Severe respiratory syncytial virus infection in early life is associated with increased type 2 cytokine production in Gambian children.

BACKGROUND: Severe respiratory syncytial virus (RSV) infection in early childhood has been associated with subsequent wheezing and atopy. The aim of this study was to test if severe RSV infection in early life was associated with an increase in type 2 cytokine production and atopy in Gambian children 5 years later. METHODS: A cohort of children with severe RSV infection during the first year of life ('cases', n = 66) and without ('controls', n = 122) was followed-up at 5 years of age. Immediate hypersensitivity to common allergens, airway reactivity, serum IgE concentration and the production of IFN-gamma, IL-5 and IL-13 by lymphocytes activated in vitro with RSV F-G or control antigens was determined. RESULTS: After adjustment for confounders, cases produced significantly higher concentrations of IL-13 in response to RSV F-G and of IL-5 and IL-13 in response to tuberculin. Cases were more likely to have presented with a wheezy lower respiratory tract infection in the first 3 years of life (adjusted odds ratio = 9.9; 95% CI 1.6-61.0), but not thereafter. Cases and controls had similar skin response to allergens, airway reactivity and serum IgE concentrations. CONCLUSION: Severe RSV infection in early life is associated with a higher production of type 2 cytokines in Gambian children at 5 years of age. However this does not appear to result in increased risk of atopy or clinical allergy at that age.

Natural measles causes prolonged suppression of interleukin-12 production.

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.

Antigen-specific expansion of cytotoxic T lymphocytes in acute measles virus infection.

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.

Ex vivo analysis of cytotoxic T lymphocytes to measles antigens during infection and after vaccination in Gambian children.

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.

Human leukocyte antigen class I- and class II-restricted cytotoxic T lymphocyte responses to measles antigens in immune adults.

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.