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 inThe Journal of immunology (1950) Vol. 181; no. 11; pp. 7948 - 7957
Main Authors Bertholet, Sylvie, Ireton, Gregory C, Kahn, Maria, Guderian, Jeffrey, Mohamath, Raodoh, Stride, Nicole, Laughlin, Elsa M, Baldwin, Susan L, Vedvick, Thomas S, Coler, Rhea N, Reed, Steven G
Format Journal Article
LanguageEnglish
Published England Am Assoc Immnol 01.12.2008
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ISSN0022-1767
1550-6606
1550-6606
DOI10.4049/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.
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
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  fullname: Coler, Rhea N
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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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StartPage 7948
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
URI http://www.jimmunol.org/cgi/content/abstract/181/11/7948
https://www.ncbi.nlm.nih.gov/pubmed/19017986
https://www.proquest.com/docview/69812457
https://pubmed.ncbi.nlm.nih.gov/PMC2586986
Volume 181
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