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JoAnne L Flynn

Publications and source records attributed to JoAnne L Flynn.

At least 19 recordsLinked to original sources
PubMed2006

IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection.

IL-17 is a cytokine produced by T cells in response to IL-23. Recent data support a new subset of CD4 Th cells distinct from Th1 or Th2 cells that produce IL-17 and may contribute to inflammation. In this study, we demonstrate that, in naive mice, as well as during Mycobacterium tuberculosis infection, IL-17 production is primarily from gammadelta T cells and other non-CD4(+)CD8(+) cells, rather than CD4 T cells. The production of IL-17 by these cells is stimulated by IL-23 alone, and strongly induced by the cytokines, including IL-23, produced by M. 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.

Animals↗
PubMed2006

Lessons from experimental Mycobacterium tuberculosis infections.

Mycobacterium tuberculosis is the cause of enormous human morbidity and mortality each year. Although this bacterium can infect and cause disease in many animals, humans are the natural host. For the purposes of studying the pathogenesis of M. tuberculosis, as well as the protective and immunopathologic host responses against this pathogen, suitable animal models must be used. However, modeling the human infection and disease in animals can be difficult, and interpreting the data from animal models must be done carefully. In this paper, the animal models of tuberculosis are discussed, as well as the limitations and advantages of various models. In particular, the lessons we have learned about tuberculosis from the mouse models are highlighted. 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.

Animals↗
PubMed2005

Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis.

Inflammatory cells migrate to the lungs in response to Mycobacterium tuberculosis infection. These infiltrating cells organize into a structure called a granuloma, which controls and contains infection. The signals that influence the formation of granulomas are largely unknown. Tumor necrosis factor (TNF) has been demonstrated to be required for formation of granulomas, in mouse models of tuberculosis, and for control of latent tuberculosis, in humans. We investigated the mechanisms by which TNF controls cell migration in response to M. tuberculosis infection, focusing on the effects of this cytokine on chemokine expression. 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.

Animals↗
PubMed2005

Long-term control of Mycobacterium tuberculosis infection is mediated by dynamic immune responses.

The primary goal of this study was to determine how chronic exposure to Ag influences the functionality of Mycobacterium tuberculosis-specific T cell responses. The frequency of IFN-gamma-producing effector CD4(+) and CD8(+) T cells dynamically changed during persistent M. tuberculosis infection. CD8(+) T cells used differential effector functions during acute and chronic phases of the immune response, where CD8(+) T cells produced negligible amounts of IFN-gamma early in infection, but switched to cytokine production during the chronic stage of infection. Using limiting dilution analysis, CD8(+) T cells isolated during the initial phase of infection demonstrated lytic potential, but this waned in the chronic stage. The apparent loss of cytotoxic activity was not associated with the lack of perforin. 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.

Acute Disease↗
PubMed2005

What's good for the host is good for the bug.

Tuberculosis, caused by Mycobacterium tuberculosis, kills approximately two million people each year. The infection is characterized by an inflammatory response culminating in the formation of a granuloma, a collection of immune cells that controls the infection. However, the granuloma can be the source of immunopathology that encourages transmission. Recent data support the idea that mycobacterial products can positively and negatively regulate the inflammatory response. Our contention is that induction of the immune response and subsequent granuloma formation is beneficial to the host for control of infection, and is also beneficial to the bacillus, as a place to hide and as a means for transmitting the infection to naive hosts.

Humans↗
PubMed2005

Induction of Mycobacterium tuberculosis-specific primary and secondary T-cell responses in interleukin-15-deficient mice.

Several studies have provided evidence that interleukin-15 (IL-15) can enhance protective immune responses against Mycobacterium tuberculosis infection. However, the effects of IL-15 deficiency on the functionality of M. tuberculosis-specific CD4 and CD8 T cells are unknown. In this study, we investigated the generation and maintenance of effector and memory T-cell responses following M. tuberculosis infection of IL-15(-/-) mice. IL-15(-/-) mice had slightly higher bacterial numbers during chronic infection, which were accompanied by an increase in gamma interferon (IFN-gamma)-producing CD4 and CD8 T cells. There was no evidence of increased apoptosis or a defect in proliferation of CD8 effector T cells following M. tuberculosis infection. The induction of cytotoxic and IFN-gamma CD8 T-cell responses was normal in the absence of IL-15 signaling. The infiltration of CD4 and CD8 T cells into the lungs of "immune" IL-15(-/-) mice was delayed in response to M. 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.

Animals↗
PubMed2004

CCR5-deficient mice control Mycobacterium tuberculosis infection despite increased pulmonary lymphocytic infiltration.

