JoAnne L Flynn

..Studying both the host and the pathogen will elucidate potential vaccine candidates. In this review, the known functions of immune components in the response to M. tuberculosis and implications for vaccine development will be discussed...

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..tuberculosis. In this review, we focus on the key role of the macrophage in balancing inflammation in the granuloma...

..M. tuberculosis also modulates antigen presentation to prevent the detection of infected macrophages by CD4(+) T cells...

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..The careful and thoughtful use of animal models is essential to furthering our understanding of M. tuberculosis, and this knowledge will enhance the discovery of improved treatment and prevention strategies...

..The pace of this research must be maintained if we are to realize an effective vaccine in the next decades...

..Finally, we have observed a spectrum of disease not only in monkeys with active disease but also in those with latent infection that provides insight into human latent tuberculosis...

..This study was undertaken to investigate immune modulation in the setting of TNF neutralization in primary and latent tuberculosis in a non-human primate model...

..Granulomas from these animals demonstrated histopathologic characteristics consistent with a chronically active disease process. These results suggest initial T cell depletion may strongly influence outcomes of HIV-Mtb co-infection...

..From these studies, we conclude that immune responses to M. tuberculosis are relatively slow in the local and peripheral compartments and that necrosis occurs surprisingly quickly during granuloma formation...

..The animals had a protracted period of asymptomatic colonization with P. carinii before progression to PCP. The development of a model of PCP in SIV-infected rhesus macaques provides the means to study AIDS-associated PCP...

..Moreover, it appears that mycobacteria-specific multifunctional T cells are better correlates of Ag load (i.e., disease status) than of protection...

..tuberculosis antigens at the site of infection, including lung granulomas and thoracic lymph nodes. These antibodies likely have the capacity to modulate local control of infection in tissues...

..tuberculosis challenge. These findings demonstrate that efficient effector CD4 and CD8 T cells can be developed following M. tuberculosis infection in the absence of IL-15 but that recall T-cell responses may be impaired...

..These results suggest that expression of CXCR3 ligands and the subsequent recruitment of CXCR3(+) cells are involved in granuloma formation and maintenance...

..We sought to determine whether a higher frequency of regulatory T (T(reg)) cells predispose an individual toward active disease or whether T(reg) cells develop in response to active disease...

..Ag dose could potentially govern the functional program of CD8(+) T cells. Collectively, these results depict a host immune response mounted against M. tuberculosis of a significantly more dynamic nature than previously recognized...

..Therefore, TNF affects the expression of chemokines by macrophages in vitro and CD11b(+) cells in vivo, which probably influences the local chemokine gradients and granuloma formation...

..We are using animal models to understand how TNF neutralization by these drugs can lead to reactivation of tuberculosis...

..IL-12 therapy reduced the pathology of M. tuberculosis-infected lungs, as granulomas were smaller and less numerous. These studies support an immunoregulatory role for IL-12 in tuberculosis...

..Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56...

..Chemokines are small molecules that direct the migration of cells within the body. Our data support the notion that TNF is required for appropriate chemokine expression by M. tuberculosis-infected macrophages, both in vitro and in vivo...

..We undertook this study to determine the effect of abatacept treatment in a murine model of chronic M tuberculosis infection...

..SHIV-89.6P induced more IFN-gamma expression than SHIV-KU2. These results indicate SHIV-89.6P and SHIV-KU2 infect cynomolgus macaques and may be used to accurately model effects of HIV infection on latent TB...

..These findings begin to clarify the mechanistic difference between anti-TNF agents and their role in the exacerbation of tuberculosis...

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..Bacterial numbers in the lymph nodes were also higher in CCR5(-/-) mice. Therefore, CCR5 may play a role in the migration of dendritic cells to and from the lymph nodes during M. tuberculosis infection...

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..Our data in the nonhuman primate model of active and latent TB supports targeting bacteria in hypoxic environments for preventing reactivation of latent infection and possibly shortening the duration of therapy in active TB...

..In addition, this model will provide an opportunity to study the latent M. tuberculosis infection observed in approximately 90% of all infected humans...

..In this review, the current literature on chemokines and M. tuberculosis infection, as well as the specific role that tumor necrosis factor alpha (TNF-alpha) plays in granuloma formation and chemokine expression are discussed...

..Consequently, the effector T-cell response and inflammation were greater in the lungs of ICAM-1-/- mice, resulting in morbidity due to overwhelming pathology...

