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Thomas J Braciale

Publications and source records attributed to Thomas J Braciale.

17 recordsLinked to original sources
PubMed2006

Comparative activities of oseltamivir and A-322278 in immunocompetent and immunocompromised murine models of influenza virus infection.

We developed an immunocompromised murine model of influenza virus infection and demonstrated comparable efficacy of oral oseltamivir and A-322278 (both given at dosages of 10 mg/kg/day) in reducing viral replication, decreasing weight loss, and prolonging survival. Once the treatment was discontinued, severe combined immunodeficient (SCID) mice had progressive viral replication and clinical decline. Drug-resistant variants were detected in 4 (29%) of 14 and 2 (13%) of 15 mice (both BALB/c and SCID) treated with oseltamivir or A-322278, respectively; no resistant variants were detected in placebo-treated mice. Amino acid substitutions in the hemagglutinin receptor-binding site at aa 137 or 225 were detected in cloned resistant isolates. A substitution in the neuraminidase (NA) active site (Arg292Lys) was detected in the cloned virus recovered from an oseltamivir-treated mouse. This model would be useful for elucidation of the molecular mechanisms of resistance to NA inhibitors and for testing of anti-influenza therapy options that might prevent the emergence of resistant variants.

Acetamides↗
PubMed2005

Preferential migration of effector CD8+ T cells into the interstitium of the normal lung.

The respiratory tract is a primary site of infection and exposure to environmental antigens and an important site of memory T cell localization. We analyzed the migration and retention of naive and activated CD8+ T cells within the noninflamed lungs and quantitated the partitioning of adoptively transferred T cells between the pulmonary vascular and interstitial compartments. Activated but not naive T cells were retained within the lungs for a prolonged period. Effector CD8+ T cells preferentially egressed from the pulmonary vascular compartment into the noninflamed pulmonary interstitium. T cell retention within the lung vasculature was leukocyte function antigen-1 dependent, while the egress of effector T cells from the vascular to the interstitium functions through a pertussis toxin-sensitive (PTX-sensitive) mechanism driven in part by constitutive CC chemokine ligand 5 expression in the lungs. These results document a novel mechanism of adhesion receptor- and pulmonary chemokine-dependent regulation of the migration of activated CD8+ T cells into an important nonlymphoid peripheral site (i.e., the normal/noninflamed lung).

Animals↗
PubMed2005

Transient loss of MHC class I tetramer binding after CD8+ T cell activation reflects altered T cell effector function.

Engagement of the Ag receptor on naive CD8+ T cells by specific peptide-MHC complex triggers their activation/expansion/differentiation into effector CTL. The frequency of Ag-specific CD8+ T cells can normally be determined by the binding of specific peptide-MHC tetramer complexes to TCR. In this study we demonstrate that, shortly after Ag activation, CD8+ T cells transiently lose the capacity to efficiently bind peptide-MHC tetramer complexes. This transient loss of tetramer binding, which occurs in response to naturally processed viral peptide during infection in vitro and in vivo, is associated with reduced signaling through the TCR and altered/diminished effector activity. This change in tetramer binding/effector response is likewise associated with a change in cell surface TCR organization. These and related results suggest that early during CD8+ T cell activation, there is a temporary alteration in both cell surface Ag receptor display and functional activity that is associated with a transient loss of cognate tetramer binding.

Animals↗
PubMed2005

Frequency, specificity, and sites of expansion of CD8+ T cells during primary pulmonary influenza virus infection.

We have used intracellular cytokine staining and MHC class I tetramer binding in conjunction with granzyme B protease expression and in vivo BrdU uptake to characterize the primary murine CD8(+) T cell response to pulmonary influenza virus infection. We have observed that the majority (>90%) of the CD8(+) T cell response to the A/Japan/305/57 virus in the lung at the peak of the response (days 9-11) is directed to four epitopes (three dominant and one subdominant). Using induction of granzyme B as a surrogate to identify specific activated CD8(+) T cells, we found that an unexpectedly large fraction ( approximately 70%) of lung-infiltrating CD8(+) T cells expressed granzyme B on day 6 of infection when estimates by MHC tetramer/intracellular cytokine staining yielded substantially lower frequencies ( approximately 30%). In addition, by using intranasal administration of BrdU during infection, we obtained evidence for proliferative expansion of activated CD8(+) T cells in the infected lung early (days 5-7) in the primary response. These results suggest that the frequency and number of specific CTL present in the lung early in infection may be underestimated by standard detection methods, and primary CD8(+) T cell expansion may occur in both secondary lymphoid organs and the infected lung.

