Winner of the 2007 Society for Thermal Medicine Young Investigator Award. Fever-range whole body hyperthermia prevents the onset of type 1 diabetes in non-obese diabetic mice.

PURPOSE: Type 1 diabetes (T1D) is an autoimmune disease in which the insulin producing beta cells of the pancreatic islets are destroyed by cytotoxic T lymphocytes (CTLs). It has been demonstrated that the injection of complete Freund's adjuvant (CFA) can prevent disease onset in non-obese diabetic (NOD) mice. This effect has been attributed to CFA-enhanced natural killer (NK) cell mediated control of autoimmune CTLs. Fever-range whole body hyperthermia (FR-WBH) has also been shown to stimulate NK cell cytotoxicity. This led to the hypothesis that FR-WBH can prevent disease onset in NOD mice by a thermally regulated mechanism. METHODS: FR-WBH or mock treatment was administered weekly until the NOD mice reached 32 weeks of age. Blood glucose levels were monitored weekly, with measurements > or =33.5 mM indicating onset of diabetes, at which time the mice were euthanized for histological and cellular analyses. RESULTS: Weekly FR-WBH prevented the onset of T1D in NOD mice and this effect correlated with increased NK cell cytotoxicity and control of blood glucose concentration. Histological analysis revealed significantly fewer lymphocytes infiltrating the pancreatic islets of FR-WBH treated mice than those of untreated mice, suggesting a relationship between thermally induced protection of beta cells and their ability to regulate blood glucose concentrations. CONCLUSIONS: These studies show, for the first time, that mild systemic hyperthermia can prevent the generation of T1D in a clinically relevant mouse model. Further study of the thermally sensitive aspects of immunoregulation could lead to the development of heat-based therapies for the prevention or treatment of autoimmune diseases.

An important role for granulocytes in the thermal regulation of colon tumor growth.

Several lines of research show that cells of the immune response are sensitive to thermal variations in their microenvironment, such as that which occurs during inflammation and fever; these data have led to the hypothesis that strategic applications of heat could assist in controlling tumor growth in animal models. The innate immune response is known to play a critical role in the development of effective anti-tumor immunity and granulocytes such as polymorphonuclear neutrophils (PMNs), as key mediators of inflammation, have been suggested to have the potential to initiate immune response cascades against tumors. Thus, we hypothesized that PMNs may play a crucial role in mediating the anti-tumor effects of a mild, fever-range whole-body hyperthermia (FR-WBH) protocol, where core body temperatures are raised to 39.5-40 degrees C for 8 hrs. Indeed, in BALB/c mice bearing the colon tumor CT26, the anti-tumor effect of WBH correlates with increased granulocytic infiltrate at the tumor site as determined using immunohistochemical analysis for Gr-1+ cells. In both BALB/c mice bearing CT26 and SCID mice bearing human colon tumors, PMN depletion in vivo using anti-Gr-1 ascites ablated the anti-tumor effect of mild WBH. Because mild thermal stress is also found to enhance the respiratory burst of granulocytes, these data collectively suggest that the thermal stimulation of granulocytes may help to prevent tumor establishment. Overall, these results may have implications for the design of thermal therapy protocols in cancer immunotherapy.