concanavalin-a and Herpes-Simplex

Prolonged, exhaustive exercise has been associated with impaired immune responsiveness and increased susceptibility to infection. We have shown that one bout of exercise to fatigue followed by viral challenge increases mortality. Stress hormones such as corticosteroids and catecholamines have been suggested as potential mediators of exhaustive exercise-induced immunosuppression. The purpose of this study was to determine whether the administration of pharmacological agents to block the effect of catecholamines or corticosteroids would minimize the immunosuppression associated with this type of exercise. Mice either exercised to fatigue or were exposed to control conditions, and mice received an i.p. injection of either nadolol (beta-adrenergic receptor antagonist), RU486 (glucocorticoid type II receptor antagonist), or vehicle. Fifteen minutes post-exercise, mice were exposed to viral infection (Herpes simplex virus; HSV) via an intranasal route, and cells were collected 3 days post-infection. The results showed that exercise suppressed HSV-specific cell proliferation, HSV-specific IL-2, and IFN-gamma, but did not alter these same immune parameters when the mitogen ConA was used to stimulate cells. In addition, exercise reduced NK cell cytotoxicity, alveolar cell TNFalpha, and peritoneal IL-1beta, but did not affect IL-10. The pharmacological blockade did not attenuate the exercise-associated immunosuppression. In fact, RU486 treatment exacerbated the exercise-induced decline in HSV-induced IL-2 production and cell proliferation. RU486 and nadolol treatment also tended to decrease IL-10, IFN-gamma, TNFalpha (nadolol only), and IL-1beta (RU486 only) in both exercise and control mice, suggesting that stress hormones may be necessary during infection for optimal responsiveness. These findings suggest that suppression of immune defenses during viral infection persists for at least 3 days post-exercise, and stress hormones may be essential for optimal immune defense to viral challenge, rather than detrimental.

Topics: Animals; Antigens, Viral; Catecholamines; Cell Proliferation; Cell Survival; Cells, Cultured; Concanavalin A; Cytokines; Glucocorticoids; Herpes Simplex; Herpesvirus 1, Human; Interleukin-2; Killer Cells, Natural; Macrophages, Peritoneal; Male; Mice; Mice, Inbred BALB C; Mitogens; Physical Exertion; Pulmonary Alveoli; Th1 Cells; Th2 Cells; Virus Diseases

Beta-adrenergic blockade was used to determine whether the exercise training-induced adaptations of immune response to viral infection were mediated by catecholamines in young and old mice. Young (2 mo) and older (16 mo) male BALB/c mice were randomly assigned to an exercise or control group, and half of the mice in each group received the beta-adrenergic receptor antagonist nadolol. After 8 wk of moderate exercise training, mice were challenged with herpes simplex virus (HSV) 24 h postexercise. The results showed that exercise treatment increased anti-HSV IgM antibody, enhanced IL-10, and altered the kinetics of IFN-gamma and IL-2 production in young and old mice. Unique to older mice, exercise decreased mitogen-induced proliferation, increased splenocytes, and tended to decrease memory cells (CD44(hi+)). In contrast, exercise increased mitogen-induced proliferation but decreased the number of splenic lymphocyte and CD4+ cells in young mice. beta-Adrenergic blockade blunted the exercise-induced changes in anti-HSV IgM, IL-2, IFNgamma, and mitogen-induced proliferation in old but not young mice. The findings suggest that some of the immunomodulatory effects of chronic exercise are mediated via beta-adrenergic receptors and that the role of beta-adrenergic receptors is age dependent.

