracted by simultaneous NAC-treatment; in contrast, the CS reaction is even more enhanced in animals treated with DiNAC together with the glutathione-depleting agent buthionine sulfoximine. These data suggest that DiNAC acts via redox processes. Immunohistochemically, ear specimens from oxazolone-sensitized and -challenged BALB/c mice treated with DiNAC display increased numbers of CD8(+) cells. DiNAC treatment augments the CS reaction also when fluorescein isothiocyanate is used as a sensitizer in BALB/c mice; this is a purported TH2 type of response. However, when dinitrofluorobenzene is used as a sensitizer, inducing a purported TH1 type of response, DiNAC treatment reduces the reaction. Treatment with DiNAC also reduces a DTH footpad-swelling reaction to methylated BSA. Collectively, these data indicate that DiNAC in vivo acts as a potent and effective immunomodulator that can either enhance or reduce the CS or DTH response depending on the experimental conditions. (+info)
Effect of tripterine on collagen-induced arthritis in rats.
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AIM: To study the therapeutic effect of tripterine (Tri) on collagen-induced arthritis (CIA). METHODS: Collagen type II (Col) 1.5 mg was injected intradermally to induce CIA in rats. Hind paw volumes of rats were measured with a water displacement method. The serum anti-collagen antibody was measured by an enzyme-linked immunosorbent assay. Delayed hypersensitivity was reflected by skin response to Col. Interleukin-1 (IL-1) and interleukin-2 (IL-2) activities were evaluated by [3H]TdR uptake. Joint was evaluated histologically. RESULTS: Tri 15 and 30 mg.kg-1.d-1 given i.g. to rats 3 d after the first sign of arthritis reduced inflammatory swelling, suppressed humoral and skin response to Col, inhibited IL-2 and IL-1 production, reduced pathological progression of joint. CONCLUSION: Tri has a therapeutic effect on CIA. (+info)
Effects of interleukin-1 receptor antagonist overexpression on infection by Listeria monocytogenes.
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Interleukin-1 receptor antagonist (IL-1ra) is a naturally occurring cytokine whose only known function is the inhibition of interleukin-1 (IL-1). Using a reverse genetic approach in mice, we previously showed that increasing IL-1ra gene dosage leads to reduced survival of a primary listerial infection. In this study, we characterize further the role of endogenously produced IL-1ra and, by inference, IL-1 in murine listeriosis. IL-1ra overexpression inhibits, but does not eliminate, primary immune responses, reducing survival and increasing bacterial loads in the target organs. We demonstrate that IL-1ra functions in the innate immune response to regulate the peak leukocyte levels in the blood, the accumulation of leukocytes at sites of infection, and the activation of macrophages during a primary infection. Reduced macrophage class II major histocompatibility complex expression was observed despite increased gamma interferon (IFN-gamma) levels, suggesting that IL-1 activity is essential along with IFN-gamma for macrophage activation in vivo. We also show that IL-1ra plays a more limited role during secondary listeriosis, blunting the strength of the delayed-type hypersensitivity response to listerial antigen while not significantly altering cellular immunity to a second infectious challenge. When these results are compared to those for other mutant mice, IL-1ra appears to be unique among the cytokines studied to date in its regulation of leukocyte migration during primary listeriosis. (+info)
Differential avian and human tuberculin skin testing in non-tuberculous mycobacterial infection.
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OBJECTIVE: To determine the sensitivity of differential avian and human delayed-type hypersensitivity skin testing in the diagnosis of non-tuberculous mycobacterial lymphadenitis. METHOD: Retrospective review of all patients with culture proved non-tuberculous mycobacterial lymph node infections who also had differential avian and human skin testing performed over a 10 year period from 1986 to 1996. RESULTS: One hundred and twenty four patients had non-tuberculous mycobacteria isolated from lymph nodes over this period, 59 of whom had differential skin testing performed. The sensitivity of a response of >/= 10 mm to the avian precipitin was 58 of 59. No patient had both a negative human and avian Mantoux. The sensitivity of the human Mantoux alone for diagnosing non-tuberculous mycobacterial infection was 81% for a response of >/= 5 mm and 66% for >/= 10 mm. Ten patients had a 0 human response. Fifty five of the 59 patients had an avian response at least 2 mm greater than the human response. CONCLUSION: The avian Mantoux is a very sensitive method of diagnosing non-tuberculous mycobacterial infection in children. The human Mantoux is not sensitive enough to be used alone as a surrogate to diagnose non-tuberculous mycobacterial infection. (+info)
Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin.
