Identification of Human T Cell Antigens for the Development of Vaccines against Mycobacterium tuberculosis
Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) depends on the identification of Ags that induce appropriate T cell responses. Using bioinformatics, we selected a panel of 94 Mtb genes based on criteria that included growth in macrophages, up- or down-regulation under hypoxic c...
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Published in | The Journal of immunology (1950) Vol. 181; no. 11; pp. 7948 - 7957 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Am Assoc Immnol
01.12.2008
|
Subjects | |
Online Access | Get full text |
ISSN | 0022-1767 1550-6606 1550-6606 |
DOI | 10.4049/jimmunol.181.11.7948 |
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Abstract | Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) depends on the identification of Ags that induce appropriate T cell responses. Using bioinformatics, we selected a panel of 94 Mtb genes based on criteria that included growth in macrophages, up- or down-regulation under hypoxic conditions, secretion, membrane association, or because they were members of the PE/PPE or EsX families. Recombinant proteins encoded by these genes were evaluated for IFN-γ recall responses using PBMCs from healthy subjects previously exposed to Mtb. From this screen, dominant human T cell Ags were identified and 49 of these proteins, formulated in CpG, were evaluated as vaccine candidates in a mouse model of tuberculosis. Eighteen of the individual Ags conferred partial protection against challenge with virulent Mtb. A combination of three of these Ags further increased protection against Mtb to levels comparable to those achieved with bacillus Calmette-Guérin vaccination. Vaccine candidates that led to reduction in lung bacterial burden following challenge-induced pluripotent CD4 and CD8 T cells, including Th1 cell responses characterized by elevated levels of Ag-specific IgG2c, IFN-γ, and TNF. Priority vaccine Ags elicited pluripotent CD4 and CD8 T responses in purified protein derivative-positive donor PBMCs. This study identified numerous novel human T cell Ags suitable to be included in subunit vaccines against tuberculosis. |
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AbstractList | Development of a subunit vaccine for
Mycobacterium tuberculosis
(
Mtb
) depends on the identification of antigens that induce appropriate T cell responses. Using bioinformatics, we selected a panel of 94
Mtb
genes based on criteria which included growth in macrophages, up- or down-regulation under hypoxic conditions, secretion, membrane association, or because they were members of the PE/PPE or EsX families. Recombinant proteins encoded by these genes were evaluated for IFN-γ recall responses using PBMC from healthy subjects previously exposed to
Mtb
. From this screen, dominant human T-cell antigens were identified and 49 of these proteins, formulated in CpG, were evaluated as vaccine candidates in a mouse model of tuberculosis (TB). Eighteen of the individual antigens conferred partial protection against challenge with virulent
Mtb
. A combination of three of these antigens further increased protection against
Mtb
to levels comparable to those achieved with BCG vaccination. Vaccine candidates that led to reduction in lung bacterial burden following challenge induced pluripotent CD4 and CD8 T cells, including T
H
1 cell responses characterized by elevated levels of antigen-specific IgG2c, IFN-γ and TNF. Priority vaccine antigens elicited pluripotent CD4 and CD8 T responses in PPD
+
donor PBMC. This study identified numerous novel human T cell antigens suitable to be included in subunit vaccines against TB. Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) depends on the identification of Ags that induce appropriate T cell responses. Using bioinformatics, we selected a panel of 94 Mtb genes based on criteria that included growth in macrophages, up- or down-regulation under hypoxic conditions, secretion, membrane association, or because they were members of the PE/PPE or EsX families. Recombinant proteins encoded by these genes were evaluated for IFN-gamma recall responses using PBMCs from healthy subjects previously exposed to Mtb. From this screen, dominant human T cell Ags were identified and 49 of these proteins, formulated in CpG, were evaluated as vaccine candidates in a mouse model of tuberculosis. Eighteen of the individual Ags conferred partial protection against challenge with virulent Mtb. A combination of three of these Ags further increased protection against Mtb to levels comparable to those achieved with bacillus Calmette-Guérin vaccination. Vaccine candidates that led to reduction in lung bacterial burden following challenge-induced pluripotent CD4 and CD8 T cells, including Th1 cell responses characterized by elevated levels of Ag-specific IgG2c, IFN-gamma, and TNF. Priority vaccine Ags elicited pluripotent CD4 and CD8 T responses in purified protein derivative-positive donor PBMCs. This study identified numerous novel human T cell Ags suitable to be included in subunit vaccines against tuberculosis.Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) depends on the identification of Ags that induce appropriate T cell responses. Using bioinformatics, we selected a panel of 94 Mtb genes based on criteria that included growth in macrophages, up- or down-regulation under hypoxic conditions, secretion, membrane association, or because they were members of the PE/PPE or EsX families. Recombinant proteins encoded by these genes were evaluated for IFN-gamma recall responses using PBMCs from healthy subjects previously exposed to Mtb. From this screen, dominant human T cell Ags were identified and 49 of these proteins, formulated in CpG, were evaluated as vaccine candidates in a mouse model of tuberculosis. Eighteen of the individual Ags conferred partial protection against challenge with virulent Mtb. A combination of three of these Ags further increased protection against Mtb to levels comparable to those achieved with bacillus Calmette-Guérin vaccination. Vaccine candidates that led to reduction in lung bacterial burden following challenge-induced pluripotent CD4 and CD8 T cells, including Th1 cell responses characterized by elevated levels of Ag-specific IgG2c, IFN-gamma, and TNF. Priority vaccine Ags elicited pluripotent CD4 and CD8 T responses in purified protein derivative-positive donor PBMCs. This study identified numerous novel human T cell Ags suitable to be included in subunit vaccines against tuberculosis. Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) depends on the identification of Ags that induce appropriate T cell responses. Using bioinformatics, we selected a panel of 94 Mtb genes based on criteria that included growth in macrophages, up- or down-regulation under hypoxic conditions, secretion, membrane association, or because they were members of the PE/PPE or EsX families. Recombinant proteins encoded by these genes were evaluated for IFN-γ recall responses using PBMCs from healthy subjects previously exposed to Mtb. From this screen, dominant human T cell Ags were identified and 49 of these proteins, formulated in CpG, were evaluated as vaccine candidates in a mouse model of tuberculosis. Eighteen of the individual Ags conferred partial protection against challenge with virulent Mtb. A combination of three of these Ags further increased protection against Mtb to levels comparable to those achieved with bacillus Calmette-Guérin vaccination. Vaccine candidates that led to reduction in lung bacterial burden following challenge-induced pluripotent CD4 and CD8 T cells, including Th1 cell responses characterized by elevated levels of Ag-specific IgG2c, IFN-γ, and TNF. Priority vaccine Ags elicited pluripotent CD4 and CD8 T responses in purified protein derivative-positive donor PBMCs. This study identified numerous novel human T cell Ags suitable to be included in subunit vaccines against tuberculosis. Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) depends on the identification of Ags that induce appropriate T cell responses. Using bioinformatics, we selected a panel of 94 Mtb genes based on criteria that included growth in macrophages, up- or down-regulation under hypoxic conditions, secretion, membrane association, or because they were members of the PE/PPE or EsX families. Recombinant proteins encoded by these genes were evaluated for IFN-gamma recall responses using PBMCs from healthy subjects previously exposed to Mtb. From this screen, dominant human T cell Ags were identified and 49 of these proteins, formulated in CpG, were evaluated as vaccine candidates in a mouse model of tuberculosis. Eighteen of the individual Ags conferred partial protection against challenge with virulent Mtb. A combination of three of these Ags further increased protection against Mtb to levels comparable to those achieved with bacillus Calmette-Guérin vaccination. Vaccine candidates that led to reduction in lung bacterial burden following challenge-induced pluripotent CD4 and CD8 T cells, including Th1 cell responses characterized by elevated levels of Ag-specific IgG2c, IFN-gamma, and TNF. Priority vaccine Ags elicited pluripotent CD4 and CD8 T responses in purified protein derivative-positive donor PBMCs. This study identified numerous novel human T cell Ags suitable to be included in subunit vaccines against tuberculosis. |
Author | Coler, Rhea N Bertholet, Sylvie Guderian, Jeffrey Mohamath, Raodoh Laughlin, Elsa M Ireton, Gregory C Baldwin, Susan L Stride, Nicole Reed, Steven G Kahn, Maria Vedvick, Thomas S |
Author_xml | – sequence: 1 fullname: Bertholet, Sylvie – sequence: 2 fullname: Ireton, Gregory C – sequence: 3 fullname: Kahn, Maria – sequence: 4 fullname: Guderian, Jeffrey – sequence: 5 fullname: Mohamath, Raodoh – sequence: 6 fullname: Stride, Nicole – sequence: 7 fullname: Laughlin, Elsa M – sequence: 8 fullname: Baldwin, Susan L – sequence: 9 fullname: Vedvick, Thomas S – sequence: 10 fullname: Coler, Rhea N – sequence: 11 fullname: Reed, Steven G |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/19017986$$D View this record in MEDLINE/PubMed |
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Snippet | Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) depends on the identification of Ags that induce appropriate T cell responses. Using... Development of a subunit vaccine for Mycobacterium tuberculosis ( Mtb ) depends on the identification of antigens that induce appropriate T cell responses.... |
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SubjectTerms | Adjuvants, Immunologic - genetics Adjuvants, Immunologic - pharmacology Animals Antibodies, Bacterial - immunology Antigens, Bacterial - genetics Antigens, Bacterial - immunology Antigens, Bacterial - pharmacology CD8-Positive T-Lymphocytes - immunology Computational Biology Disease Models, Animal Female Humans Immunoglobulin G - immunology Interferon-gamma - immunology Mice Mycobacterium bovis - immunology Mycobacterium tuberculosis - genetics Mycobacterium tuberculosis - immunology Oligodeoxyribonucleotides - genetics Oligodeoxyribonucleotides - immunology Oligodeoxyribonucleotides - pharmacology Recombinant Proteins - genetics Recombinant Proteins - immunology Recombinant Proteins - pharmacology Th1 Cells - immunology Tuberculosis Vaccines - genetics Tuberculosis Vaccines - immunology Tuberculosis Vaccines - pharmacology Tuberculosis, Pulmonary - genetics Tuberculosis, Pulmonary - immunology Tuberculosis, Pulmonary - prevention & control Tumor Necrosis Factor-alpha - immunology |
Title | Identification of Human T Cell Antigens for the Development of Vaccines against Mycobacterium tuberculosis |
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