Biomedical subjects

Deborah A Lewinsohn

Publications and source records attributed to Deborah A Lewinsohn.

8 recordsLinked to original sources

PubMed2026

Immunodominant Tuberculosis Antigens Recognized by Human CD4+ and CD8+ T Cells.

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (MTB), represents an important cause of morbidity and mortality worldwide for which an improved vaccine and immunodiagnostics are urgently needed. CD4+ and CD8+ T cells play an important role in host defense to TB. Definition of the immunodominant antigens recognized by these T cells is critical for improved understanding of the immunobiology of TB and for development of vaccines and diagnostics. Herein, we review antigens and epitopes recognized by classically human leukocyte antigen (HLA) class I- and class II-restricted CD4+ and CD8+ T cells in humans infected with MTB, as defined using either targeted or genome-wide approaches. We address the extent to which these antigens have been defined as immunodominant, protective, and/or specific to disease stages in humans and, with particular relevance to CD8+ T-cell recognition, whether these antigens are displayed by MTB-infected cells.

Journal Article↗

PubMed2006

High resolution radiographic and fine immunologic definition of TB disease progression in the rhesus macaque.

Mycobacterium tuberculosis infection in non-human primates parallels human tuberculosis, and provides a valuable vaccine evaluation model. However, this model is limited by the availability of real-time, non-invasive information regarding disease progression. Consequently, we have combined computed tomography scanning with enumeration of antigen-specific T cell responses. Four rhesus monkeys were infected with M. tuberculosis strain H37Rv (1000 cfu) in the right lower lobe via a bronchoscope. All uniformly developed progressive tuberculosis, and required euthanasia at 12 weeks. Computed tomography scanning provided detailed real-time imaging of disease progression. At necropsy, computed tomography and pathohistologic findings were tightly correlated, and characteristic of human disease. Immunologic monitoring demonstrated progressive evolution of high frequency M. tuberculosis-specific CD4(+) and CD8(+) T cell responses. Peripheral blood effector cell frequencies were similar to those observed in tissues. In summary, computed tomography scanning in conjunction with immunologic monitoring provides a non-invasive, accurate, and rapid assessment of tuberculosis in the non-human primate.

Animals↗

PubMed2006

Purified neonatal plasmacytoid dendritic cells overcome intrinsic maturation defect with TLR agonist stimulation.

Neonates are more susceptible than adults to viral and bacterial diseases. We hypothesized that plasmacytoid dendritic cells, the cells that provide large amounts of IFN-alpha in response to Toll-like receptor 9 (TLR9) agonists, are defective in neonates. To assess the intrinsic functionality of plasmacytoid dendritic cells from neonates we compared IFN-alpha production by plasmacytoid dendritic cells derived from neonates versus adults in both whole blood and in purified plasmacytoid dendritic cells. TLR9-stimulation of whole blood from adults and neonates resulted in comparable amounts of IFN-alpha production. However, we observed small but significant differences in IFN-alpha production from purified CD123+ plasmacytoid dendritic cells from neonates after stimulation with the TLR9 ligand CpG-DNA. Furthermore, we assessed surface expression of co-stimulatory molecules on plasmacytoid dendritic cells after stimulation. While purified CD123+ plasmacytoid dendritic cells from adults up-regulated co-stimulatory molecules CD80 and CD86 with IL-3 alone those from neonates required the addition of CpG-DNA to reach adult levels. Therefore, the intrinsic deficiencies of neonatal plasmacytoid dendritic cells can be mitigated by TLR9 agonists. These results are consistent with the observation that vaccines that effect strong adjuvant activity on dendritic cells can induce protective responses in neonates.

Adult↗

PubMed2003

Mycobacterium tuberculosis-specific CD8+ T cells preferentially recognize heavily infected cells.

Both CD4+ and CD8+ T cells are important for successful immunity to tuberculosis and have redundant effector functions, such as cytolysis and release of potent antimycobacterial cytokines such as interferon-gamma and tumor necrosis factor-alpha. We hypothesized that CD8+ T cells play a unique role in host defense to Mycobacterium tuberculosis infection as well. Possibilities include preferential and/or enhanced release of granular constituents and/or preferential recognition of heavily infected cells. Utilizing human, Mycobacterium tuberculosis-specific, CD4+ and CD8+ T cell clones, we demonstrate that, after recognition of antigen-presenting cells displaying peptide antigen, CD4+ T cells preferentially release interferon-gamma, whereas CD8+ T cells preferentially lyse antigen-presenting cells. Furthermore, utilizing dendritic cells infected with Mycobacterium tuberculosis expressing green fluorescent protein, we show that CD8+ T cells preferentially recognize heavily infected cells that constitute the minority of infected cells. These data support the hypothesis that the central role of CD8+ T cells in the control of infection with Mycobacterium tuberculosis may be that of surveillance; in essence, recognition of cells in which the containment of Mycobacterium tuberculosis is no longer effective.