Topics: Adaptation, Physiological; Adrenergic beta-Antagonists; Aging; Animals; Antibodies, Viral; Antibody Formation; Catecholamines; Cell Division; Concanavalin A; Herpes Simplex; Herpesvirus 1, Human; Immune System; Immunoglobulin M; Interferon-gamma; Interleukin-10; Interleukin-2; Male; Mice; Mice, Inbred BALB C; Nadolol; Physical Conditioning, Animal; Phytohemagglutinins; Random Allocation; Receptors, Adrenergic, beta; Spleen

Direct intratumor injection of a disabled infectious single cycle HSV-2 virus encoding the murine GM-CSF gene (DISC/mGM-CSF) into established murine colon carcinoma CT26 tumors induced a significant delay in tumor growth and complete tumor regression in up to 70% of animals. Pre-existing immunity to HSV did not reduce the therapeutic efficacy of DISC/mGM-CSF, and, when administered in combination with syngeneic dendritic cells, further decreased tumor growth and increased the incidence of complete tumor regression. Direct intratumor injection of DISC/mGM-CSF also inhibited the growth of CT26 tumor cells implanted on the contralateral flank or seeded into the lungs following i.v. injection of tumor cells (experimental lung metastasis). Proliferation of splenocytes in response to Con A was impaired in progressor and tumor-bearer, but not regressor, mice. A potent tumor-specific CTL response was generated from splenocytes of all mice with regressing, but not progressing tumors following in vitro peptide stimulation; this response was specific for the gp70 AH-1 peptide SPSYVYHQF and correlated with IFN-gamma, but not IL-4 cytokine production. Depletion of CD8(+) T cells from regressor splenocytes before in vitro stimulation with the relevant peptide abolished their cytolytic activity, while depletion of CD4(+) T cells only partially inhibited CTL generation. Tumor regression induced by DISC/mGM-CSF virus immunotherapy provides a unique model for evaluating the immune mechanism(s) involved in tumor rejection, upon which tumor immunotherapy regimes may be based.

Topics: Animals; Colonic Neoplasms; Combined Modality Therapy; Concanavalin A; Cytokines; Cytotoxicity, Immunologic; Dendritic Cells; Epitopes; Female; Genetic Vectors; Granulocyte-Macrophage Colony-Stimulating Factor; Herpes Simplex; Herpesvirus 1, Human; Immunity, Active; Injections, Subcutaneous; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Spleen; T-Lymphocytes, Cytotoxic; Virus Activation

Previous studies have indicated that suberythemal ultraviolet B (UV-B) irradiation of C3H mice before primary infection with herpes simplex virus (HSV) type 1 does not result in increased morbidity or mortality, but a suppressed delayed type hypersensitivity (DH) to the virus can be demonstrated. Any effect of UV radiation on pathogenesis during secondary epidermal HSV infection has not been previously examined. Mice were immunized by subcutaneous injection of inactivated HSV and, 5 days later, one group was UV-B-irradiated. The next day all mice were challenged epidermally with HSV. Most of the mice (92%) in the irradiated group developed severe lesions, whilst 59% of the non-irradiated group had mild lesions and 30% no lesions. Infectious virus was not isolated from the adrenal glands after challenge in either group. In addition, the DH to the virus was not affected by the UV exposure. The numbers of lymphocytes and dendritic cells in the lymph nodes draining the site of epidermal infection were increased in the UV group compared with the non-irradiated group. Following challenge, the percentage of CD4+ and CD8+ lymphocytes in lymph nodes was unaltered but the MHC class II expression on dendritic cells in these lymph nodes was reduced by UV exposure. The lymphoproliferative response in vitro of lymph node cells revealed a suppressed response to HSV and to the mitogen concanavalin A in the irradiated group. Thus, UV irradiation prior to epidermal secondary infection with HSV led to more severe infections due, perhaps, to a modulation in local antigen presentation.

Topics: Animals; Antibodies, Viral; Chlorocebus aethiops; Concanavalin A; Female; Herpes Simplex; Herpesvirus 1, Human; Humans; Hypersensitivity, Delayed; Immunity; Lymph Nodes; Lymphocyte Activation; Lymphocyte Count; Lymphocytes; Mice; Mice, Inbred C3H; Ultraviolet Rays; Vero Cells; Viral Vaccines

