Glutamine and Leucine Provide Enhanced Protective Immunity Against Mucosal Infection with Herpes Simplex Virus Type 1

Besides their role as building blocks of protein, there are growing evidences that some amino acids have roles in regulating key metabolic pathways that are necessary for maintenance, growth, reproduction, and immunity. Here, we evaluated the modulatory functions of several amino acids in protective immunity against mucosal infection of herpes simplex virus type 1 (HSV-1). We found that glutamine (Gln) and leucine (Leu) showed enhanced protective immunity to HSV-1 mucosal infection when two administration of Gln and single administration of Leu per day, but not when administered in combinations. Ameliorated clinical signs of HSV-1 challenged mice by the intraperitoneal administration of Gln and Leu were closely associated with viral burden and IFN-gamma production in the vaginal tract at 2 and 4 days post-infection. In addition, the enhanced production of vaginal IFN-gamma appeared to be caused by NK and HSV-1 antigen-specific Th1-type CD4+ T cells recruited into vaginal tract of mice treated with Gln and Leu, which indicates that IFN-gamma, produced by NK and Th1-type CD4+ T cells, may be critical to control the outcome of diseases caused by HSV-1 mucosal infection. Collectively, our results indicate that intraperitoneal administration of Gln and Leu following HSV-1 mucosal infection could provide beneficial effects for the modulation of protective immunity, but dosage and frequency of administration should be carefully considered, because higher frequency and overdose of Gln and Leu, or their combined treatment, showed detrimental effects to protective immunity.

Mast cells play a key role in Th2 cytokine-dependent asthma model through production of adhesion molecules by liberation of TNF-alpha

Mast cells are well recognized as key cells in allergic reactions, such as asthma and allergic airway diseases. However, the effects of mast cells and TNF-alpha on T-helper type 2 (Th2) cytokine-dependent asthma are not clearly understood. Therefore, an aim of this study was to investigate the role of mast cells on Th2 cytokine-dependent airway hyperresponsiveness and inflammation. We used genetically mast cell-deficient WBB6F1/J-KitW/KitW-v (W/Wv), congenic normal WBB6F1/J-Kit+/Kit+ (+/+), and mast cell-reconstituted W/Wv mouse models of allergic asthma to investigate the role of mast cells in Th2 cytokine-dependent asthma induced by ovalbumin (OVA). And we investigated whether the intratracheal injection of TNF-alpha directly induce the expression of ICAM-1 and VCAM-1 in W/Wv mice. This study, with OVA-sensitized and OVA-challenged mice, revealed the following typical histopathologic features of allergic diseases: increased inflammatory cells of the airway, airway hyperresponsiveness, and increased levels of TNF-alpha, intercellular adhesion molecule (ICAM)-1, and vascular cellular adhesion molecule (VCAM)-1. However, the histopathologic features and levels of ICAM-1 and VCAM-1 proteins in W/Wv mice after OVA challenges were significantly inhibited. Moreover, mast cell-reconstituted W/Wv mice showed restoration of histopathologic features and recovery of ICAM-1 and VCAM-1 protein levels that were similar to those found in +/+ mice. Intratracheal administration of TNF-alpha resulted in increased ICAM-1 and VCAM-1 protein levels in W/Wv mice. These results suggest that mast cells play a key role in a Th2 cytokine-dependent asthma model through production of adhesion molecules, including ICAM-1 and VCAM-1, by liberation of TNF-alpha.