The control of Mycobacterium tuberculosis infection is dependent on the development of an adaptive immune response, which is mediated by granulomas. The granuloma is a dynamic structure that forms in the lung and consists primarily of macrophages and lymphocytes. For this structure to be effective in containment of the bacillus, it must develop in an organized and timely manner. The formation of the granuloma is dependent on recruitment of activated cells through adhesion molecules and chemokines. M. tuberculosis infection causes an increase in the expression of beta-chemokines CCL3, CCL4, and CCL5, and their receptor CCR5, in the lungs. In this study, we demonstrate that CCR5-transgenic knockout mice were capable of recruiting immune cells to the lung to form granulomas. CCR5(-/-) mice successfully induced a Th1 response and controlled infection. Unexpectedly, M. tuberculosis infection in these mice resulted in greater numbers of lymphocytes migrating to the lung and higher levels of many inflammatory cytokines, compared with wild-type mice, without apparent long-term detrimental effects. In the absence of CCR5, there were more dendritic cells in the lung-draining lymph nodes and more primed T lymphocytes in these mice. 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.

Animals↗
PubMed2004

Dendritic cell trafficking and antigen presentation in the human immune response to Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) is an extraordinarily successful human pathogen, one of the major causes of death by infectious disease worldwide. A key issue for the study of tuberculosis is to understand why individuals infected with Mtb experience different clinical outcomes. To better understand the dynamics of Mtb infection and immunity, we coupled nonhuman primate experiments with a mathematical model we previously developed that qualitatively and quantitatively captures important processes of cellular priming and activation. These processes occur between the lung and the nearest draining lymph node where the key cells mediating this process are the dendritic cells (DC). The nonhuman primate experiments consist of bacteria and cell numbers from tissues of 17 adult cynomolgus macaques (Macaca fascicularis) that were infected with Mtb strain Erdman ( approximately 25 CFU/animal via bronchoscope). The main result of this work is that delays in either DC migration to the draining lymph node or T cell trafficking to the site of infection can alter the outcome of Mtb infection, defining progression to primary disease or latent infection and reactivated tuberculosis. Our results also support the idea that the development of a new generation of treatment against Mtb should optimally elicit a fast DC turnover at the site of infection, as well as strong activation of DCs for maximal Ag presentation and production of key cytokines. This will induce the most protective T cell response.

Animals↗
PubMed2004

TNF influences chemokine expression of macrophages in vitro and that of CD11b+ cells in vivo during Mycobacterium tuberculosis infection.

Granulomas, focal accumulations of immune cells, form in the lung during Mycobacterium tuberculosis infection. Chemokines, chemotactic cytokines, are logical candidates for inducing migration of T lymphocytes and monocytes to and within the lung. TNF influences chemokine expression in some models. TNF-deficient mice infected with M. tuberculosis are highly susceptible to disease, and granuloma formation is inhibited. Through in vitro assays, we demonstrate that neutralization of TNF in M. tuberculosis-infected macrophages led to a reduction in many inflammatory chemokines, such as C-C chemokine ligand 5, CXC ligand 9 (CXCL9), and CXCL10. In TNF-deficient mice, immune cells migrated to the lungs early after infection, but did not organize to form granulomas within the lung. Although chemokine expression, as measured in whole lung tissue, was not different, the expression of chemokines in the CD11b(+) subset of cells isolated ex vivo from the lungs of TNF-deficient mice had reduced expression of C-C chemokine ligand 5, CXCL9, and CXCL10 at early time points after TNF neutralization. Local expression of CXCR3-binding chemokines within the lungs, as determined by in situ hybridization, was also affected by TNF. 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.

Animals↗
PubMed2004

Immunology of tuberculosis and implications in vaccine development.

Mycobacterium tuberculosis is a very successful pathogen that can survive and persist in the human host in the face of a robust immune response. This immune response is sufficient to prevent disease in the majority of infected persons, providing compelling evidence that immunity to tuberculosis is possible. However, it is more striking that the strong immune response is not generally effective at eliminating the organisms, during either initial infection or the persistent or latent phase of infection. Studies in animal models and in humans have demonstrated the wide range of immune components involved in the effective response against M. tuberculosis. These components include T cells (both CD4+ and CD8+), cytokines, including IFN-gamma, IL-12, TNF-alpha, and IL-6, and macrophages. The precise roles and functions of these cells and molecules (and others) are still being defined and may differ in acute and chronic infection. These immune responses are directed towards containing or eliminating the tubercle bacillus within the tissues of the host. The estimated eight million new cases of tuberculosis each year clearly demonstrate that these responses are not always effective. M. tuberculosis has obviously evolved a variety of mechanisms to evade destruction by the immune response. 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.

Cytokines↗
PubMed2004

Interleukin-12 therapy reduces the number of immune cells and pathology in lungs of mice infected with Mycobacterium tuberculosis.

Alternate modalities for the treatment of Mycobacterium tuberculosis are needed due to the rise in numbers of immunosuppressed individuals at risk for serious disease and the increasing prevalence of multidrug-resistant isolates. Interleukin-12 (IL-12) has been shown to improve immune responses against M. tuberculosis infection in both humans and mice. Previous studies using high-dose IL-12 in various disease models reported a paradoxical immunosuppression. We demonstrate here that exogenous administration of IL-12 for 8 weeks after an aerosolized low dose of M. tuberculosis results in increased survival and decreased pulmonary bacterial loads for CD4-T-cell-deficient mice, most likely due to an early increase in gamma interferon. IL-12 treatment did not impair or enhance the ability of the wild-type mice to control infection, as measured by bacterial numbers. Two novel findings are reported here regarding exogenous IL-12 therapy for M. tuberculosis infections: (i). IL-12 treatment resulted in decreased numbers of immune cells and reduced frequencies of lymphocytes (CD8(+), CD4(+), and NK cells) in the lungs of infected mice and (ii). 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.