Antigens, Bacterial↗

PubMed2003

TB vaccines at the turn of the century: insights into immunity to M. tuberculosis and modern approaches for prevention of an ancient disease.

Tuberculosis (TB) remains a leading cause of infectious disease mortality worldwide, accounting for nearly 2 million deaths annually. Despite the availability of effective anti-TB therapy, the world's case burden of TB continues to climb, in part owing to the concurrent acquired immune deficiency syndrome pandemic. The widespread use of the current TB vaccine, the bacille Calmette-Guérin strain of M. bovis (BCG), has failed to curtail the TB epidemic and therefore strategies for the eradication of TB have centered on aggressive case-finding and managed treatment, such as directly observed treatment short course (DOTS). Although DOTS continues to have a significant impact, the ability of DOTS to eradicate TB is limited. Therefore, TB eradication will require the development of an improved vaccine, which, in turn, will require application of state-of-the-art vaccine technology and of our knowledge of TB immunology and TB genomics to this problem. In this article, knowledge about the requisite components of protective immunity, modern vaccine strategies, and elements of clinical trials required to evaluate vaccine efficacy, as well as the status of current TB vaccine candidates, are reviewed.

BCG Vaccine↗

PubMed2002

HLA-E-dependent presentation of Mtb-derived antigen to human CD8+ T cells.

Previous studies in mice and humans have suggested an important role for CD8+ T cells in host defense to Mtb. Recently, we have described human, Mtb-specific CD8+ cells that are neither HLA-A, B, or C nor group 1 CD1 restricted, and have found that these cells comprise the dominant CD8+ T cell response in latently infected individuals. In this report, three independent methods are used to demonstrate the ability of these cells to recognize Mtb-derived antigen in the context of the monomorphic HLA-E molecule. This is the first demonstration of the ability of HLA-E to present pathogen-derived antigen. Further definition of the HLA-E specific response may aid development of an effective vaccine against tuberculosis.

Antigen Presentation↗

PubMed2002

Human dendritic cells presenting adenovirally expressed antigen elicit Mycobacterium tuberculosis--specific CD8+ T cells.

Previous studies in murine and human models have suggested an important role for CD8+ T cells in host defense to Mycobacterium tuberculosis (Mtb). Consequently, a successful tuberculosis vaccine may require the elicitation of sustained CD4+ and CD8+ T cell responses. We tested the hypothesis that the potent CD4+ T cell antigen Mtb39 is also a CD8+ T cell antigen. A recombinant adenovirus-expressing Mtb39 (adenoMtb39) was used to infect monocyte-derived dendritic cells. Using interferon-gamma enzyme-linked immunospot, Mtb39-specific CD8+ T lymphocytes were detected in three healthy individuals with latent tuberculosis infection who also had strong anti-Mtb39-specific CD4+ T cell responses. An Mtb39-specific CD8+ T cell line was generated using Mtb39-expressing dendritic cells. Mtb39-specific T cell clones were obtained by limiting dilution cloning. All seven T cell clones obtained were HLA-B44 restricted. Using a panel of synthetic overlapping peptides representative of Mtb39, the peptide epitope was identified for two clones. Furthermore, all T cell clones recognized Mtb-infected dendritic cells and were cytolytic. We conclude that infection of dendritic cells with adenoviral vectors expressing Mtb proteins allows for measurement of antigen-specific CD8+ T cell responses from peripheral blood mononuclear cells. The technique will be useful in defining CD8+ T cell antigens and in measuring immunogenicity of tuberculosis vaccines.

Adenoviridae↗

PubMed2002

HIV-1 Vpr does not inhibit CTL-mediated apoptosis of HIV-1 infected cells.

HIV-1 infected persons develop a robust CTL response to HIV antigens, yet HIV-1 is able to evade this host response and successfully replicate. The mechanism(s) of evasion is not completely defined but has been suggested to include resistance of infected cells to CTL-mediated apoptosis. The HIV-1 Vpr protein induces G2 arrest by indirectly inhibiting activation of cyclin B/p34cdc2 kinase. Granzyme B, the principle mediator of CTL-induced apoptosis, prematurely activates this same kinase complex. Therefore, we assessed the susceptibility of HIV-1 infected cells to CTL-mediated apoptosis to determine whether the expression of Vpr protected the infected cells from CTL-induced apoptosis. Antigen-specific CD8(+) CTL were able to induce apoptosis in HIV-1 infected cells and cells labeled with peptide corresponding to the CTL epitope with equivalent efficiency. This demonstrates that neither HIV-1 Vpr nor any other HIV protein directly inhibits CTL effector functions. Furthermore, we confirm that HIV-1 Nef is able to provide partial protection from CTL recognition of infected cells. Thus, the inability of CTL to control HIV-1 infection is likely not due to direct inhibition of CTL-mediated apoptosis.

Apoptosis↗