Activated lymphocytes are used as a modality of immunotherapy, especially for cancer treatment. Our studies of activated killer cells are in two areas: (a) Effect of aging on cytolytic T lymphocytes (CTL) activity, using a murine model in vitro and in vivo, and (b) Activation of natural killer (NK) cells to produce lymphokine activated killer (LAK) activity, using a human model in vitro. A. CTL and aging: (i) Although the proportion of alloantigen-stimulated cells producing perforin or pore-forming protein (pfp) is decreased with age, the majority of the age-related reduction in Pfp production was due to diminished Pfp production by individual cells. These findings suggested that a threshold level of Pfp may be required for potency of effector cell function, and that aging may affect most or all potential effector cells rather than a """"""""mosaic"""""""" of cells. (ii) The frequency of phenotypically naive cells (defined as CD44-dim), decreases with advancing age and is accompanied by an increase in the proportion of memory cells (CD44-bright). However, the decreased frequency of naive cells with aging does not fully explain the diminished CTL activity because purified naive cells from aged mice still exhibit an inherently compromised ability to generate CTL compared to those from young mice. (iii) Studies on the involvement of IL-12 in the age related decline have been initiated. B. NK and LAK: (i) Signal transduction through the integrin, LFA-1 is more important and efficient in IL-2 activated LAK compared to native NK cells, and the specific biosynthetic turnover of LFA-1 is more rapid in LAK compared to NK cells. (ii) Optimal generation of LAK activity is regulated by oxidation-reduction, requiring a reducing microenvironment, and in particular, the synthesis of reduced type glutathione. (iii) Studies on the importance of chemokines in the generation of LAK cells are being initiated.
