title: Differential effects of myeloid dendritic cells retrovirally transduced to express mammalian or viral interleukin-10 on cytotoxic T lymphocyte and natural killer cell functions and resistance to tumor growth.
abstract: BACKGROUND
  Genetic engineering of dendritic cells (DC) to express immunosuppressive molecule(s) offers potential for therapy of allograft rejection and autoimmune disease. Viral (v) interleukin (IL)-10, encoded by the Epstein-Barr virus, is highly homologous to mammalian (m) IL-10, but lacks certain of its T-cell stimulatory activities. Our aim was to evaluate and compare the influence of vIL-10 and mIL-10 gene transfer on the T-cell and natural killer (NK) cell stimulatory activity of DC, and their impact on the growth of transplantable tumors.
  
  
  METHODS
  Myeloid DC progenitors, propagated from the bone marrow of C57BL/6J (H2b) mice in granulocyte-macrophage colony-stimulating factor + IL-4, were transduced using retroviral supematant from the BOSC ecotropic packaging cell line. The function of the IL-b gene-modified DC was assessed by examining their ability to induce naive allogeneic T-cell proliferation and cytotoxic T lymphocyte (CTL) generation. MCA205 (H2b) sarcoma cells mixed with either vIL-10-, mIL-10-, or Zeo (control gene)-transduced DC were inoculated intradermally into C57BL/6J (syngeneic) or BALB/cJ (H2d) (allogeneic) recipients, which were monitored for tumor growth. The role of specific host effector cell populations in tumor resistance was determined by antibody depletion.
  
  
  RESULTS
  Compared with control gene-modified DC, both vIL-10- and mIL-10-transduced DC, which secreted the transgene product, showed reduced surface expression of MHC class II and costimulatory molecules, and impaired ability to induce T-cell proliferation. vIL-10-transduced DC were also inhibited with respect to CTL induction but did not affect the generation of NK cells. By contrast, mIL-10-transduced DC augmented CTL generation and NK cell activity. In the tumor transplant model, vIL-10-transduced DC enhanced tumor growth both in syngeneic and allogeneic hosts, whereas mIL-10-transduced cells inhibited tumor development. Depletion of CD4+ or CD8+ T cells or NK cells in mice given mIL-10-transduced DC reversed this therapeutic effect.
  
  
  CONCLUSIONS
  mIL-10 gene-modified myeloid DC promote CTL and NK cell-mediated responses and inhibit tumor growth. By contrast, vIL-10-engineered DC, which elicit diminished CTL responses and do not promote NK cell activity, seem to have therapeutic potential for inhibition of T cell-mediated immunity.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA.
authors.forename: T
authors.initials: T
authors.lastname: Takayama
authors.forename: H
authors.initials: H
authors.lastname: Tahara
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology* / Q000821:virology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D016753:Interleukin-10 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology*; D012190:Retroviridae / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000821:virology*; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000166:cytology; D019139:Tumor Escape / Q000187:drug effects / Q000502:physiology
chemical_list: D000949:Histocompatibility Antigens Class II; D016753:Interleukin-10