RESUMEN
Among vaccine-preventable diseases, measles is the preeminent killer of children worldwide. Infection with measles virus (MV) is associated with prolonged suppression of cell-mediated immune responses, a phenomenon that is thought to underlie the susceptibility to secondary infections that accounts for most measles-related mortality. Interleukin (IL)-12 is critical for the orchestration of cellular immunity. MV specifically ablates IL-12 production by monocyte/macrophages in vitro through binding to CD46, a complement regulatory protein that is an MV receptor. To address the effect of MV on IL-12 responses in vivo, cytokine production was examined in Gambian patients with measles. IL-12 production by peripheral blood monocytes from such patients is markedly suppressed, which provides a unifying mechanism for many of the immunologic abnormalities associated with measles. This suppression is prolonged, with significant, stimulus-specific inhibition of IL-12 production demonstrable months after recovery from acute infection. However, despite this suppression, IL-12 responsiveness remains intact.
Asunto(s)
Interleucina-12/biosíntesis , Sarampión/inmunología , Adolescente , Adulto , Antígenos CD/metabolismo , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Gambia , Humanos , Lactante , Interferón gamma/biosíntesis , Macrófagos/inmunología , Masculino , Vacuna Antisarampión , Proteína Cofactora de Membrana , Glicoproteínas de Membrana/metabolismo , Monocitos/inmunología , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Skewing of the T-cell receptor repertoire of CD8(+) T cells has been shown in some persistent infections with viruses, such as human immunodeficiency virus, simian immunodeficiency virus, and Epstein-Barr virus. We have demonstrated that similar distortions also occur in nonpersistent measles virus infection. In addition, two of four children immunized with live, attenuated measles virus showed larger and more persistent CD8(+) T-cell expansions than their naturally infected counterparts. The expanded lymphocyte populations were monoclonal or oligoclonal and lysed target cells infected with recombinant vaccinia virus expressing measles virus protein. These results demonstrate that the expansions of CD8(+) T lymphocytes are antigen driven.
Asunto(s)
Antígenos Virales/inmunología , Vacuna Antisarampión/inmunología , Sarampión/inmunología , Linfocitos T Citotóxicos/inmunología , Enfermedad Aguda , Secuencia de Aminoácidos , Niño , Preescolar , Humanos , Lactante , Datos de Secuencia Molecular , Receptores de Antígenos de Linfocitos T alfa-beta/análisisRESUMEN
The study of cytotoxic T cell responses to measles antigens during infection and after vaccination may provide insight into the immunopathology of the infection. It will also provide a knowledge of the immunity conferred by wild or attenuated virus, which will help in the design of new vaccines. Direct cytotoxic T cell responses, which did not require in vitro restimulation, were measured from peripheral blood by a standard 51Cr-release assay in 35 patients with acute measles, using HLA class I matched allogeneic B cells as targets. 77% showed specific responses to measles fusion protein, 69% to the hemagglutinin, and 50% to the nucleoprotein. These responses, which were related to severity of disease and history of previous vaccination, had waned by 14-24 wk after measles when memory responses to the same antigens could be elicited by restimulation in 71% of the 13 patients tested. A similar pattern followed vaccination: direct cytotoxic responses to fusion and hemagglutinin proteins were shown in 70% of the 20 children tested while 50% responded to the nucleoprotein. These responses, which were mediated by both CD8(+) and CD4(+) cells, faded over 6 wk when memory responses could be restimulated. Thus, a vigorous cytotoxic T lymphocyte response to fusion, hemagglutinin, and nucleoproteins is important in both natural and vaccine-induced immunity to measles.
Asunto(s)
Antígenos Virales/inmunología , Vacuna Antisarampión/farmacología , Virus del Sarampión/inmunología , Sarampión/inmunología , Linfocitos T Citotóxicos/inmunología , Vacunación , Adolescente , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Niño , Preescolar , Citotoxicidad Inmunológica , Brotes de Enfermedades , Gambia/epidemiología , Antígenos HLA/inmunología , Hemaglutininas Virales/inmunología , Humanos , Inmunidad Celular , Memoria Inmunológica , Lactante , Sarampión/epidemiología , Proteínas de la Nucleocápside , Nucleoproteínas/inmunología , Proteínas Virales de Fusión/inmunología , Proteínas Virales/inmunologíaRESUMEN
The study of cytotoxic T cell (CTL) responses to measles polypeptides in persons with different HLA frequencies will provide information for the design of new vaccines. Peripheral blood mononuclear cells derived from African blacks and Caucasians were stimulated with measles virus-infected autologous cells and tested in a standard 51Cr-release assay against autologous B cells infected with vaccinia virus recombinants expressing measles virus antigens. The proportion of subjects who generated CTL to the fusion, hemagglutinin, and nucleoprotein antigens was 43%, 38%, and 28%, respectively. The use of HLA-mismatched targets showed killing to be restricted by both HLA class I and class II antigens, although CD8-mediated class I cytotoxicity predominated. Measles vaccine boosted CTL responses in subjects with low initial activity. These data suggest that the fusion and hemagglutinin proteins are important targets for the measles CTL response.