This study examines the role of immune defence mechanisms in herpes simplex virus (HSV) infections in atopic eczema and whether impairment of these mechanisms explains the susceptibility of some children with atopic eczema to cutaneous HSV infections. Ten children with eczema herpeticum and 13 with atopic eczema and recurrent HSV infection affecting multiple skin sites were studied, together with relevant control groups. In all children with atopic eczema, in vitro lymphoproliferation in response to stimulation with concanavalin A (Con A) was significantly decreased and natural killer (NK) cells (CD16 + 56) were reduced compared with non-atopic controls. IL-2 receptors, a marker for lymphocyte activation, were decreased during the acute phase of eczema herpeticum, and for 1 month thereafter. A positive stimulation index (> 3) to HSV antigen, and high HSV IgG antibody titres measured by ELISA, Western blotting and neutralization assay, were seen in children with eczema herpeticum by 6 weeks, and also in children with atopic eczema and recurrent HSV infections. No evidence of an HSV-specific immune defect (either cell-mediated or humoral) was found in atopic eczema. Impairment of cell-mediated immunity in atopic eczema was suggested by the reduced response to Con A. It is likely that reduced numbers of circulating NK cells and a decrease in IL-2 receptors during early eczema herpeticum contribute to the susceptibility of children with atopic eczema to cutaneous HSV infections.

Topics: Acute Disease; Antibodies, Viral; Antigens, Viral; Child; Concanavalin A; Dermatitis, Atopic; Herpes Simplex; Humans; Immunoglobulin G; Kaposi Varicelliform Eruption; Lymphocyte Activation; Opportunistic Infections; Recurrence; Simplexvirus; T-Lymphocyte Subsets

Interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production and lymphocyte proliferation in response to herpes simplex virus (HSV) antigen were assessed in 13 neonates and 3 parturient women with primary HSV infection. In comparison with 9 nonparturient adults, the neonates and parturient women showed significantly (P less than .01) diminished HSV antigen-stimulated lymphocyte proliferation and IFN-gamma production in the first 3-6 weeks after onset of infection. TNF alpha production did not differ significantly among HSV-infected groups. The impairment in neonatal cellular immunity was due, at least in part, to a specific deficit in response to HSV antigen. Lymphocyte proliferation and TNF alpha production in response to the mitogen concanavalin A (ConA) were comparable in adults and infants, but ConA-stimulated IFN-gamma production in infants was diminished throughout the study period. In contrast, HSV antigen-stimulated IFN-gamma production was comparable in infants and adults after 6 weeks. Not all patients with diminished cellular immune responses to HSV antigen manifested severe clinical disease. Nevertheless, patients with significant clinical morbidity had diminished cellular immune responses to HSV antigen. These results suggest that delayed acquisition of antigen-specific cellular immunity in primary HSV infection predisposes to more severe clinical disease.

Topics: Antibodies, Viral; Antigens, Viral; Blotting, Western; Concanavalin A; Female; Herpes Genitalis; Herpes Simplex; Humans; Immunity, Cellular; Immunity, Maternally-Acquired; Infant, Newborn; Interferon-gamma; Lymphocyte Activation; Pregnancy; Puerperal Infection; Simplexvirus; Time Factors; Tumor Necrosis Factor-alpha

The murine model of acquired immunodeficiency disease was used to evaluate both the antiretroviral and antiherpetic activities of the acyclic nucleotide analog 9-(2-phosphonylmethoxyethyl)adenine (PMEA). The antiretroviral activity of PMEA was compared with that of azidothymidine (AZT) in mice receiving the drug either immediately after infection or at late times in disease progression. Both AZT (oral, 30 mg/kg) and PMEA (parenteral, 25 and 5 mg/kg) were effective in slowing the development of disease when administered daily beginning on the day of infection. In contrast, neither drug alone was effective in modifying disease outcome when administered several weeks after viral infection. Human recombinant alpha interferon (rhuIFN alpha-B/D at 5 x 10(7) U/kg) was also ineffective when administered late in the course of disease. However, when administered in combination, both alpha interferon and PMEA (25 mg/kg) were able to suppress disease progression even when treatment was initiated as late as 3 weeks postinfection. Mice that were immunocompromised due to LP-BM5 virus infection were highly susceptible to acute (lethal) infection with herpes simplex virus type 1, whereas their immunocompetent littermates were not. PMEA was as effective as acyclovir in the treatment of opportunistic herpes simplex virus type 1 infections in LP-BM5 virus-infected mice. Thus, like AZT, PMEA was effective against retrovirus infection, and, like acyclovir, PMEA was effective against herpes simplex virus type 1 infection. This gives PMEA the unique potential of being useful in the treatment of opportunistic herpes simplex virus infections as well as the underlying retroviral disease.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Animals; Antiviral Agents; Concanavalin A; Herpes Simplex; Interferons; Mice; Mice, Inbred C57BL; Mitogens; Opportunistic Infections; Organophosphonates; Spleen; Zidovudine

