PARENT SESSION
3:45 PM to 5:15 PM
Saturday, April 20, 2002
NAHS Mini-Symposium 1
NAHS Physiological and Metabolic Aspects of Hyperthermia
Room: Nevada 1-2
Chair: Song, Chang ²²Radiation Biology Section, Dept. of Therapeutic Radiology, Minneapolis, MN
Speakers: Dewhirst, Mark⁴; Evans, Sharon ⁵; Spitz, Doug⁶⁴Division of Radiation Oncology, Durham, NC⁵Dept. of Immunology, Roswell Park Cancer Institute, Buffalo⁶Free Radical and Radiation Biology Program, Iowa City, IA

(MS01-3) Dynamic Control of Lymphocyte Trafficking By Fever-Range Thermal Stress.

Chen, Qing¹, Ginnetti, John¹, Baumann, Heinz¹, Kraybill, William¹, Ostberg, Julie¹, Repasky, Elizabeth¹, Wang, Wan-Chao¹, Evans, Sharon^*,1, ¹ Roswell Park Cancer Institute, Buffalo, NY

ABSTRACT-
The febrile component of fever is associated with increased survival during host responses to infection although its mechanism of action is largely unknown. The ability to protect against infection is dependent on migration of blood-borne lymphocytes across endothelial barriers in secondary lymphoid tissues and at sites of tissue damage. This process is mediated by chemokines and a molecular array of adhesion molecules. Here we show an integrated mechanism whereby fever-range temperatures control lymphocyte trafficking through the regulation of adhesion in two distinct cell types. Exposure of lymphocytes either in vitro or in vivo to fever-like hyperthermia (40^oC for 6 h) stimulates L-selectin and 47 integrin-dependent adhesion under shear to specialized high endothelial venules. The function of endothelial counter-receptors for L-selectin and 47 integrin (i.e., PNAd and MAdCAM-1) is also increased in murine models during fever-range whole body hyperthermia treatment or febrile responses associated with LPS or turpentine-induced inflammation. Notably, the thermal effects on endothelial adhesion are restricted to selected vascular beds of secondary lymphoid tissues, inflamed tissues, and tumor microvasculature, while normal non-activated endothelium is not affected. Although fever-range thermal stress does not induce chemokine biosynthesis by endothelial cells, it potentiates G-protein dependent lymphocyte responses to selected chemokines (i.e., SLC, SDF-1). Finally, fever-range thermal stress was shown in experimental models to enhance lymphocyte-endothelial adhesion in vitro and in vivo through a signaling pathway mediated by IL-6/soluble IL-6 receptor (sIL-6R) complexes. The biological relevance of this mechanism is supported by evidence that the proadhesive bioactivity of circulating IL-6/sIL-6R is transiently increased in advanced cancer patients undergoing clinical fever-range whole body hyperthermia therapy (39 - 40^oC for 3-6 h). These results highlight a novel mechanism by which lymphocyte trafficking is amplified during physiologic febrile responses and clinical hyperthermia. (Supported by NIH grants [CA79765, CA71599, DK33886] and Department of Defense grant DAMD17-98-1-8311).

KEYWORDS: recirculation/recruitment, adhesion molecules, chemokines, IL-6