..tuberculosis Hsp70 elicited IL-12 production from WT dendritic cells. This response was absent in both CD40(-/-) dendritic cells and CD40(-/-) mice, suggesting that M. tuberculosis Hsp70 serves as an alternative ligand for CD40 in vivo...

..CD4 depletion influences CD8 T cell function. This study has important implications for human HIV-M. tuberculosis coinfection...

..tuberculosis-infected dendritic cells. IL-23 is present in the lungs early in infection and the IL-17-producing cells, such as gammadelta T cells, may represent a central innate protective response to pulmonary infection...

..On the other hand we also found several species and pathogen specific response patterns. These results provide new insights into mechanisms by which the innate immune system responds to, and interacts with, invading pathogens...

..Functional assays may be necessary to reveal roles for components of the multifactorial immune system...

..The immunology of TB is complex and multifaceted. Identifying the immune mechanisms that lead to control of initial infection and prevent reactivation of latent infection is crucial to combating this disease...

..This review aims to summarize the recent findings in human and non-human primate models of tuberculosis that have led to new concepts of latent tuberculosis...

..This review examines the data that support each hypothesis of how HIV manipulates TB pathology while emphasizing a need for more tissue-based experiments...

..These are collaborative studies between experimental immunologists, mathematicians, and computer scientists...

..Thus, although CD4 T cells play additional roles in the control of M. tuberculosis infection, IFN-γ is a major function by which these cells participate in resistance to tuberculosis...

..They also demonstrate that polymorphisms in LTA(4)H are associated with susceptibility to mycobacteria in humans...

..These results are similar to immunologic findings in human AIDS-associated PCP and support the usefulness of this model in the study of immune responses to P. carinii...

..P2X7(-/-) mice controlled infection in lungs as well as wild-type mice, suggesting that the P2X7 receptor is not required for control of pulmonary M. tuberculosis infection...

..Thus, three independent lines of evidence support the hypothesis that hypoxic microenvironments are an important feature of some lesions in these animal models of tuberculosis...

..In addition, the MMIA serodetection system has a potential for mining M. tuberculosis open reading frames (about 4,000) to discover novel target proteins for the development of more-comprehensive TB serodiagnostic tests...

..Alternatively, the dose and timing of anti-TNF therapy could be modified. Anti-TNF therapy will likely lead to numerous incidents of primary TB if used in areas where exposure is likely...

..We discuss here current understanding of both host and bacterial factors that contribute to latent and reactivation tuberculosis...

..This will induce the most protective T cell response...

..We also determined the minimum levels of effector memory cells of each T cell subset (CD4(+) and CD8(+)) in providing effective protection following vaccination...

..The data presented in this supplement highlight the need for further research into these key areas, and illustrate our current understanding of the mode of action of TNF blockers as only the tip of the iceberg...

..In this article we describe the characteristics of these newer screening tests and discuss their potential contributions to NHP tuberculosis surveillance programs...

..Once a non-human primate model for tuberculosis is established, it could be used to test vaccines, immunotherapy, and new treatment options for tuberculosis. ..

..The results obtained are relevant to vaccine design and efficacy, as well as to understanding treatment and prevention of tuberculosis in HIV+ (and therefore CD4 T cell deficient) individuals. ..

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..These studies are the first to study reactivation in an immunologically tractable animal model that is similar to human latent tuberculosis. ..

..Determine whether CD8 T cell memory is initiated, maintained and recalled in the setting of cured or latent tuberculosis, and the factors that contribute to the ineffective memory response. ..

..This application will address how CD4 T cells contribute to immunity to tuberculosis, and provide insight into improving the CD4 T cell response, and possibly improving vaccines against this disease. ..

..Determine whether CD8 T cell memory is initiated, maintained and recalled in the setting of cured or latent tuberculosis, and the factors that contribute to the ineffective memory response. ..

..This application will address how CD4 T cells contribute to immunity to tuberculosis, and provide insight into improving the CD4 T cell response, and possibly improving vaccines against this disease. ..

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..This meeting seeks to bring together researchers from a variety of fields, with the common goal of understanding how persistent pathogens survive and how the host responds to such pathogens. ..

..Here we integrate data from humans and animal models with computational and mathematical models in a comprehensive systems biology approach to a better understanding of latent TB and the factors that lead to reactivation. ..