Defective production of antibodies to herpes simplex virus (HSV) and low resistance to HSV infection in neonatal mice could be reconstituted by using macrophages from syngeneic adult mice plus concanavalin A-stimulated supernatants prepared from adult mouse spleen cells or adult human peripheral blood lymphocytes. In each supernatant, interleukin-2 (IL-2) produced by T helper cells (positive for Lyt 1.2 or OKT4) was necessary to provide reconstitution. Supernatants from neonatal mice failed to mediate reconstitution because of an age-dependent absence of production of IL-2. Although supernatants from neonatal human cell cultures contained IL-2, they failed to reconstitute production of antibody to HSV and resistance to HSV infection because of a suppressor of IL-2 activity. Early antibody production and antibody-dependent cellular effector function are important defenses against HSV infection and are critically defective in the neonate.

Topics: Animals; Animals, Newborn; Antibodies, Viral; Antibody-Dependent Cell Cytotoxicity; Cells, Cultured; Concanavalin A; Herpes Simplex; Humans; Infant, Newborn; Interleukin-2; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Simplexvirus; T-Lymphocytes, Helper-Inducer

Nude mice have been shown to be as resistant to intraperitoneal infection with herpes simplex virus type 1 (HSV) as their heterozygous littermates. Here we document that both activation of natural killer (NK) cells and interferon induction were normal in nu/nu mice after injection of HSV. Injection of silica caused increased mortality by HSV in C57BL/6 mice. Silica, in addition, led to a significant reduction of NK cell activity but had no effect on the interferon response. Treatment of C57BL/6 mice with anti-asialo GM1 (an antiserum with a predominant effect on NK cells) caused complete abolition of the NK cell response, but had no effect on interferon induction or virus-induced mortality. In further studies a monoclonal anti-thy-1.2 antibody was utilized which possessed high activity in vivo in depleting T cell responses in mice. Injection of anti-thy-1.2 decreased NK cell activation but was without effect on the interferon response. Unexpectedly, in view of the data in nu/nu mice, this antibody increased HSV-induced mortality in C57BL/6 mice. Similar data were obtained when anti-thy-1.2 was injected into nu/nu mice. Our results are compatible with the hypothesis that T cell precursors sensitive to anti-thy-1.2 present in homozygous nude mice play a role in resistance against HSV. Furthermore, the data in the euthymic mice may indicate a role of T cells in the primary resistance of mice against HSV.

Topics: Animals; Concanavalin A; G(M1) Ganglioside; Glycosphingolipids; Herpes Simplex; Immune Sera; Immunity, Innate; Interferons; Isoantibodies; Killer Cells, Natural; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Phytohemagglutinins; Silicon Dioxide; T-Lymphocytes

Numerous clinical situations, demonstrated to be associated with reactivation of herpes simplex virus infections, have also been shown to produce increases in local levels of prostaglandins. The current study was initiated to determine if prostaglandins play a role in the immune response and control of herpes simplex virus infections. Lymphocytes from volunteers were stimulated with concanavalin A, herpes simplex virus 1, or herpes simplex virus 2 in the presence of prostaglandin E2 or ibuprofen, and the lymphocytes served as their own controls. The data suggest a statistically significant suppression in nonspecific T cell mitogen stimulation (concanavalin A), as well as specific herpes simplex virus 1 and 2 stimulations as measured by tritiated thymidine uptake by lymphocytes when stimulated in the presence of prostaglandin E2. Ibuprofen did not alter the proliferative response to concanavalin A, herpes simplex virus 1, or herpes simplex virus 2 stimulation. This report examines the involvement of prostaglandins in herpesvirus infection such as the suppression of T cell function, allowing for a clinical recurrence. The usefulness of nonsteroidal antiinflammatory agents in the therapy of herpes simplex virus infections is also discussed.