Animals↗
PubMed2005

Lymph node dendritic cells control CD8+ T cell responses through regulated FasL expression.

The lethal outcome of high-dose pulmonary virus infection is thought to reflect high-level, sustained virus replication and associated lung inflammation prior to development of an adaptive immune response. Herein, we demonstrate that the outcome of lethal/sublethal influenza infection instead correlates with the initial virus replication tempo. Furthermore, the magnitude of early lung antiviral CD8+ T cell responses varies inversely with inoculum dose and is controlled by lymph-node-resident dendritic cells (LNDC) through IL-12p40-regulated FasL-dependent T cell apoptosis. These results suggest that the inoculum dose and replication rate of a pathogen entering the respiratory tract may regulate the strength of the adaptive immune response, and the subsequent outcome of infection and that LNDC may serve as regulators (gatekeepers) in the development of CD8+ T cell responses.

Adoptive Transfer↗
PubMed2005

Respiratory syncytial virus and T cells: interplay between the virus and the host adaptive immune system.

Respiratory syncytial virus (RSV) is a major cause of morbidity in young infants and is increasingly recognized as an important cause of serious illness/morbidity in the elderly. This agent has also been implicated both in the etiopathogenesis of asthma/airway hyperreactivity and in the exacerbation of wheezing episodes in individuals with asthma. This review deals with our current knowledge of the host adaptive immune response to RSV, focusing on the interaction of the virus with T lymphocytes. Current information on the impact of RSV infection on the function of responding CD4 (+) and, in particular, CD8 (+) T lymphocytes will be reviewed; and the potential implications of this virus/immune cell interaction on the development of RSV-induced disease in the respiratory tract will be discussed. In addition, the long-standing conundrum concerning the development of an effective vaccine against RSV will be discussed in the context of the vaccine-induced enhanced disease during RSV infection and the interplay between the virus and immune/memory T cells in the development of pulmonary injury in vaccinated individuals after the RSV infection.

CD4-Positive T-Lymphocytes↗
PubMed2004

Activation, differentiation, and migration of naive virus-specific CD8+ T cells during pulmonary influenza virus infection.

The low precursor frequency of individual virus-specific CD8(+) T cells in a naive host makes the early events of CD8(+) T cell activation, proliferation, and differentiation in response to viral infection a challenge to identify. We have therefore examined the response of naive CD8(+) T cells to pulmonary influenza virus infection with a murine adoptive transfer model using hemagglutinin-specific TCR transgenic CD8(+) T cells. Initial activation of CD8(+) T cells occurs during the first 3 days postinfection exclusively within the draining lymph nodes. Acquisition of CTL effector functions, including effector cytokine and granule-associated protease expression, occurs in the draining lymph nodes and differentially correlates with cell division. Division of activated CD8(+) T cells within the draining lymph nodes occurs in an asynchronous manner between days 3 and 4 postinfection. Despite the presence of Ag for several days within the draining lymph nodes, dividing T cells do not appear to maintain contact with residual Ag. After multiple cell divisions, CD8(+) T cells exit the draining lymph nodes and migrate to the infected lung. Activated CD8(+) T cells also disseminate throughout lymphoid tissue including the spleen and distal lymph nodes following their emigration from draining lymph nodes. These results demonstrate an important role for draining lymph nodes in orchestrating T cell responses during a local infection of a discrete organ to generate effector CD8(+) T cells capable of responding to infection and seeding peripheral lymphoid tissues.

