Hyperthermia has been shown to modulate immune function. The direction of this modulation, however, is controversial. Previous in vitro studies, including our own preliminary experiments, have suggested a differential susceptibility to heat by various subpopulations of lymphoid cells. In response to mitogens we propose an hierarchy of heat sensitivity of cells responding to: Con A > PHA > PWM >- LPS. We propose the order of heat sensitivity of cytotoxic effector cells to be CTL > K > NK. We have preliminary data supporting a portion of this hierarchy in both instances. We will test this hypotheses by heating mouse spleen cells in vitro (37-45 degree C, 10-90 min) and subsequently evaluating the cells phenotypically and functionally to define effects on discrete subpopulations. Proliferative responses to mitogens that activate different subpopulations of cells will be evaluated followed by immunofluorescence microscopy and flow cytometry to evaluate the phenotype of the responding lymphocytes. Heat will be applied prior to mitogen stimulation and at various intervals following mitogen exposure. Cytotoxic effector function will be evaluated in terms of antibody-dependent cell-mediated cytotoxicity (ADCC) K-cell function, cytotoxic T-lymphocytes (CTL) and natural killer (NK) cell activity. The effects of hydrogen ion concentration will be considered by monitoring pH and altering pH of the medium from 6.2 - 7.8. Cell fractionation studies will be done to evaluate the differential development in heatshock proteins (HSP) in cells that appear functionally to be most sensitive and resistant to heat. These baseline studies will be followed by experiments designed to evaluate whether the effects of hyperthermia on immune functions can be altered, either during or following heating, by well-defined substances known to affect the immune functions being studied. These will include: ethanol and acetaldehyde, calcium and calcium ionophores, retinoids, indomethacin and two recombinant cytokines; IL-2 and Gamma Interferon. We will also evaluate whether brief exposure to sublethal heating or ethanol can induce resistance to the effects of heating at higher temperatures (i.e., relative thermotolerance). These studies should provide insight into the relative sensitivities to heat of different lymphoid cell populations and their functions and yield useful information about the combined effects of hyperthermia and other known immunomodulators.
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