Anti-IgE mAb Suppresses Systemic Anaphylaxis through the Inhibitory IgG Receptor FcgammaRIIb in Mice: Interaction between Anti-IgE and FcgammaRIIb

BACKGROUND: Anti-IgE mAb which binds circulating but not receptor-bound IgE has been shown to be effective in treatment for asthma and other allergic diseases. However, the mechanisms by which anti-IgE mAb influences the pathophysiological responses are remained to be illustrated. This study was undertaken to examine the therapeutic efficacy of non-anaphylactogenic anti-mouse IgE mAb using murine models of IgE-induced systemic fatal anaphylaxis. METHODS: Active systemic anaphylaxis was induced by either penicillin V (Pen V) or OVA and passive systemic anaphylaxis was induced by either anaphylactogenic anti-mouse IgE or a mixture of anti-chicken gamma globulin (CGG) IgG1 mAb and CGG. The binding of the Fc portion of anti-IgE to CHO-stable cell line expressing mouse FcgammaRIIb was examined using flow cytometry. Fc fragments of anti-IgE mAb were prepared using papain digestion. The expression of phosphatases in lungs were assessed by Western blotting and immunohistochemistry. RESULTS: Anti-IgE mAb prevented IgE- and IgG-induced active and passive systemic fatal reactions. In both types of anaphylaxis, anti-IgE mAb suppressed antigen-specific IgE responses, but not those of IgG. Anti-IgE mAb neither prevented anaphylaxis nor suppressed the IgE response in FcgammaRIIb-deficient mice. The Fc portion of anti-IgE mAb was bound to murine FcgammaRIIb gene-transfected CHO cells and inhibited systemic anaphylaxis. Anti-IgE mAb blocked the anaphylaxis-induced downregulation of FcgammaRIIb-associated phosphatases such as src homology 2 domain-containing inositol 5-phosphatase (SHIP) and phosphatase and tensin homologue deleted on chromosome ten (PTEN). CONCLUSION: Anti-IgE mAb prevented anaphylaxis by delivering nonspecific inhibitory signals through the inhibitory IgG receptor, FcgammaRIIb, rather than targeting IgE.

Dexamethasone Does Not Inhibit Airway CXC Chemokine Expression and Neutrophilia in a Murine Model of Asthma - Mechanism of Steroid Resistance in Asthma

BACKGROUND: Although glucocorticoids (GCs) are effective in controlling asthma in the majority of patients, a subset of asthmatics fails to demonstrate a satisfactory response, even to systemic GC therapy. This population is referred to as being "steroid-resistant". The actual mechanism underlying steroid resistance in asthma remains to be elucidated. METHODS: We have investigated how dexamethasone (DEX) regulates asthmatic phenotypes in a murine model of asthma, in which mice received i.p. immunization twice, followed by two bronchoprovocations with aerosolized OVA with a one-week interval, which we have recently described. RESULTS: Pretreatment with DEX resulted in an inhibition of NF-kappaB activation in asthmatic lungs, and also inhibited bronchoalveolar lavage (BAL) levels of NF-kappaB-dependent cytokines such as TNF-alpha and CC chemokines [eotaxin and monocyte chemotactic protein (MCP)-1]. DEX was effective in suppressing airway hyperresponsiveness (AHR) at 10 h, Th2-dependent asthmatic phenotypes such as airway eosinophilia, BAL levels of Th2 cytokines (IL-5 and IL-13), and mucin production. However, DEX failed to suppress BAL levels of CXC chemokines [macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC)] and airway neutrophilia. CONCLUSION: Airway neutrophilia is among the phenomena observed in patients with severe GC-resistant asthma. This study will provide insight into the molecular basis for airway neutrophila seen in steroid-resistant asthma. Further studies are required to delineate the underlying mechanism of CXC chemokine expression in asthma.

Roles of TNF-alpha and IgE in the late phase of contact hypersensitivity induced by trimellitic anhydride

