Biomedical subjects

Heidrun Moll

Publications and source records attributed to Heidrun Moll.

9 recordsLinked to original sources

PubMed2003

Influenza A virus infection inhibits the efficient recruitment of Th2 cells into the airways and the development of airway eosinophilia.

Most infections with respiratory viruses induce Th1 responses characterized by the generation of Th1 and CD8(+) T cells secreting IFN-gamma, which in turn have been shown to inhibit the development of Th2 cells. Therefore, it could be expected that respiratory viral infections mediate protection against asthma. However, the opposite seems to be true, because viral infections are often associated with the exacerbation of asthma. For this reason, we investigated what effect an influenza A (flu) virus infection has on the development of asthma. We found that flu infection 1, 3, 6, or 9 wk before allergen airway challenge resulted in a strong suppression of allergen-induced airway eosinophilia. This effect was associated with strongly reduced numbers of Th2 cells in the airways and was not observed in IFN-gamma- or IL-12 p35-deficient mice. Mice infected with flu virus and immunized with OVA showed decreased IL-5 and increased IFN-gamma, eotaxin/CC chemokine ligand (CCL)11, RANTES/CCL5, and monocyte chemoattractant protein-1/CCL2 levels in the bronchoalveolar lavage fluid, and increased airway hyperreactivity compared with OVA-immunized mice. These results suggest that the flu virus infection reduced airway eosinophilia by inducing Th1 responses, which lead to the inefficient recruitment of Th2 cells into the airways. However, OVA-specific IgE and IgG1 serum levels, blood eosinophilia, and goblet cell metaplasia in the lung were not reduced by the flu infection. Flu virus infection also directly induced AHR and goblet cell metaplasia. Taken together, our results show that flu virus infections can induce, exacerbate, and suppress features of asthmatic disease in mice.

Allergens↗

PubMed2003

Dendritic cell (DC)-based protection against an intracellular pathogen is dependent upon DC-derived IL-12 and can be induced by molecularly defined antigens.

Upon loading with microbial Ag and adoptive transfer, dendritic cells (DC) are able to induce immunity to infections. This offers encouragement for the development of DC-based vaccination strategies. However, the mechanisms underlying the adjuvant effect of DC are not fully understood, and there is a need to identify Ag with which to arm DC. In the present study, we analyzed the role of DC-derived IL-12 in the induction of resistance to Leishmania major, and we evaluated the protective efficacy of DC loaded with individual Leishmania Ag. Using Ag-pulsed Langerhans cells (LC) from IL-12-deficient or wild-type mice for immunization of susceptible animals, we showed that the inability to release IL-12 completely abrogated the capacity of LC to mediate protection against leishmaniasis. This suggests that the availability of donor LC-derived IL-12 is a requirement for the development of protective immunity. In addition, we tested the protective effect of LC loaded with Leishmania homolog of receptor for activated C kinase, gp63, promastigote surface Ag, kinetoplastid membrane protein-11, or Leishmania homolog of eukaryotic ribosomal elongation and initiation factor 4a. The results show that mice vaccinated with LC that had been pulsed with selected molecularly defined parasite proteins are capable of controlling infection with L. major. Moreover, the protective potential of DC pulsed with a given Leishmania Ag correlated with the level of their IL-12 expression. Analysis of the cytokine profile of mice after DC-based vaccination revealed that protection was associated with a shift toward a Th1-type response. Together, these findings emphasize the critical role of IL-12 produced by the sensitizing DC and suggest that the development of a DC-based subunit vaccine is feasible.

Animals↗

PubMed2003

Dendritic cells as a tool to combat infectious diseases.

Dendritic cells (DCs) form a network of potent antigen-presenting cells that initiate and amplify immune responses. The detection and capture of microorganisms by DCs trigger stimulus-specific maturation programs that enable DCs to convey pathogen-associated signals to the adaptive branch of the immune system. The appropriate activation of DCs is critical for their ability to direct the development of either a Th1 or a Th2 response, thereby determining the outcome of microbial infections. Advances in the understanding of DC interactions with microbes provide new concepts for immune interventions. In different models of infectious disease, it has been demonstrated that DCs can serve as vaccine carriers, mediating protection against various types of pathogens. The studies of the requirements of ex vivo manipulations of DCs may lead to the design of vaccines that induce protective immunity to infections by appropriate targeting of DCs in vivo.

Animals↗

PubMed2003

Dendritic cells and host resistance to infection.

Host defence against infection requires an integrated response of both the innate and adaptive arms of the immune system. Emerging data indicate that dendritic cells contribute an essential part to the initiation and regulation of adaptive immunity. Dendritic cells guard the sites of pathogen entry to the host and are uniquely suited to detect and capture invading microbes. Upon recognition of microbial structures and appropriate activation, a maturation programme is triggered and dendritic cells migrate to lymphoid organs to stimulate a primary cell-mediated immune response. Moreover, dendritic cells play a critical role in shaping the emerging response, thereby controlling the course of infection. They can discriminate between various types of microorganisms and are capable of producing different cytokines in response to different microbial stimuli. On the other hand, pathogens developed numerous strategies to evade and subvert dendritic cell functions. Elucidating the interactions of dendritic cells with microbial pathogens may lead to novel strategies for combating infectious diseases by dendritic cell-based vaccination and immunotherapy. This review highlights recent advances in our knowledge of the unique role of dendritic cells in counteracting microbial infections.

Animals↗

PubMed2002

Infection with influenza a virus leads to flu antigen-induced cutaneous anaphylaxis in mice.

