RESUMEN
Ocular herpes simplex virus (HSV) infection results in an immune-mediated inflammation of the corneal stroma known as herpetic stromal keratitis (HSK). Recurrent HSK is a common cause of virus-induced corneal blindness in humans. The role of CD4(+) and CD8(+) T cell subsets in the disease pathogenesis is ill defined and varies with the virus strain and host genetic background. To examine the contribution of T cell subsets to corneal disease, we studied the development of recurrent HSK in CD4 or CD8 gene knockout (KO) mice ocularly infected with HSV-1 McKrae strain. Following UV-B induced viral reactivation, corneal opacity in latently infected BALB/c (HSV sensitive) CD4 and CD8 KO mice was reduced compared to infected BALB/c mice with normal genotype. In contrast, opacity in C57BL/6 (HSV resistant) CD4 and CD8 KO latent mice did not differ from genetically normal latent mice. Virus-induced corneal opacity was not demonstrable in C57BL/6 CD4/CD8 double KO mice. Increased viral shedding, measured by reactivation rate, days shedding or viral titers, occurred in CD4 KO mice of both strains. Our findings indicate that both CD4(+) and CD8(+) cells play a role in the immunopathogenesis of recurrent HSK, and their role is dependent upon the host genetic profile.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Queratitis Herpética/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos CD8/inmunología , Chlorocebus aethiops , Enfermedades de la Córnea/inmunología , Modelos Animales de Enfermedad , Herpesvirus Humano 1/genética , Queratitis Herpética/genética , Queratitis Herpética/virología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Células VeroRESUMEN
PURPOSE: Recurrent herpetic stromal keratitis (HSK) is a potentially blinding, immune-mediated disease. To better understand the immunopathology of recurrent HSK, we examined the cytokine profile of mouse corneas with the condition. METHODS: The eyes of latently infected mice were examined for corneal pathology and cytokine content following UV-B-stimulated herpes simplex virus (HSV) reactivation. RESULTS: Peak HSV-induced corneal disease, manifested by stromal opacification, occurred 7-14 days after viral reactivation in latently infected mice. In qualitative RT-PCR analyses, IFNgamma, IL-10, IL-4, and IL-12 p40 mRNA were simultaneously expressed before and during recurrent HSK. Competitive, semi-quantitative RT-PCR evaluation of cytokine mRNA revealed highest IFNgamma expression before and during clinical disease with a decline thereafter. IL-4 levels peaked and declined before day 14, while IL-10 peaked on days 7 or 14 and paralleled IFNgamma at lower levels. Small amounts of IL-12 p40 mRNA were detected late in the disease course. ELISA evaluation of corneal extracts demonstrated similar results, featuring early expression of Th2 cytokines relative to disease. CONCLUSIONS: The presence of Th2 cytokines during early stages of recurrent herpetic corneal lesions indicate the presence of a mixed Th1 and Th2 cell infiltrate, which is likely associated with a memory response to viral antigens. These data suggest that disease resolution in corneas with recurrent HSK may depend upon the balance between destructive and protective cytokines at individual sites of viral recurrence.
Asunto(s)
Sustancia Propia/inmunología , Citocinas/genética , Herpesvirus Humano 1/crecimiento & desarrollo , Queratitis Herpética/inmunología , Animales , Sustancia Propia/patología , Sustancia Propia/virología , Citocinas/metabolismo , Cartilla de ADN/química , Ensayo de Inmunoadsorción Enzimática , Femenino , Queratitis Herpética/patología , Queratitis Herpética/virología , Ratones , Ratones Endogámicos , ARN Mensajero/metabolismo , Recurrencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células TH1/inmunología , Células Th2/inmunología , Factores de Tiempo , Activación ViralRESUMEN
PURPOSE: To better understand the role of interleukin (IL)-1 and tumor necrosis factor (NF)alpha in recurrent herpetic stromal keratitis (HSK), the cytokine content and the effects of anti-cytokine antibodies on mouse corneas with the disease were examined. METHODS: Competitive reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent analyses of IL-1alpha and TNF-alpha content were performed on corneas removed 3, 5, 7, 10, 14, and 21 days after latently infected NIH mice were irradiated with UV-B light to reactivate herpes simplex virus (HSV). In separate experiments, mice were injected with anti-IL-1 or anti-TNF-a antibodies 1 day before and 7 days after reactivation. RESULTS: UV-B irradiation stimulated an increase in corneal IL-la mRNA in reactivated (virus shedding) mice. This increase persisted longer and was higher than in UV-B irradiated uninfected control animals. IL-1alpha and TNF-alpha protein in corneas of reactivated mice was significantly elevated on days 3 to 10 compared with day 0 levels, and exceeded levels in control corneas on the same days. Anti-IL-1 and anti-TNF-alpha antibody administration both resulted in significantly decreased virus-induced corneal opacity between 7 and 21 days after UV-B exposure. CONCLUSIONS: IL-1alpha and TNF-alpha are upregulated in corneas in mice experiencing recurrent HSK. Abrogation of virus-induced corneal disease by anti-cytokine antibodies suggests that these cytokines play important roles in the pathogenesis of recurrent disease. Therefore, neutralization of specific proinflammatory cytokines may have potential therapeutic value.