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TNF and lymphotoxin-alpha (LT alpha) may act at various stages of the host response to Mycobacterium tuberculosis. To dissect the effects of TNF independent of LT alpha, we have used C57BL/6 mice with a disruption of the TNF gene alone (TNF-/-). Twenty-one days following aerosol M. tuberculosis infection there was a marked increase in the number of organisms in the lungs of TNF-/- mice, and by 28-35 days all animals had succumbed, with widespread dissemination of M. tuberculosis. In comparison with the localized granulomas containing activated macrophages and T cells in lungs and livers of C57BL/6 wild-type (wt) mice, cellular infiltrates in TNF-/- mice were poorly formed, with extensive regions of necrosis and neutrophilic infiltration of the alveoli. Phenotypic analysis of lung homogenates demonstrated similar numbers of CD4+ and CD8+ T cells in TNF-/- and wt mice, but in TNF-deficient mice the lymphocytes were restricted to perivascular and peribronchial areas rather than colocated with macrophages in granulomas. T cells from TNF-/- mice retained proliferative and cytokine responses to purified protein derivative, and delayed-type hypersensitivity to purified protein derivative was demonstrable. Macrophages within the lungs of TNF-/- and wt mice showed similar levels of MHC class II and inducible nitric oxide synthase expression, and levels of serum nitrite were comparable. Thus, the enhanced susceptibility of TNF-/- is not compensated for by the presence of LT alpha, and the critical role of TNF is not in the activation of T cells and macrophages but in the local organization of granulomas. (+info)
Fibroin allergy. IgE mediated hypersensitivity to silk suture materials.
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Delayed-type hypersensitivity with granulomatous lesions to silk sutures is rather rare. Yet, braided silk sutures often act as a non-immunologic foreign-body and cause a granulomatous inflammatory reaction years after surgery. We report here a case of recurrent granulomas with remarkable infiltration of eosinophils that may have resulted from an IgE-mediated hypersensitivity reaction to silk fibroin, a component of the braided silk suture. Under normal circumstances exposure to fibroin is rather rare. Therefore, the present patient may have developed this reaction to the silk sutures used in a previous surgery. (+info)
Protective effect of the type IV phosphodiesterase inhibitor rolipram in EAU: protection is independent of IL-10-inducing activity.
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PURPOSE: Experimental autoimmune uveoretinitis (EAU) is a cell-mediated model of retinal autoimmunity that is negatively regulated by interleukin (IL)-10. The antidepressant drug rolipram, a type IV phosphodiesterase inhibitor, enhances IL-10 production by monocyte/macrophages. The effect of rolipram on induction of EAU and its associated immunologic responses was investigated. METHODS: Mice were challenged for EAU induction by immunization with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP) or by adoptive transfer of uveitogenic T cells and were treated with rolipram. EAU severity and immunologic responses to IRBP were analyzed. In addition, the effect of rolipram added to the culture on antigen-driven responses of primed lymph node cells was tested. RESULTS: Rolipram treatment from days -1 to 7 after immunization (afferent phase) was not protective, but severity of EAU was reduced to 50% by treatment from days 8 to 16 after immunization or when EAU was induced by adoptive transfer (efferent phase). Antigen-specific proliferation and interferon (IFN)-gamma production ex vivo by lymph node cells of protected mice were not reduced. However, the addition of rolipram directly to the culture suppressed IRBP-driven proliferation and IFN-gamma production by primed lymph node cells. Freshly explanted lymph node cells of treated mice showed inhibition of IFN-gamma mRNA but no parallel enhancement of IL-10 mRNA by quantitative polymerase chain reaction. Rolipram inhibited EAU in IL-10 knockout mice equally well compared with controls and suppressed their primed lymph node cells in culture. CONCLUSIONS: Rolipram appears to inhibit the expansion and effector function of uveitogenic T cells, raising the possibility that it may be useful for treatment of established disease. Contrary to expectations based on in vitro studies, the protective effects in vivo appear to be independent of IL-10. The observation that suppression of antigen-specific responses is demonstrable only in the physical presence of the drug suggests that, in a clinical setting, continuous administration of rolipram might be needed to sustain its therapeutic effect. (+info)