It is well established, that viral infections may trigger urticaria or allergic asthma; however, as viral infections induce T helper 1 polarized responses, which lead to the inhibition of T helper 2 cell development, the opposite would be plausible. We wanted to investigate how viral infections may mediate allergic symptoms in a mouse model; therefore, we infected BALB/C mice with influenza A virus intranasally. Histologic analyses of lung sections and bronchoalveolar lavages were performed. In addition, cells from the mediastinal lymph nodes were restimulated in vitro to analyze which types of cytokines were induced by the flu infection. Furthermore, flu-specific antibody titers were determined and local anaphylaxis was measured after rechallenge with flu antigen. We found that airways inflammation consisted predominately of macrophages and lymphocytes, whereas only a few eosinophils were observed. interferon-gamma but no interleukin-4 and little interleukin-5 could be detected in the culture supernatants from in vitro restimulated T cells from the draining lymph nodes. The antibody response was characterized by high levels of virus-specific IgG2a, IgG2b, and IgG1 and, surprisingly, low levels of virus-specific IgE antibodies. Interestingly, flu-infected mice developed active and passive cutaneous anaphylaxis after rechallenge with flu-antigen. As the passive cutaneous anaphylaxis reaction persisted over 48 h and was significantly lower after passive transfer of the serum, which was IgE depleted, local anaphylaxis seemed to be mediated predominately by specific IgE antibodies. Taken together, our results demonstrate that mice infected with flu virus develop virus-specific mast cell degranulation in the skin. Our results may also have implications for the pathogenesis of urticaria or other atopic disorders in humans.

Anaphylaxis↗

PubMed2002

The course of Leishmania major infection in mice lacking granzyme-mediated mechanisms.

We previously showed that T cells expressing granzyme (gzm) A are more frequent in skin lesions of susceptible mice than in those of resistant mice infected with the intracellular parasite Leishmania major. To determine the in vivo role of gzm in cutaneous leishmaniasis, we examined the course of L. major infection in gzmA-deficient mice. Despite a delay in host colonization of susceptible mice, the lack of gzmA did not influence the course of lesion development or result in a discernible alteration of the interferon-gamma and interleukin-4 production. Moreover, no differences in these parameters were observed between wild-type controls and mice deficient in gzmB or both gzmA and gzmB. These findings indicate that neither gzmA nor gzmB are critical for the development of T helper cell responses and the outcome of L. major infection.

Animals↗

PubMed2002

Infection with the helminth Nippostrongylus brasiliensis does not interfere with efficient elimination of Mycobacterium bovis BCG from the lungs of mice.

Infection with Mycobacterium tuberculosis continues to be one of the major global health threats. Strong mycobacterium-specific Th1 immune responses correlate with protection, and decreased Th1 responses correlate with disease progression. In contrast, the impact of Th2 responses on the development of protective immune responses to mycobacteria remains unclear. To analyze whether ongoing Th2 responses present in the lung influence the development of a protective Th1 immune response to mycobacteria, we coinfected mice with the helminth Nippostrongylus brasiliensis and Mycobacterium bovis BCG. We found that the T cells from the lymph nodes of coinfected mice secreted significantly less gamma interferon than did the T cells from mice infected with M. bovis BCG after in vitro stimulation with purified protein from M. tuberculosis when 10(8) CFU of M. bovis BCG were used for the infection. This result indicates that the helminth infection reduced the Th1 immune response to the mycobacteria in the lung. However, mycobacterial clearance was not delayed in the coinfected animals. Importantly, the infection with BCG after the helminth infection did not reduce the helminth-induced Th2 response in the lung, ruling out the possibility that the lack of a reduction in bacterial clearance in the coinfected mice was due to a downmodulation of the helminth-induced Th2 response. Taken together, our results suggest that ongoing Th2 responses in the lung do not necessarily lead to increased susceptibility to mycobacterial infection.

Animals↗

PubMed2002

Increased interleukin 4 (IL-4) receptor expression and IL-4-induced decrease in IL-12 production by Langerhans cells infected with Leishmania major.

Langerhans cells (LC) take up Leishmania major and are critical for the induction of the parasite-specific T-cell response. Their functional activities are regulated by cytokines. We analyzed whether infection of LC with L. major modulates the expression of their cytokine receptors. The expression of the interleukin 4 (IL-4) receptor was increased on infected LC from susceptible mice but not on those from resistant mice. Moreover, IL-4 treatment strongly decreased the lipopolysaccharide-induced IL-12 response of infected LC from susceptible mice. This modulation of IL-4 receptor expression and IL-12 production by infection of LC with Leishmania may contribute to the development of Th2 cells and to susceptibility to infection.

Animals↗

PubMed2002

[Leishmania major lipophosphoglycan modulates the expression of receptors involved in parasite internalization in skin Langerhans cells].

Despite the immunological changes recognized to be produced during Leishmania infection and the central role played by Langerhans cells, it is not known whether Leishmaina lipophosphoglycan, the most abundant glycolipid on the parasite surface, affects the functions of Langerhans cells. Here, we provide evidence that exposure of Langerhans cells to Leishmaina (L.) major lipophosphoglycan has consequences for the expression of surface receptors. Down-regulation of receptors involved in host cell-parasite interaction are observed after 4 h exposure of Langerhans cells to lipophosphoglycan. Many of the changes are also induced in Langerhans cells incubated with L. major-conditioned medium, indicating that the observed effects may be mediated by soluble factors released by the parasite into the culture, as it is the case for the carbohydrate moiety of lipophosphoglycan. Taken together, these results indicate that the changes in surface molecule expression induced by the exposure of Langerhans cells to lipophosphoglycan might reflect changes in their signalling functions from the infected skin.

Animals↗