The impact of endemic parasitic infection on vaccine efficacy is an important consideration for vaccine development and deployment. We have examined whether intestinal infection with the natural murine helminth Heligmosomoides polygyrus bakeri alters antigen-specific antibody and cellular immune responses to oral and parenteral vaccination in mice. We found that oral vaccination of mice with a clinically relevant, live, attenuated, recombinant Salmonella vaccine that expresses chicken egg ovalbumin (Salmonella-OVA) disrupts ovalbumin-specific regulatory T cell networks in the gut associated lymphoid tissue and promotes T-effector responses to OVA. Chronic intestinal helminth infection significantly reduced Th1-skewed antibody responses to oral vaccination with Salmonella-OVA. Activated, adoptively-transferred, OVA-specific CD4+ T cells accumulated in draining mesenteric lymph nodes (MLN) of vaccinated mice, irrespective of their helminth-infection status. However, helminth infection increased the frequencies of adoptively-transferred OVA-specific CD4+ T cells producing IL-4 and IL-10 in the MLN. Chronic intestinal helminth infection also significantly reduced Th2-skewed antibody responses to parenteral vaccination with OVA adsorbed to alum. These findings suggest helminth-induced impairment of vaccine antibody responses may be driven by the development of IL-10-secreting CD4+ T regulatory cells. They also underscore the potential need to treat parasitic infection before mass vaccination campaigns in helminth-endemic areas.
The impact of endemic parasitic infection on vaccine efficacy is an important consideration for vaccine development and deployment. We have examined whether intestinal infection with the natural murine helminth Heligmosomoides polygyrus bakeri alters Ag-specific Ab and cellular immune responses to oral and parenteral vaccination in mice. Oral vaccination of mice with a clinically relevant, live, attenuated, recombinant Salmonella vaccine expressing chicken egg OVA (Salmonella-OVA) induced the accumulation of activated, OVA-specific T effector cells rather than OVA-specific regulatory T cells in the GALT. Intestinal helminth infection significantly reduced Th1-skewed Ab responses to oral vaccination with Salmonella-OVA. Activated, adoptively transferred, OVA-specific CD4+ T cells accumulated in draining mesenteric lymph nodes of vaccinated mice, regardless of their helminth infection status. However, helminth infection increased the frequencies of adoptively transferred OVA-specific CD4+ T cells producing IL-4 and IL-10 in the mesenteric lymph node. Ab responses to the oral Salmonella-OVA vaccine were reduced in helminth-free mice adoptively transferred with OVA-specific CD4+ T cells harvested from mice with intestinal helminth infection. Intestinal helminth infection also significantly reduced Th2-skewed Ab responses to parenteral vaccination with OVA adsorbed to alum. These findings suggest that vaccine-specific CD4+ T cells induced in the context of helminth infection retain durable immunomodulatory properties and may promote blunted Ab responses to vaccination. They also underscore the potential need to treat parasitic infection before mass vaccination campaigns in helminth-endemic areas.
Alpha-gal syndrome, typically characterized by delayed allergic reactions to mammalian meat, is associated with IgE to galactosealpha-1,3-galactose (alpha-gal), a carbohydrate moiety found in nonprimate mammals. Greater than 90% of alpha-gal allergic patients report urticaria following ingestion of alpha-gal. However, no one has demonstrated that alpha-gal-containing compounds can activate human mast cells sensitized with alpha-gal-specific IgE. METHODS: Primary human skin and lung mast cells were sensitized overnight with human plasma containing alpha-gal-specific IgE ranging from 0.1 to 58 IU/ml. The next day, cells were washed and challenged with anti-FcEpsilonRI antibodies, beef thyroglobulin (BTG), or cetuximab for 30 minutes. Mast cell mediators released into cell culture supernatants were measured. RESULTS: Alpha-gal-containing compounds, including BTG and cetuximab, induced mediator release from skin, but not lung, mast cells. The extent of skin mast cell degranulation and cytokine production correlated with plasma alpha-gal-specific IgE levels. CONCLUSIONS: Alpha-gal-containing compounds activate primary skin-derived human mast cells sensitized with plasma from alpha-gal allergic subjects, resulting in mast cell degranulation and cytokine production. Notably, lung-derived human mast cells sensitized with alpha-gal allergic plasma do not respond to challenge with the doses of alpha-gal-containing compounds that activate skin mast cells. We speculate that the non-responsiveness of the predominantly mucosal lung mast cells (MC T) compared to connective tissue skin mast cells (MC TC) following challenge with alpha-gal may reflect the typical allergic symptoms reported by alpha-gal allergic subjects. Specifically, most subjects experience cutaneous symptoms while a smaller proportion reports respiratory distress, suggesting potential functional differences between skin and lung mast cells.
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