Larga duración de la respuesta inmunitaria celular inducida en lactantes y niños inmunizados con vacuna proteoliposómica antimeningocócica BC / Long-lasting cellular immune response in babies, children, and pre-teenagers vaccinated with a proteoliposome based anti-meningococcal BC vaccine

VA-MENGOC-BC® es una vacuna contra los sero grupos B y C de Neisseria meningitidis. La respuesta humoral ha sido extensivamente evaluada pero no la respuesta celular. Estudios prospectivos y retrospectivos fueron realizados para especificar la inducción y duración de la respuesta inmunitaria. El estudio prospectivo fue llevado a cabo en 62 lactantes usando un test de hipersensibilidad retardada (DTH) antes de la primera (3,5 meses de edad), junto a la segunda (42 días después) y 28 días después de la segunda dosis. En los lactantes, la DTH fue negativa antes y 100 por ciento positiva después de la vacunación. El estudio retrospectivo incluyó 535 niños que habían sido vacunados entre 2 y 7 años antes. La positividad de la DTH fue de 100 por ciento en todos los grupos. En los niños vacunados 5 ó 7 años antes, las técnicas de linfoproliferación (LP) y las células secretoras de anticuerpos (ASC) fueron también determinadas. La LP fue positiva en el 26 y 34 por ciento antes de la dosis de re fuerzo en los niños vacunados de 5 y 7 años, respectivamente y decreció posteriormente. Los ASC fueron negativos antes de la dosis de refuerzo y generalmente positivos 7 días después de ésta. No obstante, en los niños vacunados hacía 7 años el 12 por ciento tuvo una pequeña cantidad de ASC antes del refuerzo, los cuales pudieran estar relacionados con la alta frecuencia de circulación de Neisseria en la población o de microorganismos con reactividad cruzada. El mayor incremento en los ASC después del refuerzo (desde 0,73 hasta 166,24 x 106 PBMC) fue observado en aquellos negativos que tenían bajos números de ASC antes del refuerzo al compararlos con los totalmente negativos (desde 0 hasta 67,7 x 106 PBMC). Estos resultados muestran claramente la inducción de respuesta celular en lactantes, la persistencia de respuesta celular en los grupos vacunados hacía tiempo y la memoria de larga duración detectada por una tercera dosis (AU)

Up-regulation of IL-10R1 expression is required to render human neutrophils fully responsive to IL-10.

We have recently shown that IL-10 fails to trigger Stat3 and Stat1 tyrosine phosphorylation in freshly isolated human neutrophils. In this study, we report that IL-10 can nonetheless induce Stat3 tyrosine phosphorylation and the binding of Stat1 and Stat3 to the IFN-gamma response region or the high-affinity synthetic derivative of the c-sis-inducible element in neutrophils that have been cultured for at least 3 h with LPS. Similarly, the ability of IL-10 to up-regulate suppressor of cytokine signaling (SOCS)-3 mRNA was dramatically enhanced in cultured neutrophils and, as a result, translated into the SOCS-3 protein. Since neutrophils' acquisition of responsiveness to IL-10 required de novo protein synthesis, we assessed whether expression of IL-10R1 or IL-10R2 was modulated in cultured neutrophils. We detected constitutive IL-10R1 mRNA and protein expression in circulating neutrophils, at levels which were much lower than those observed in autologous monocytes or lymphocytes. In contrast, IL-10R2 expression was comparable in both cell types. However, IL-10R1 (but not IL-10R2) mRNA and protein expression was substantially increased in neutrophils stimulated by LPS. The ability of IL-10 to activate Stat3 tyrosine phosphorylation and SOCS-3 synthesis and to regulate IL-1 receptor antagonist and macrophage-inflammatory protein 1beta release in LPS-treated neutrophils correlated with this increased IL-10R1 expression, and was abolished by neutralizing anti-IL-10R1 and anti-IL-10R2 Abs. Our results demonstrate that the capacity of neutrophils to respond to IL-10, as assessed by Stat3 tyrosine phosphorylation, SOCS-3 expression, and modulation of cytokine production, is very dependent on the level of expression of IL-10R1.

Immune response induction and new effector mechanisms possibly involved in protection conferred by the Cuban anti-meningococcal BC vaccine.

This report explores the participation of some afferent mechanisms in the immune response induced by the Cuban anti-meningococcal vaccine VA-MENGOC-BC. The induction of delayed-type hypersensitivity in nursing babies and lymphocyte proliferation after immunization is demonstrated. The presence of gamma interferon IFN-gamma and interleukin-2 (IL-2) mRNAs but absence of IL-4, IL-5, and IL-10 mRNAs were observed in peripheral blood mononuclear cells from immunized subjects after in vitro challenge with outer membrane vesicles. In addition, some effector functions were also explored. The presence of opsonic activity was demonstrated in sera from vaccinees. The role of neutrophils as essential effector cells was shown. In conclusion, we have shown that, at least in the Cuban adult population, VA-MENGOC-BC induces mechanisms with a T-helper 1 pattern in the afferent and effector branches of the immune response.

Gene expression and production of tumor necrosis factor alpha, interleukin-1beta (IL-1beta), IL-8, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and gamma interferon-inducible protein 10 by human neutrophils stimulated with group B meningococcal outer membrane vesicles.

Accumulation of polymorphonuclear neutrophils (PMN) into the subarachnoidal space is one of the hallmarks of Neisseria meningitidis infection. In this study, we evaluated the ability of outer membrane vesicles (OMV) from N. meningitidis B to stimulate cytokine production by neutrophils. We found that PMN stimulated in vitro by OMV produce proinflammatory cytokines and chemokines including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-8, macrophage inflammatory protein 1alpha (MIP-1alpha), and MIP-1beta. A considerable induction of gamma interferon (IFN-gamma)-inducible protein 10 (IP-10) mRNA transcripts, as well as extracellular IP-10 release, was also observed when neutrophils were stimulated by OMV in combination with IFN-gamma. Furthermore, PMN stimulated by OMV in the presence of IFN-gamma demonstrated an enhanced capacity to release TNF-alpha, IL-1beta, IL-8, and MIP-1beta compared to stimulation with OMV alone. In line with its downregulatory effects on neutrophil-derived proinflammatory cytokines, IL-10 potently inhibited TNF-alpha, IL-1beta, IL-8, and MIP-1beta production triggered by OMV. Finally, a neutralizing anti-TNF-alpha monoclonal antibody (MAb) did not influence the release of IL-8 and MIP-1beta induced by OMV, therefore excluding a role for endogenous TNF-alpha in mediating the induction of chemokine release by OMV. In contrast, the ability of lipopolysaccharide from N. meningitidis B to induce the production of IL-8 and MIP-1beta was significantly inhibited by anti-TNF-alpha MAb. Our results establish that, in response to OMV, neutrophils produce a proinflammatory profile of cytokines and chemokines which may not only play a role in the pathogenesis of meningitis but may also contribute to the development of protective immunity to serogroup B meningococci.

Nitric oxide participates in the immune response against Neisseria meningitidis serogroup B.

The present report explores the role of nitric oxide into the immune response against Neisseria meningitidis serogroup B. Here we show that NO mediates the alphaTNF increase induced by N. meningitidis derived lipopolysaccharides (LPS), at the same time that participates in the bactericidal activity of resting or gammaIFN activated macrophages and plays a role in the specific DTH and IgG response induced by a commercial anti-meningococcal vaccine. Our findings suggest a positive role for NO at the final effector mechanisms and in the early events driving the immunity against N. meningitidis, suggesting also an insight into its role in endotoxic shock.