Trimellitic anhydride (TMA) is widely used industrially to make epoxy and alkyd resins, plasticizers and surfactants. The purpose of this study was to investigate whether contact hypersensitivity (CHS) is induced by repeated TMA challenge and the role of TNF-a and IgE in the TMA-induced CHS. The repetition of the challenge enlarged the extent of an early and a late phase of CHS in TNF-alpha+/+ (B6129SF2/J) and Balb/c mice. In the late phase of TMA-induced CHS, the peak of ear swelling responses by single challenge showed at 24 h after challenge, but the peak was observed at 8 h after repeated challenge. In the TNF-a knockout TNF-alpha-/- (B6;129S-Tnf(tm1Gk1) mice, the repetition of the TMA challenges enlarged the extent of the late phase of CHS, but less than those in TNF-alpha+/+ mice. Injection of anti-TNF-alpha antibody into the peritoneal cavity of Balb/c mice significantly decreased the extent of the late phase of CHS. Subcutaneous injection of anti-IgE antibody into Balb/c mice also decreased the extent of the late phase of CHS in dose-dependent manner. Histologically, infiltration of polymorphonuclear leukocytes and eosinophils was more pronounced in repeatedly TMA-challenged TNF-alpha+/+ and Balb/c mice than in the TNF-alpha-/- mice and anti-TNF-alpha or anti-IgE antibodies treated Balb/c mice. These results indicate that mice sensitized by TMA could possibly offer a useful model to study the mechanism of CHS, and TNF-a and IgE may act as potential modulators in the late phase of TMA-induced CHS. Neutralization of TNF-alpha and IgE by anti-TNF-a or anti-IgE antibodies may provide therapeutic tools for the treatment of TMA-induced CHS.

Bacteriocin ("vulnificin") typing of Vibrio vulnificus

Vibrio vulnificus, a halophilic vibrio is an estuarine gram-negative bacteria that is associated with severe and frequently fatal wound infections and life-threatening septicemia. Bacteriocins are defined as antibacterial substance produced by various species of bacteria which are usually active against closely related organisms. Bacteriocins have found widespread application in epidemiological studies as specific markers of bacteria. It was proposed by Ha et al. (1990. J. Korean. Soc. Microbiol. 25: 586.) to give the bacteriocins produced by V. vulnificus the name "vulnificins". In the present study, a total of 72 strains of V. vulnificus isolated from patients and oysters were subjected to screen potential producers and indicators of vulnificin, applying ultraviolet induction method. Sensitivity of several strains of Serratia marcesans, Pseudomonas aeruginosa, Shigella flexneri, Salmonella typhi and Yersinia enterocolitica to vulnificins were also examined out. All the tested strains of V. vulnificus produced vulnificins active against indicator strains with various different inhibitory patterns. The spectrum of vulnificin activity and sensitive spectrum of indicator strains were considerably broad. Interestingly, almost all strains of S. marcescens, P. aeruginosa, Salmonella sp., Shigella sp. and Y. enterocolitica tested were sensitive to 1-7 vulnificin(s). Taken together, the present study demonstrated that all of the isolates of V. vulnificus produced vulnificins and that 8 good vulnificin producers and 10 good indicators were detected. These strains can be employed efficiently for establishing vulnificin typing scheme of V. vulnificus and for the detection of bacteriocinogeny and sensitivity in V. vulnificus. Biological role of vulnificin remains to be further elucidated.

Oral Tolerance in Active Fatal Anaphylaxis / 대한면역학회지

We have investigated whether oral administration of ovalbumin (OVA) could prevent active systemic anaphylaxis to the antigen. Oral tolerance was induced by a single feecfing with 40 mg OVA before, but not after, sensitization characterized by diminished OVA-specific IgE and IgG responses. Feeding 15 mg OVA suppressed anaphylaxis and antibody responses to a lesser extent. Spleen cells from tolerant donors were incapable of transferring the tolerance to naive recipients. Pretreatment of cyclophosphamide (100 mg/kg) 2 days before OVA feeding did not restore the tolerance. Furthermore, in vitro cell mixing studies showed that the proliferation of spleen cells from OVA- sensitized donors was not inhibited by the addition of spleen cells from tolerant donors, arguing against the role of suppressor cells. Anergy was demonstrated by the ability to reverse the tolerant state after culturing tolerant cells in the presence of IL-2. These findings indicate that only a high-dose (40 mg) feeding OVA was found to be effective in inducing tolerance in this experimental system, and demonstrate anergy as the mechanism underlying oral tolerance to systemic anaphylaxis.

