Improved Protection against Disseminated Tuberculosis by Mycobacterium bovis Bacillus Calmette-Guérin Secreting Murine GM-CSF Is Associated with Expansion and Activation of APCs1

Modulating the host-immune response by the use of recombinant vaccines is a potential strategy to improve protection against microbial pathogens. In this study, we sought to determine whether secretion of murine GM-CSF by the bacillus Calmette-Guérin (BCG) vaccine influenced protective immunity against Mycobacterium tuberculosis. BCG-derived GM-CSF stimulated the in vitro generation of functional APCs from murine bone marrow precursors, as demonstrated by the infection-induced secretion of IL-12 by differentiated APCs, and the ability of these cells to present Ag to mycobacterium-specific T cells. Mice vaccinated with BCG-secreting murine GM-CSF (BCG:GM-CSF) showed increased numbers of CD11c+MHCII+ and CD11c−CD11b+F480+ cells compared with those vaccinated with control BCG, and this effect was most apparent in the draining lymph nodes at 7 and 14 days postvaccination. Vaccination with BCG:GM-CSF also resulted in enhanced expression of costimulatory molecules on migratory dendritic cells in the draining lymph nodes. The increased APC number was associated with an increase in the frequency of anti-mycobacterial IFN-γ-secreting T cells generated after BCG:GM-CSF vaccination compared with vaccination with control BCG, and this effect was sustained up to 17 wk in the spleens of immunized mice. Vaccination with BCG:GM-CSF resulted in an ∼10-fold increase in protection against disseminated M. tuberculosis infection compared with control BCG. This study demonstrates the potential of BCG-secreting immunostimulatory molecules as vaccines to protect against tuberculosis and suggests BCG:GM-CSF merits further appraisal as a candidate to control M. tuberculosis infection in humans.

[1]  M. O'Donnell,et al.  Improved protection against disseminated tuberculosis by Mycobacterium bovis bacillus Calmette-Guérin secreting murine GM-CSF is associated with expansion and activation of APCs , 2008, The Journal of Immunology.

[2]  E. Sercarz,et al.  Immunodominance in the TCR repertoire of αTCR peptide-specific CD4+ Treg population that controls experimental autoimmune encephalomyelitis , 2008, The Journal of Immunology.

[3]  P. Lipsky,et al.  CD4+ T cells recognizing a single self-peptide expressed by APCs induce spontaneous autoimmune arthritis , 2008, The Journal of Immunology.

[4]  K. Jooss,et al.  Recombinant IL-7 enhances the potency of GM-CSF-secreting tumor cell immunotherapy. , 2007, Clinical immunology.

[5]  J. Chabalgoity,et al.  The relevance of cytokines for development of protective immunity and rational design of vaccines. , 2007, Cytokine & growth factor reviews.

[6]  Y. Luo,et al.  Mycobacterium bovis bacillus Calmette–Guérin (BCG) induces human CC‐ and CXC‐chemokines in vitro and in vivo , 2006, Clinical and experimental immunology.

[7]  W. Janssen,et al.  A phase-I Trial Using a Universal GM-CSF-producing and CD40L-expressing Bystander Cell Line (GM.CD40L) in the Formulation of Autologous Tumor Cell-based Vaccines for Cancer Patients with Stage IV disease , 2007, Annals of Surgical Oncology.

[8]  Y. Soong,et al.  Novel codon-optimized GM-CSF gene as an adjuvant to enhance the immunity of a DNA vaccine against HIV-1 gag , 2006, Retrovirology.

[9]  B. Fazekas de St. Groth,et al.  Severely Impaired Clonal Deletion of CD4+ T Cells in Low-Dose Irradiated Mice: Role of T Cell Antigen Receptor and IL-7 Receptor Signals1 , 2006, The Journal of Immunology.

[10]  W. Britton,et al.  Secretion of Functional Monocyte Chemotactic Protein 3 by Recombinant Mycobacterium bovis BCG Attenuates Vaccine Virulence and Maintains Protective Efficacy against M. tuberculosis Infection , 2006, Infection and Immunity.

