Macrophage colony-stimulating factor can modulate immune responses and attract dendritic cells in vivo.

Studies have indicated that professional APCs in the periphery, such as dendritic cells and macrophages, play an important role in initiating DNA vaccine-specific immune responses. To engineer the immune response induced by DNA vaccines in vivo we investigated the modulatory effects of codelivering growth factor genes for the hematopoietic APCs along with DNA vaccines. Specifically, we examined the effects on the antigen-specific immune responses following the codelivery of the gene expression cassettes for M-CSF, G-CSF, and GM-CSF along with HIV-1 DNA immunogen constructs. We observed that coimmunization with GM-CSF increased the antibody response and resulted in a significant enhancement of lymphoproliferative response. Furthermore, among all coinjection combinations, we found that M-CSF coinjections resulted in a high level of CTL enhancement. This enhancement of CTL responses observed from the coinjection with M-CSF was CD8+ T cell dependent and was associated with the presence of CD11c+ cells at the site of injection and with the antigen-specific induction of the beta-chemokine MIP-1beta, suggesting a role for this chemokine in CTL induction. These results suggest that hematopoietic growth factors should be further studied as potential adjuvants for in vivo modulators of immune responses.

[1]  G. Bahr,et al.  Enhanced maturation and functional capacity of monocyte‐derived immature dendritic cells by the synthetic immunomodulator Murabutide , 2001, Immunology.

[2]  H. Heslop,et al.  Gene therapy for paediatric leukaemia , 2001, Expert opinion on biological therapy.

[3]  A. Chalian,et al.  CD86 (B7-2) can function to drive MHC-restricted antigen-specific CTL responses in vivo. , 1999, Journal of immunology.

[4]  A. Chalian,et al.  Molecular and immunological analysis of genetic prostate specific antigen (PSA) vaccine , 1998, Oncogene.

[5]  D. Weiner,et al.  Enhancement of protective humoral (Th2) and cell‐mediated (Th1) immune responses against herpes simplex virus‐2 through co‐delivery of granulocyte‐macrophage colony‐stimulating factor expression cassettes , 1998, European journal of immunology.

[6]  S. Hoffman,et al.  Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. , 1998, Science.

[7]  A. Chalian,et al.  CD8 positive T cells influence antigen-specific immune responses through the expression of chemokines. , 1998, The Journal of clinical investigation.

[8]  G. Bartsch,et al.  Human monocyte‐derived dendritic cells produce macrophage colony‐stimulating factor: enhancement of c‐fms expression by interleukin‐10 , 1998, European journal of immunology.

[9]  D. Weiner,et al.  First human trial of a DNA-based vaccine for treatment of human immunodeficiency virus type 1 infection: safety and host response. , 1998, The Journal of infectious diseases.

[10]  D. Weiner,et al.  Specific immune induction following DNA-based immunization through in vivo transfection and activation of macrophages/antigen-presenting cells. , 1998, Journal of immunology.

[11]  A. Chalian,et al.  Modulation of amplitude and direction of in vivo immune responses by co‐administration of cytokine gene expression cassettes with DNA immunogens , 1998, European journal of immunology.

[12]  J. Kim,et al.  An HIV type 2 DNA vaccine induces cross-reactive immune responses against HIV type 2 and SIV. , 1997, AIDS research and human retroviruses.

[13]  R. Steinman,et al.  Antigen Presentation by Dendritic Cells after Immunization with DNA Encoding a Major Histocompatibility Complex Class II–restricted Viral Epitope , 1997, The Journal of experimental medicine.

[14]  A. Chalian,et al.  Engineering of in vivo immune responses to DNA immunization via codelivery of costimulatory molecule genes , 1997, Nature Biotechnology.

[15]  A. Iwasaki,et al.  Enhanced CTL responses mediated by plasmid DNA immunogens encoding costimulatory molecules and cytokines. , 1997, Journal of immunology.

[16]  D. Weiner,et al.  Protection of chimpanzees from high-dose heterologous HIV-1 challenge by DNA vaccination , 1997, Nature Medicine.

