RECRUITMENT OF HEPATIC NATURAL KILLER CELLS BY EXOGENOUS CYTOKINE THERAPY WITH EITHER IL-2 OR IL-12

Abstract

Natural killer (NK) cells are an important component of the innate immune response against a variety of microbial pathogens and tumors. Earlier studies have shown that a number of biochemical and biological agents can induce the recruitment and extravasation of NK cells from the peripheral blood into both lymphoid and nonlymphoid organs, by mechanisms that are dependent upon endogenous cytokine production. The use of exogenously administered cytokine may therefore further enhance the recruitment of NK cells from the vascular compartment into sites of tissue inflammation, providing a beneficial effect for a host trying to resolve a localized inflammatory event. In this study we examined the critical steps involved in the ability of exogenously administered interleukin-2 (IL-2) or interleukin-12 (IL-12) to regulate the recruitment of NK cells and T cells to murine liver, a non-immunological organ which is a frequent site of microbial infection as well as metastatic disease. The results of these studies demonstrate an interesting dichotomy in the ability of IL-2 or IL-12 to recruit NK cells into hepatic parenchyma. Daily dosing with IL-2 induces a continual increase in the numbers of NK cells and T cells found in the liver of treated mice over the period of therapy, as well as an increase in NK cell cytolytic activity. IL-12 therapy, in contrast, leads to a rapid initial peak of NK cell accumulation and cytolytic activity in the liver which then decreases over time with continued therapy, and is accompanied by a gradual increase in hepatic T cell number. The decline in hepatic NK cells in mice receiving exogenous IL-12 was not observed in severe combined immunodeficiency (SCID) mice treated with IL-12, implying T cell involvement in the reduction of liver-associated NK cells during cytokine therapy. The use of a gene-knockout mouse model for interferon gamma (IFN-𝑦) identified that endogenous IFN-𝑦 production is critical for the recruitment of NK cells, but not T cells, by IL-12, and has no effect on the recruitment of NK cells or T cells to the liver by IL-2. In vivo administration of blocking monoclonal antibodies to the endothelial cell-associated adhesion molecules intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) demonstrated that the hepatic recruitment of both NK cells and T cells by IL-12 therapy could be blocked by anti-VCAM-1 antibody, but only T cell recruitment was abrogated by anti-ICAM-1 antibody. These studies demonstrate that NK cells can e effectively recruited to the hepatic parenchyma by exogenous administration of either IL-12 or IL-2, and that the survival of IL-12 recruited hepatic NK cells may be actively regulated by cells of the adaptive immune system.