Topics: Adolescent; Adult; Cell Transformation, Viral; Concanavalin A; Dinoprostone; Female; Herpes Genitalis; Herpes Simplex; Humans; Ibuprofen; Leukocyte Count; Lymphocyte Activation; Male; Middle Aged; Prostaglandins E; Stomatitis, Herpetic; T-Lymphocytes; Time Factors

Topics: Aged; Antibodies, Viral; Cell Count; Cell Line; Cells, Cultured; Child, Preschool; Concanavalin A; Herpes Simplex; Humans; Male; Phytohemagglutinins; Simplexvirus; T-Lymphocytes; Time Factors

The role of antibody, interferon, and cell-mediated immunity (CMI) were studied to determine the mechanisms for progesterone enhancement of vaginal herpes simplex virus type 2 (HSV 2) infection in mice. Three groups of mice were studied: nonpregnant control, pregnant, and nonpregnant progesterone-treated mice. Vaginal infection with HSV 2 did not elicit a neutralizing antibody or a systemic interferon response in any of the groups tested. Splenic lymphocytes from noninfected and infected mice were stimulated in vitro with a nonspecific T-cell mitogen concanavalin (Con A) to measure the proliferative phase of CMI in these groups of mice. No suppression of (3H) thymidine (3HTdR) uptake was found in the pregnant or nonpregnant, progesterone-treated animals as compared to nonpregnant control mice. When progesterone was added directly to the splenic lymphocytes and continuously present during Con A stimulation a statistically significant depression of 3HTdR incorporation was found. We concluded that progesterone depresses Con A stimulation of murine lymphocytes, but progesterone must be continuously present to do so.

Topics: Animals; Antibodies, Viral; Concanavalin A; Dose-Response Relationship, Drug; Female; Herpes Simplex; Immunity, Cellular; Interferons; Lymphocyte Activation; Mice; Pemphigoid Gestationis; Pregnancy; Progesterone; Simplexvirus; Vaginal Diseases

The relationship between herpes simplex virus (HSV) infection and specific cell-mediated immunity was investigated in 141 patients before and for the first four months after marrow transplant. Sixty-two (82%) of 76 seropositive patients but only one of 65 seronegative patients developed HSV infection. Lymphocyte responses to HSV antigen were suppressed immediately after transplant and subsequently became reactive in those patients with HSV infection. The presence or absence of antibody to HSV in the donor before transplant did not influence the response. Seventy long-term survivors of marrow transplant were also studied. Among 60 patients who had pretransplant serum available for study, 26 (68%) of 38 who had been seropositive before transplant had positive responses compared with none of 22 who had been seronegative. Recovery of responsiveness to HSV antigen after marrow transplant is primarily related to recurrent virus infection and not to the pretransplant immune status of the donor.

Topics: Antigens, Viral; Antilymphocyte Serum; Bone Marrow Transplantation; Concanavalin A; Graft vs Host Reaction; Herpes Simplex; Humans; Immunity, Cellular; Lymphocyte Activation; Phytohemagglutinins; Simplexvirus; T-Lymphocytes; Transplantation, Homologous

Mitogen responsiveness and suppressor cell function were determined in patients with multiple sclerosis. Mitogen response to concanavalin A, expressed as stimulation index, decreased with age in both patients and controls. Although responses in the overall group of young patients did not differ from controls, the stimulation index was reduced in clinically inactive patients. Patients with recent flare-ups showed responses comparable to controls. Suppressor cell activity increased with age in both disease and control groups. Among young patients, suppressor activity was borderline low in inactive patients but increased significantly in those with recent exacerbations.

Topics: Adolescent; Adult; Age Factors; Aged; Concanavalin A; Herpes Simplex; Humans; Middle Aged; Mitogens; Multiple Sclerosis; T-Lymphocytes