Human dendritic cell (DC)-based anti-infective therapy: engineering DCs to secrete functional IFN-gamma and IL-12.
An imbalance in the Th1- and Th2-type cytokine responses may allow certain microbes to modify the host response to favor their own persistence. We now show that infection/pulsing of human CD34+ peripheral blood hemopoietic progenitor cell-derived dendritic cells (DCs) with Leishmania donovani promastigotes, Histoplasma capsulatum, and Mycobacterium kansasii impairs the constitutive production of IL-12 from these cells. Thus, strategies aimed at modulating a dysregulated Th1/Th2 response to infection would be of great interest. To both augment the host immune response and deliver potent immunomodulatory cytokines such as IL-12 and IFN-gamma, our goal is to develop a therapeutic strategy using genetically modified, microbial Ag-pulsed DCs. Toward developing such immunotherapies, we used retrovirus-mediated somatic gene transfer techniques to engineer human DCs to secrete biologically active IL-12 and IFN-gamma. DCs pulsed with microbial antigens (e.g., leishmania and histoplasma Ags) were capable of inducing proliferative responses in autologous CD4+ lymphocytes. CD4+ lymphocytes cocultured with IL-12-transduced autologous DCs had enhanced Ag-specific proliferative responses compared with CD4+ lymphocytes cocultured with nontransduced or IFN-gamma- transduced DCs. In this cell culture model system we demonstrate that IL-12 has a negative effect on IL-4 secretion that is independent of its ability to induce IFN-gamma secretion. Taken together, these results indicate that IL-12-transduced DCs may be specifically suited in inducing or down-modulating Ag-specific Th1 or Th2 responses, respectively, and thus may be useful as adjunctive therapy in those intracellular infections in which a dominant Th1 response is critical for the resolution of infection.
Ahuja
S S
SS
University of Texas Health Science Center, San Antonio 78284, USA. ahuja@uthscsa.edu
Mummidi
S
S
Malech
H L
HL
Ahuja
S K
SK
D016475:3T3 Cells; D000818:Animals; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D018952:Antigens, CD34 / Q000032:analysis; D000946:Antigens, Fungal / Q000494:pharmacology; D000953:Antigens, Protozoan / Q000494:pharmacology; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D005818:Genetic Engineering / Q000379:methods*; D005822:Genetic Vectors / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006658:Histoplasma / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007893:Leishmania donovani / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics; D019909:Mycobacterium kansasii / Q000276:immunology; D018417:Th1 Cells / Q000378:metabolism; D014161:Transduction, Genetic / Q000276:immunology
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D018952:Antigens, CD34; D000946:Antigens, Fungal; D000953:Antigens, Protozoan; D018664:Interleukin-12; D007371:Interferon-gamma