Objective: We recently observed that type 1 diabetes (T1D) in non-obese diabetic (NOD) mice is prevented by weekly mild (fever-range) whole body hyperthermia (WBH) treatments. Our lab has also demonstrated a role for mild thermal stress in increasing human natural killer (NK) cell cytotoxicity. In NOD mice, T1D is an autoimmune disease in which Beta-cell specific cytotoxic T lymphocytes (CTL) target the insulin producing cells in the pancreas. Since the NK cells in these mice, which would control these CTLs, are known to have defective activation signaling, we hypothesize that the underlying basis by which mild WBH treatments prevent diabetes is through thermal enhancement of NK cell activity.

Methods: Fever-range WBH (39.5^oC, 6-8 hrs) was administered weekly until the NOD mice reached 32 weeks of age whereas control NOD mice were maintained under normothermic conditions. Blood glucose levels were monitored weekly in both groups to determine onset of diabetes. When concentrations reached >33mM, the mice were euthanized and various organs removed for histological or cellular analysis.

Results: Splenocytes isolated from NOD mice following treatments with weekly WBH demonstrated significantly increased NK cell cytotoxic activity when compared to those isolated from control mice. Histologically, there were significantly fewer infiltrating immune cells within the islets of WBH treated mice compared to controls. Interestingly, although CFA also prevents T1D, CFA treated mice exhibited a higher degree of invasive insulitis. While the islets of WBH treated mice demonstrated peri-insulitis, the islets of mice treated with CFA exhibited actual insulitis in which they were infiltrated with lymphocytes, which had breached the surrounding Schwann cells.

Conclusions: Overall, these studies suggest, for the first time, the existence of thermally sensitive, NK-cell dependent, immune regulatory pathways that can prevent immune cell infiltration and destruction of islets. Identifying and understanding these thermally sensitive aspects of immune regulation could be critical for development of new, thermally based therapies for the treatment and/or prevention of autoimmune diseases.