Asunto(s)
Sustancia Propia/metabolismo , Interleucina-1/metabolismo , Queratitis Herpética/etiología , Queratitis Herpética/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Sustancia Propia/patología , Sustancia Propia/virología , Cartilla de ADN/química , Ensayo de Inmunoadsorción Enzimática , Femenino , Herpesvirus Humano 1/crecimiento & desarrollo , Inmunoglobulina G/administración & dosificación , Interleucina-1/genética , Interleucina-1/inmunología , Queratitis Herpética/patología , Queratitis Herpética/virología , Ratones , Ratones Endogámicos , ARN Mensajero/metabolismo , Recurrencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Regulación hacia Arriba , Activación Viral/efectos de la radiación , Esparcimiento de Virus/fisiologíaRESUMEN
The proliferative response of mononuclear cells from MS patients and normal control subjects to intact and delipidated myelin membranes was examined. The mean frequency of recognition in both groups of human subjects was greater for delipidated myelin than for intact myelin. Human T cell lines established using intact or delipidated myelin as the antigen were highly heterogeneous in response, and were each able to recognize myelin basic protein and myelin proteolipid protein peptides. However, there was no difference in the frequency of recognition of either form of myelin membrane when MS patients were compared to control subjects. Our results suggest that the presentation of delipidated forms of membrane proteins might enhance the response to myelin antigens in vivo, and be relevant to demyelinating diseases.
Asunto(s)
Sistema Nervioso Central/metabolismo , Lípidos de la Membrana/metabolismo , Esclerosis Múltiple/metabolismo , Vaina de Mielina/fisiología , Adulto , Estudios de Casos y Controles , División Celular/fisiología , Femenino , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Proteína Básica de Mielina/metabolismo , Proteína Proteolipídica de la Mielina/metabolismo , Linfocitos T/inmunologíaRESUMEN
The protective efficacy of a glycoprotein D subunit vaccine (gD2 SB AS4) was evaluated in a mouse model of human recurrent herpetic stromal keratitis (HSK). When administered before primary infection, gD2 SB AS4 protected mice against corneal pathology, mortality, and latency resulting from ocular viral challenge with herpes simplex virus type 1 (HSV-1) McKrae strain. In addition, gD2 SB AS4 significantly decreased postreactivation corneal disease. A control vaccine, gD2 alum, protected against acute ocular infection only. When administered after primary infection, gD2 SB AS4 vaccination decreased postreactivation ocular shedding but had no other significant effects. Vaccination with gD2 SB AS4 was associated with high anti-gD antibody responses and low delayed-type hypersensitivity responses. These results have identified a prophylactic vaccine, gD2 SB AS4, with activity against acute and recurrent HSK in mice and emphasize the need for vaccine evaluation in both primary and recurrent ocular herpetic disease models.
Asunto(s)
Herpesvirus Humano 1/inmunología , Vacunas contra Herpesvirus , Queratitis Herpética/prevención & control , Queratitis Herpética/terapia , Proteínas del Envoltorio Viral/inmunología , Vacunas Virales , Animales , Anticuerpos Antivirales/sangre , Córnea/patología , Modelos Animales de Enfermedad , Femenino , Herpesvirus Humano 1/aislamiento & purificación , Humanos , Hipersensibilidad Tardía , Queratitis Herpética/mortalidad , Queratitis Herpética/virología , Ratones , Ratones Endogámicos , Recurrencia , Lágrimas/virología , Ganglio del Trigémino/virología , Vacunación , Vacunas Sintéticas/uso terapéutico , Vacunas Virales/uso terapéutico , Latencia del Virus , Esparcimiento de VirusRESUMEN
Intense exercise affects various parameters of the immune system. The overall effect of exercise on immune function is dependent upon the physical condition of the subject, the intensity and duration of the exercise period, and the immune parameter assessed. Unconditioned horses subjected to a single bout of intensive exercise exhibit multiple alterations in immune function, including an augmentation of lymphokine activated killer (LAK) cell function. This increase in LAK cell activity is not due to an increase in circulating LAK precursors. While peripheral blood mononuclear cells from exercising horses exhibit greater responsiveness to IL-2, this is not due to an increase in IL-2 receptor expression. LAK cell generation in vitro is augmented by those catecholamines and neuropeptides which are produced during exercise, suggesting a direct effect of these compounds on LAK cell generation at a step post IL-2 receptor binding.