[11]  J. Markert,et al.  Genetically engineered herpes simplex viruses that express IL-12 or GM-CSF as vaccine candidates. , 2006, Vaccine.

[12]  Guangwu Xu,et al.  Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know , 2006, Cell Research.

[13]  W. Britton,et al.  Plasmid Interleukin-23 (IL-23), but Not Plasmid IL-27, Enhances the Protective Efficacy of a DNA Vaccine against Mycobacterium tuberculosis Infection , 2006, Infection and Immunity.

[14]  L. Fiette,et al.  Neutrophils rapidly migrate via lymphatics after Mycobacterium bovis BCG intradermal vaccination and shuttle live bacilli to the draining lymph nodes. , 2005, Blood.

[15]  S. Behar,et al.  In Vivo Depletion of CD11c+ Cells Delays the CD4+ T Cell Response to Mycobacterium tuberculosis and Exacerbates the Outcome of Infection1 , 2005, The Journal of Immunology.

[16]  J. Villadangos,et al.  Life cycle, migration and antigen presenting functions of spleen and lymph node dendritic cells: limitations of the Langerhans cells paradigm. , 2005, Seminars in immunology.

[17]  B. Trapnell,et al.  Disruption of granulocyte macrophage‐colony stimulating factor production in the lungs severely affects the ability of mice to control Mycobacterium tuberculosis infection , 2005, Journal of leukocyte biology.

[18]  W. Britton,et al.  Epitope-tagging vectors for the expression and detection of recombinant proteins in mycobacteria. , 2005, Plasmid.

[19]  T. van der Poll,et al.  UvA-DARE ( Digital Academic Repository ) Macrophages play a dual role during pulmonary tuberculosis in mice , 2004 .

[20]  D. Evanoff,et al.  Recombinant Mycobacterium bovis bacillus Calmette‐Guérin (BCG) expressing mouse IL‐18 augments Th1 immunity and macrophage cytotoxicity , 2004, Clinical and experimental immunology.

[21]  M. Perales,et al.  Granulocyte-Macrophage Colony Stimulating Factor: An Adjuvant for Cancer Vaccines , 2004, Hematology.

[22]  A. Pridmore,et al.  Transgenic Mice Showing Inflammation-Inducible Overexpression of Granulocyte Macrophage Colony-Stimulating Factor , 2004, Clinical Diagnostic Laboratory Immunology.

[23]  R. Alaniz,et al.  Increased Dendritic Cell Numbers Impair Protective Immunity to Intracellular Bacteria Despite Augmenting Antigen-Specific CD8+ T Lymphocyte Responses1 , 2004, The Journal of Immunology.

[24]  S. Hickman,et al.  Cutting Edge: A New Approach to Modeling Early Lung Immunity in Murine Tuberculosis1 , 2004, The Journal of Immunology.

[25]  R. Badaró,et al.  Use of Rhu-GM-CSF in pulmonary tuberculosis patients: results of a randomized clinical trial. , 2003, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases.

[26]  R. Podesta,et al.  Induction of Protective Immunity against Schistosoma mansoni via DNA Priming and Boosting with the Large Subunit of Calpain (Sm-p80): Adjuvant Effects of Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-4 , 2003, Infection and Immunity.

[27]  I. Orme,et al.  Materials and Methods Briefdefinitive Report Disseminated Tuberculosis in Interferon 7 Gene-disrupted Mice , 2022 .

[28]  R. Brunham,et al.  GM-CSF Transgene-Based Adjuvant Allows the Establishment of Protective Mucosal Immunity Following Vaccination with Inactivated Chlamydia trachomatis1 , 2002, The Journal of Immunology.

[29]  R. DeMatteo,et al.  Endogenous Granulocyte-Macrophage Colony-Stimulating Factor Overexpression In Vivo Results in the Long-Term Recruitment of a Distinct Dendritic Cell Population with Enhanced Immunostimulatory Function1 , 2002, The Journal of Immunology.