Animals↗
PubMed2004

Improved effector activity and memory CD8 T cell development by IL-2 expression during experimental respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory infection in young children and the elderly. Studies of mice suggest that RSV suppresses the effector activity of CD8 T cells and the development of pulmonary CD8 T cell memory, in which the impaired effector activity could be recovered by in vitro IL-2 treatment. To investigate the effect of in vivo IL-2 expression on RSV immunity, mice were infected with RSV followed by administration of replication-defective adenovirus expressing IL-2. The effector activity of RSV M2-specific CD8 T cells and the development of CD8 T cell memory in the lung was significantly increased by IL-2 expression. Furthermore, the Ab responses against RSV were augmented by IL-2. Interestingly, weight loss and illness caused by RSV challenge were substantially reduced by IL-2 priming, suggesting that the pathogenesis of RSV-related disease could be prevented by IL-2-mediated enhancement of beneficial immune responses. Thus, our results show that IL-2 has potential to be used as a vaccine adjuvant against RSV infection.

Adenoviruses, Human↗
PubMed2004

Respiratory syncytial virus and other pneumoviruses: a review of the international symposium--RSV 2003.

The Respiratory Syncytial Virus 2003 symposium took place from 8th-11th November 2003 in Stone Mountain, Georgia, and brought together more than 200 international investigators engaged in RSV research. RSV biology, pathogenesis, and clinical data, as well as RSV vaccines and antivirals, were addressed in the meeting, and this review will aim to briefly summarize and discuss the implications of new findings. The meeting also served as the inauguration of the Robert M. Chanock Award for lifetime achievement in RSV research, an award named in honor of the person who started the field of RSV research by recovering the first human RS virus from infants with severe bronchiolitis in 1956.

Animals↗
PubMed2004

Introduction.

Explore the source record for details and available documents.

Age Distribution↗
PubMed2004

Vbeta14(+) T cells mediate the vaccine-enhanced disease induced by immunization with respiratory syncytial virus (RSV) G glycoprotein but not with formalin-inactivated RSV.

Mice immunized with respiratory syncytial virus (RSV) G glycoprotein or with formalin-inactivated RSV (FI-RSV) exhibit severe disease following RSV challenge. This results in type 2 cytokine production and pulmonary eosinophilia, both hallmarks of vaccine-enhanced disease. RSV G-induced T-cell responses were shown to be restricted to CD4(+) T cells expressing Vbeta14 in the T-cell receptor (TCR), and the deletion of these T cells resulted in less severe disease. We therefore examined the role of Vbeta14(+) T cells in FI-RSV-induced disease. BALB/c mice were immunized with vaccinia virus expressing secreted RSV G (vvGs) or with FI-RSV. At the time of challenge with live RSV, mice were injected with antibody to the Vbeta14 component of the TCR. vvGs-immunized mice treated with anti-Vbeta14 had reduced cytokine levels in the lung. Eosinophil recruitment to the lung was also significantly reduced. In contrast, depletion of Vbeta14(+) T cells in FI-RSV-immunized mice had little impact on cytokine production or pulmonary eosinophilia. An analysis of TCR Vbeta chain usage confirmed a bias toward Vbeta14 expression on CD4(+) T cells from vvGs-immunized mice, whereas the CD4(+) T cells in FI-RSV-immunized mice expressed a diverse array of Vbeta chains. These data show that although FI-RSV and vvGs induce responses resulting in similar immunopathology, the T-cell repertoire mediating the response is different for each immunogen and suggest that the immune responses elicited by RSV G are not the basis for FI-RSV vaccine-enhanced disease.

Animals↗
PubMed2003

LFA-1 is required for retention of effector CD8 T cells in mouse lungs.

The adhesion molecules involved in the migration and retention of activated effector CD8 T cells in the lung microcirculation and their recruitment into lung tissue are largely unknown. Here, we have analyzed the role of lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) on adhesion of influenza hemagglutinin (HA)-specific CD8 T-cell clone D4 under shear conditions in an in vitro binding assay and in an in vivo homing assay to the lungs of naive or transgenic Balb/c mice expressing HA (HA-Tg) by a lung-specific promoter. Blocking LFA-1 or intercellular adhesion molecule 1 (ICAM-1) significantly inhibited adhesion of D4 cells to lung vascular endothelium and parenchyma of lung sections. However, blocking VLA-4 or vascular cell adhesion molecule 1 (VCAM-1) had no effect on cell adhesion. Blocking LFA-1 in vivo significantly delayed lethal injury following adoptive transfer of D4 cells into HA-Tg mice as assessed by weight loss and histology. Residence time of adoptively transferred Indium 111 (111In)-labeled D4 cells in lungs of normal and HA-Tg mice as analyzed by dual modality imaging revealed a significantly shorter transit time of 4 hours for the D4 cells upon in vivo blockade of LFA-1. These results demonstrate a crucial role for LFA-1 in retention of activated CD8 T cells in normal mouse lungs and in the progression of lethal injury in HA-Tg mice.