Adjuvants, Immunologic↗
PubMed2003

Experimental Pneumocystis carinii pneumonia in simian immunodeficiency virus-infected rhesus macaques.

To establish experimental Pneumocystis carinii infection in simian immunodeficiency virus (SIV)-infected macaques as a model of acquired immunodeficiency syndrome (AIDS)-associated P. carinii pneumonia (PCP), SIV-infected macaques were inoculated intrabronchially with macaque-derived P. carinii, and P. carinii-specific polymerase chain reaction (PCR) and flow cytometric analysis of bronchoalveolar lavage fluid were done biweekly for up to 44 weeks after inoculation. All inoculated animals had a P. carinii-specific PCR product after infection. CD8(+) T cells in lung lavage samples from SIV- and P. carinii-coinfected animals increased to >90% of total CD3(+) cells, a pattern associated with naturally acquired P. carinii infection. Progression of disease also was correlated with increased neutrophil infiltration to the lungs. 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.

AIDS-Related Opportunistic Infections↗
PubMed2003

Immune evasion by Mycobacterium tuberculosis: living with the enemy.

Mycobacterium tuberculosis is successful as a pathogen because of its ability to persist in an immunocompetent host. This bacterium lives within the macrophage, a cell whose function is the elimination of microbes. Recent advances have improved our understanding of how M. tuberculosis evades two major antimicrobial mechanisms of macrophages: phagolysosome fusion and the production of toxic reactive nitrogen intermediates. M. tuberculosis also modulates antigen presentation to prevent the detection of infected macrophages by CD4(+) T cells.

Animals↗
PubMed2003

CD40, but not CD40L, is required for the optimal priming of T cells and control of aerosol M. tuberculosis infection.

CD40(-/-) mice succumbed to low-dose aerosol infection with M. tuberculosis due to deficient IL-12 production leading to impaired priming of IFN-gamma T cell responses. In contrast, CD40L(-/-) mice were resistant to M. tuberculosis. This asymmetry in outcome of infection between the two knockout strains is likely due to the existence of an alternative ligand for CD40. Both in vitro M. tuberculosis infection and recombinant M. 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.

Animals↗
PubMed2003

Chemokines and tuberculosis.

Mycobacterium tuberculosis is a respiratory pathogen responsible for tuberculosis. A primary pathologic feature of M. tuberculosis infection is the formation of a granuloma. Immune cells migrate to the lung and then through the lung to the site of infection to form a granuloma. This structure contains the infection, and is often maintained for a long period of time. The signals responsible for granuloma formation and maintenance are largely unknown. Since chemokines and chemokine receptors direct cells to specific sites within the tissues, it is plausible that these cells participate in granuloma formation. 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.

Animals↗
PubMed2003

Latent tuberculosis: mechanisms of host and bacillus that contribute to persistent infection.

Most people infected with Mycobacterium tuberculosis contain the initial infection and develop latent tuberculosis. This state is characterised by evidence of an immune response against the bacterium (a positive tuberculin skin test) but no signs of active infection. It can be maintained for the lifetime of the infected person. However, reactivation of latent infection occurs in about 10% of infected individuals, leading to active and contagious tuberculosis. An estimated 2 billion people worldwide are infected with M tuberculosis--an enormous reservoir of potential tuberculosis cases. The establishment and reactivation of latent infection depend on several factors, related to both host and bacterium. Elucidation of the host immune mechanisms that control the initial infection and prevent reactivation has begun. The bacillus is well adapted to the human host and has a range of evasion mechanisms that contribute to its ability to avoid elimination by the immune system and establish a persistent infection. We discuss here current understanding of both host and bacterial factors that contribute to latent and reactivation tuberculosis.

Animals↗
PubMed2003

Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection.

Nonhuman primates were used to develop an animal model that closely mimics human Mycobacterium tuberculosis infection. Cynomolgus macaques were infected with low doses of virulent M. tuberculosis via bronchoscopic instillation into the lung. All monkeys were successfully infected, based on tuberculin skin test conversion and peripheral immune responses to M. tuberculosis antigens. Progression of infection in the 17 monkeys studied was variable. Active-chronic infection, observed in 50 to 60% of monkeys, was characterized by clear signs of infection or disease on serial thoracic radiographs and in other tests and was typified by eventual progression to advanced disease. Approximately 40% of monkeys did not progress to disease in the 15 to 20 months of study, although they were clearly infected initially. These monkeys had clinical characteristics of latent tuberculosis in humans. Low-dose infection of cynomolgus macaques appears to represent the full spectrum of human M. tuberculosis infection and will be an excellent model for the study of pathogenesis and immunology of this infection. In addition, this model will provide an opportunity to study the latent M. tuberculosis infection observed in approximately 90% of all infected humans.

Animals↗