[30]  S. Hickman,et al.  Mycobacterium tuberculosis Induces Differential Cytokine Production from Dendritic Cells and Macrophages with Divergent Effects on Naive T Cell Polarization1 , 2002, The Journal of Immunology.

[31]  W. Britton,et al.  Coexpression of Interleukin-12 Chains by a Self-Splicing Vector Increases the Protective Cellular Immune Response of DNA and Mycobacterium bovis BCG Vaccines against Mycobacterium tuberculosis , 2002, Infection and Immunity.

[32]  Yong‐jun Liu,et al.  Mouse and human dendritic cell subtypes , 2002, Nature Reviews Immunology.

[33]  C. Maliszewski,et al.  Comparison of the functional properties of murine dendritic cells generated in vivo with Flt3 ligand, GM-CSF and Flt3 ligand plus GM-SCF. , 2002, Cytokine.

[34]  L. Fiette,et al.  Dendritic Cells Are Host Cells for Mycobacteria In Vivo That Trigger Innate and Acquired Immunity1 , 2002, Journal of Immunology.

[35]  B. Pulendran,et al.  Polyethylene Glycol-Modified GM-CSF Expands CD11bhighCD11chigh But Not CD11blowCD11chigh Murine Dendritic Cells In Vivo: A Comparative Analysis with Flt3 Ligand , 2000, The Journal of Immunology.

[36]  T. Kipps,et al.  Local and systemic effects after adenoviral transfer of the murine granulocyte–macrophage colony‐stimulating factor gene into mice , 2000, British journal of haematology.

[37]  B. Pulendran,et al.  Polyethylene Glycol-Modified GM-CSF Expands CD11bCD11c But Not CD11bCD11c Murine Dendritic Cells In Vivo: A Comparative Analysis with Flt3 Ligand , 2000 .

[38]  W. Koh,et al.  Carboxyfluorescein diacetate succinimidyl ester and the virgin lymphocyte: A marriage made in heaven , 1999, Immunology and cell biology.

[39]  S. Hoffman,et al.  A plasmid encoding murine granulocyte-macrophage colony-stimulating factor increases protection conferred by a malaria DNA vaccine. , 1998, Journal of immunology.

[40]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[41]  D. Klatzmann,et al.  Three populations of mouse lymph node dendritic cells with different origins and dynamics. , 1997, Journal of immunology.

[42]  L. Old,et al.  T cell functions in granulocyte/macrophage colony-stimulating factor deficient mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[43]  D. Hart,et al.  Dendritic cells: unique leukocyte populations which control the primary immune response. , 1997, Blood.

[44]  A. Dunn,et al.  The influence of granulocyte/macrophage colony‐stimulating factor on dendritic cell levels in mouse lymphoid organs , 1997, European journal of immunology.

[45]  A. B. Lyons,et al.  The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help , 1996, The Journal of experimental medicine.

[46]  R. Young,et al.  Manipulation and potentiation of antimycobacterial immunity using recombinant bacille Calmette-Guérin strains that secrete cytokines. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[47]  P. Linsley,et al.  Regulation of immunostimulatory function and costimulatory molecule (B7-1 and B7-2) expression on murine dendritic cells. , 1994, Journal of immunology.

[48]  R. Young,et al.  Recombinant Mycobacterium bovis BCG secreting functional interleukin-2 enhances gamma interferon production by splenocytes , 1994, Infection and immunity.

[49]  I. Orme,et al.  Disseminated tuberculosis in interferon gamma gene-disrupted mice , 1993, The Journal of experimental medicine.

[50]  A. Miyajima,et al.  Receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5. , 1993, Blood.

[51]  J. Gasson.  Molecular physiology of granulocyte-macrophage colony-stimulating factor. , 1991, Blood.

[52]  D. Golde,et al.  Antibody to Mol abrogates the increase in neutrophil phagocytosis and degranulation induced by granulocyte‐macrophage colony‐stimulating factor , 1989, European journal of haematology.

[53]  D. Friend,et al.  Characterization of the cell surface receptor for granulocyte-macrophage colony-stimulating factor. , 1986, The Journal of biological chemistry.