Adoptive Transfer↗
PubMed2003

Accelerated migration of respiratory dendritic cells to the regional lymph nodes is limited to the early phase of pulmonary infection.

Respiratory dendritic cells (RDC) are believed to play a central role in the induction of adaptive immune responses to pulmonary infection. Herein we examine the basal migration of RDC from the lungs to secondary lymphoid tissues and their enhanced maturation/migration after pulmonary infection/inflammation. We demonstrate that the accelerated migration of RDC to the draining peribronchial lymph nodes occurs only during the first 24 hr after pulmonary virus infection. RDC are refractory to further migration thereafter in spite of ongoing virus replication and pulmonary inflammation. We further demonstrate that induction of this RDC refractory state suppresses additional RDC mobilization to subsequent pulmonary virus infection and results in concomitant suppression of an antiviral pulmonary CD8(+) T cell response.

Animals↗
PubMed2003

Not all effector CD8+ T cells are alike.

As naive CD8+ T cells circulate throughout the bloodstream and secondary lymphoid tissues (i.e. spleen and lymph nodes), they sample complexes of peptides and MHC class I molecules expressed on the surface of professional antigen presenting cells (APCs). A proper fit between lymphocyte and APCs sets into motion a complex series of events that result in the generation of activated cytotoxic T lymphocytes (CTLs) that are the principal immune effectors against infected and transformed cells. Owing to the severe immunopathology that can result from the aberrant stimulation of CTLs, the activation of naïve CD8(+) T cells is a tightly regulated process. A growing body of evidence suggests that the quality of stimulation naïve CD8+ T cells receive during the induction and maintenance of an immune response dictates the functional competency of the responding antigen-specific CTLs, and that CD8+ T cells and their progeny "effector cells" can exist long-term in vastly different activation states.

Animals↗
PubMed2002

Sensitive detection and quantitation of mouse eosinophils in tissues using an enzymatic eosinophil peroxidase assay: its use to rapidly measure pulmonary eosinophilia during experimental respiratory syncytial virus infection of mice.

Eosinophils are granular proinflammatory leukocytes implicated in the pathogenesis of several inflammatory processes including allergy, asthma, and in the development of enhanced disease during respiratory syncytial virus (RSV) infection. Here, we adapted a colorimetric assay to measure eosinophil peroxidase (EPO) activity in inflamed mouse lung tissue in order to quantitate pulmonary eosinophilia during experimental RSV infection. Using the substrate o-phenylenediamine dihydrochloride (OPD) in the presence of bromide ions, we show that this assay is able to quantitate limiting numbers of eosinophils in lung tissue homogenates even in the presence of large numbers of infiltrating neutrophils and macrophages. The ability of the EPO assay to selectively quantitate eosinophils in a complex tissue inflammatory infiltrate demonstrates the usefulness of this enzymatic assay as a rapid and sensitive method to quantitate the influx of eosinophils into inflamed mouse tissue such as the lung during experimental RSV infection without reliance on morphologic criteria to identify murine eosinophils in tissues or bronchial lavage fluid.

Animals↗
PubMed2002

Respiratory syncytial virus infection suppresses lung CD8+ T-cell effector activity and peripheral CD8+ T-cell memory in the respiratory tract.

Respiratory syncytial virus (RSV) is a major cause of morbidity from respiratory infection in infants, young children and the elderly. No effective vaccine against RSV is currently available and studies of the natural history of RSV infection suggest repeated infections with antigenically related virus strains are common throughout an individual's lifetime. We have studied the CD8+ T-cell response during experimental murine RSV infection and found that RSV inhibits the expression of effector activity by activated RSV-specific CD8+ T cells infiltrating the lung parenchyma and the development of pulmonary CD8+ T-cell memory by interfering with TCR-mediated signaling. These data suggest a possible mechanism to explain the limited duration of protective immunity in RSV infection.

Animals↗