Differential effects of myeloid dendritic cells retrovirally transduced toexpress mammalian or viral interleukin-10 on cytotoxic T lymphocyte and natural killer cell functions and resistance to tumor growth

Background Genetic engineering of dendritic cells (DC) to express immunosup pressive molecule(s) offers potential for therapy of allograft rejection an d 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 (WR) 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/6 J (H2(b)) mice in granulocyte-macrophage colony-stimulating factor + IL-4, were transduced using retroviral supernatant from the BOSC ecotropic packag ing cell line. The function of the IL-IO gene-modified DC was assessed by e xamining their ability to induce naive allogeneic T-cell proliferation and cytotoxic T lymphocyte (CTL) generation. MCA205 (H2b) sarcoma cells mixed w ith either vIL-10-, mIL-10-, or Zeo (control gene)-transduced DC were inocu lated intradermally into C57BL/6J (syngeneic) or BALB/cJ (H2(d)) (allogenei c) recipients, which were monitored for tumor growth, The role of specific host effector cell populations in tumor resistance was determined by antibo dy depletion. Results, Compared with control gene-modified DC, both vIL-10- and mIL-10-tr ansduced DC, which secreted the transgene product, showed reduced surface e xpression of MHC class II and costimulatory molecules, and impaired ability to induce T-cell proliferation. vIL-10-transduced DC were also inhibited w ith respect to CTL induction but did not affect the generation of NE; cells . By contrast, mIL-10-transduced DC augmented CTL generation and NH cell ac tivity. in the tumor transplant model, vIL-10-transduced DC enhanced tumor growth both in syngeneic and allogeneic hosts, whereas mIL-10-transduced ce lls inhibited tumor development, Depletion of CD4(+) or CDS' T cells or NK cells in mice given mIL-10-transduced DC reversed this therapeutic effect. Conclusion. mIL-10 gene-modified myeloid DC promote CTL and NK cell-mediate d responses and inhibit tumor growth. By contrast, vIl-10-engineered DC, wh ich elicit diminished CTE responses and do not promote NK cell activity, se em to have therapeutic potential for inhibition of T cell-mediated immunity .