Regulation of Endotoxin - Induced TNF-alpha Gene Expression

It is well known that tumor necrosis factor (TNF-a), interleukin-1, platelet-activating factor (PAF) and arachidonic acid metabolites, such as thromboxane and leukotriens, are major mediators involved in the pathogenesis of endotoxic shock. In this study, we have investigated the effect of pentoxifylline (inhibitor of TNF-a release), BN50739 (PAF antagonist), indomethacin (cyclooxygenase inhibitor) and diethylcarbamazine (lipoxygenase inhibitor) on LPS- induced lethality as well as the relationship between major mediators in endotoxic shock. All inhibitors described above except diethylcarbamazine significantly protected mice against LPS- induced lethality. BN50739 and indomethacin were also effective in protection of TNF-a-induced lethality. The elevation of circulating TNF-a by LPS was significantly blocked by BN50739, but not affected by indomethacin. Convulsion appeared shortly after LPS injection was prevented by BN50739 but not by indomethacin, whereas diarrhea and limited movement was prevented by indomethacin but not by BN50739. These results indicate that i) TNF-a, PAF and cyclooxygenase products are important mediators involved in the pathogenesis of septic shock and ii) TNF-a directly influenced the release or production of PAF as well as cyclooxygenase products, and strongly suggest that i) TNF-a and PAF stimulate the release of each other via positive feedback network but TNF-a and cyclooxygenase products do not form the network and ii) PAF and cyclooxygenase product appear not to affect the release of each other.

Anti-IL-4 antibody inhibits antigen specific IgE response but fails to prevent chicken gamma globulin-induced active systemic anaphylaxis: evidence for the involvement of IgG antibodies

It has recently been reported that interleukin-4 (IL-4) is required for the production of IgE, and anti-IL-4 monoclonal antibody (mAb) inhibits in vivo IgE responses. These suggest that blocking of IL-4 activity may be useful for the prevention or treatment of immediate hypersensitivity disorders. In this study we investigated whether anti-IL-4 has a regulatory role in chicken-gamma globulin (CGG)-induced active systemic anaphylaxis. Multiple injections of anti-IL-4 (up to 40 mg/mouse) failed to protect the mice from fatal anaphylaxis. Anti-IL-4 strongly suppressed CGG-specific IgE response (>90%) without any suppressive effect on CGG-specific IgG (IgG1, IgG2a, IgG2b, and IgG3) responses. Because these data suggest the possibility that fatal anaphylaxis could be induced by IgG antibodies, we examined the possibility using anti-CGG polyclonal and the subclasses of IgG monoclonal antibodies. Passive sensitization of mice with polyclonal antibodies elicited severe and fatal anaphylactic shock; about 50% of the mice died. The activity of antibodies was not diminished by heat treatment (56 degrees C, 2h), suggesting that the anaphylaxis was not mediated by IgE. Shock was also elicited by each subclass of IgG mAb; of these, IgG1 was the most effective. Combination of the IgG subclasses elicited more exaggerated shock; about 30% of mice died. These data indicate that IgG antibodies are themselves sufficient to induce systemic anaphylaxis. Therefore, the failure of anti-IL-4 to prevent active anaphylaxis is probably due to the inability of anti-IL-4 to suppress the production of IgG antibodies.

Effects of monoclonal anti-IL-4 antbody(11B11) and interferons onIgE production in vivo and hypersensitivity reactions I. inductionof systemic anaphylaxis in mice by antigen-specific IgG and IgG subclasses monoclonal antibodies / 대한면역학회지

No abstract available.

Regulation of cellular immunity in cryptococcosis III. induction ofcryptococcus neoformans-specific T cells and hybridoma / 대한면역학회지

No abstract available.

Regulation of cellular immunity in cryptococcosis III. induction ofcryptococcus neoformans-specific T cells and hybridoma / 대한면역학회지

No abstract available.

Failure of anti-Il-4 antibody to prevent the chicken-gamma globulin-induced active systemic anaphylaxis: involvement of IgG antibodiesin induction of the anaphylaxis / 대한면역학회지

No abstract available.