[17]  N. Ishii,et al.  Immunomodulatory effects of a plasmid expressing B7‐2 on human immunodeficiency virus‐1‐specific cell‐mediated immunity induced by a plasmid encoding the viral antigen , 1997, European journal of immunology.

[18]  J. Kim,et al.  In vivo engineering of a cellular immune response by coadministration of IL-12 expression vector with a DNA immunogen. , 1997, Journal of immunology.

[19]  M. Tao,et al.  Improvement of hepatitis B virus DNA vaccines by plasmids coexpressing hepatitis B surface antigen and interleukin-2 , 1997, Journal of virology.

[20]  M. Colston,et al.  Vaccination against tuberculosis by DNA injection , 1996, Nature Medicine.

[21]  Marc Parmentier,et al.  A Dual-Tropic Primary HIV-1 Isolate That Uses Fusin and the β-Chemokine Receptors CKR-5, CKR-3, and CKR-2b as Fusion Cofactors , 1996, Cell.

[22]  Ying Sun,et al.  The β-Chemokine Receptors CCR3 and CCR5 Facilitate Infection by Primary HIV-1 Isolates , 1996, Cell.

[23]  C. Broder,et al.  CC CKR5: A RANTES, MIP-1α, MIP-1ॆ Receptor as a Fusion Cofactor for Macrophage-Tropic HIV-1 , 1996, Science.

[24]  Virginia Litwin,et al.  HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5 , 1996, Nature.

[25]  Stephen C. Peiper,et al.  Identification of a major co-receptor for primary isolates of HIV-1 , 1996, Nature.

[26]  S. Arya,et al.  Identification of RANTES, MIP-1α, and MIP-1β as the Major HIV-Suppressive Factors Produced by CD8+ T Cells , 1995, Science.

[27]  Z. Xiang,et al.  Manipulation of the immune response to a plasmid-encoded viral antigen by coinoculation with plasmids expressing cytokines. , 1995, Immunity.

[28]  J. Levy,et al.  HIV and the Pathogenesis of AIDS , 1994, Nature Medicine.

[29]  T. Springer,et al.  Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[30]  H. Davis,et al.  DNA-based immunization induces continuous secretion of hepatitis B surface antigen and high levels of circulating antibody. , 1993, Human molecular genetics.

[31]  Bin Wang,et al.  Gene inoculation generates immune responses against human immunodeficiency virus type 1. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Ulmer,et al.  Heterologous protection against influenza by injection of DNA encoding a viral protein. , 1993, Science.

[33]  J. Berzofsky,et al.  Broad recognition of cytotoxic T cell epitopes from the HIV-1 envelope protein with multiple class I histocompatibility molecules. , 1992, Journal of immunology.

[34]  D. Tang,et al.  Genetic immunization is a simple method for eliciting an immune response , 1992, Nature.

[35]  R A Houghten,et al.  Induction of broadly cross-reactive cytotoxic T cells recognizing an HIV-1 envelope determinant. , 1992, Science.

[36]  G. Acsadi,et al.  Direct gene transfer into mouse muscle in vivo. , 1990, Science.

[37]  J. Abrams,et al.  Simultaneous production of IL-2, IL-4, and IFN-gamma by activated human CD4+ and CD8+ T cell clones. , 1988, Journal of immunology.

[38]  R. Coffman,et al.  The Role of Helper T Cell Products in Mouse B Cell Differentiation and Isotype Regulation , 1988, Immunological reviews.

[39]  D. Curiel,et al.  Selected strategies to augment polynucleotide immunization. , 1996, Gene therapy.

[40]  W. Paul,et al.  Acquisition of lymphokine-producing phenotype by CD4+ T cells. , 1994, Annual review of immunology.

[41]  M. Moore.  The clinical use of colony stimulating factors. , 1991, Annual review of immunology.

[42]  C. Sherr.  Colony-stimulating factor-1 receptor. , 1990, Blood.

[43]  R. Coffman,et al.  Lymphokine control of in vivo immunoglobulin isotype selection. , 1990, Annual review of immunology.

[44]  J. Virelizier,et al.  The interferon-macrophage alliance. , 1987, Interferon.