Host CD4+ T lymphocytes are required for the synergistic action of interferon-alpha/beta and adoptively transferred immune cells in the inhibition of visceral ESb metastases.

Effective adoptive immunotherapy of immunocompetent DBA/2 mice challenged i.v. with the highly metastatic ESb T-cell lymphoma required the combined treatment of recipient mice with tumor-sensitized spleen cells and IFN-alpha/beta. In contrast, immune spleen cells and IFN-alpha/beta treatment did not increase the survival time of ESb-injected DBA/2-nu/nu mice, DBA/2-bg/bg mice, or normal DBA/2 mice injected with antibody to CD4. Treatment of immunocompetent DBA/2 mice with antibody to asialo-GM1, silica, dichloromethylene diphosphonate-containing liposomes, or 500 rads whole-body gamma-irradiation did not diminish the antimetastatic action of ESb-immune cells and IFN-alpha/beta. These results indicate that adoptively transferred immune T lymphocytes and IFN-alpha/beta act together with host CD4+ T lymphocytes/factors to inhibit ESb visceral metastases. Combined treatment with ESb-immune cells together with interleukin-1 beta (IL-1 beta), IL-2, tumor necrosis factor-alpha, or granulocyte-macrophage colony-stimulating factor did not increase the survival time of normal DBA/2 mice challenged with ESb cells. In contrast, IL-12, which had only a slight antimetastatic effect when administered alone, did synergize with ESb-immune spleen cells and increased the survival time of ESb-challenged mice to a similar extent as did IFN-alpha/beta and immune spleen cells. Treatment of DBA/2 mice with potent antibody to IFN-alpha/beta did not abrogate the capacity of IL-12 and ESb-immune spleen cells to inhibit ESb metastases. Unlike immunotherapy with ESb-immune cells and IFN-alpha/beta, ESb-immune cells together with IL-12 inhibited ESb metastases in immunodeficient DBA/2-bg/bg mice.

Intranasal administration of IFN-alpha/beta inhibits the development of visceral tumor metastases.

Intranasal administration of 10(4) U of murine interferon (IFN)-alpha/beta prolonged the survival time of DBA/2 mice injected i.v. with 10(5) (> 20,000 LD50) IFN-alpha/beta-resistant 3C18 Friend leukemia cells (FLC). Long-term survivors rejected a second challenge with 3C18 FLC without additional IFN-alpha/beta treatment. IFN-alpha/beta administered intranasally was not effective in 3C18 FLC-challenged DBA/2 mice pretreated with antibody to IFN-alpha/beta. Recombinant human IFN-alpha BDBB, which is cross-reactive on mouse cells, also increased the survival time of 3C18 FLC-challenged DBA/2 mice. Placing 10(4) U IFN-alpha/beta twice a day into the nostrils also prolonged the survival time of DBA/2 mice with 3-day established 3C18 FLC tumors. Administration of 10(4) U IFN-alpha/beta into the nasopharynx was equally effective or more effective than an equivalent amount of IFN-alpha/beta given by the i.p or oral routes or by gavage. Intranasally administered IFN-alpha/beta also increased the survival time of C57B1/6 mice challenged i.v. with EL4 T cell lymphoma cells, DBA/2 mice challenged i.v. with L1210R B cell lymphoma cells, and C57B1/6 (H-2b) and DBA/2 (H-2d) mice challenged i.v. with B16 melanoma cells (H-2b). These results may be important in devising novel therapeutic strategies for malignant disease using type I IFN.

Effects of exercise on immune functions of undernourished mice.

Regular moderate exercise may modulate the response to a stressor and thus improve immune functions in conditions commonly associated with immunodepression and elevated levels of stress hormones. For example, anorexia nervosa patients, many of whom engage in regular aerobic exercise, generally have normal immune function and viral disease resistance in spite of their severe undernutrition. To test the hypothesis that exercise can prevent undernutrition-induced immunodepression, mice were fed a nutritionally complete, semi-purified diet, either ad libitum or in restricted quantities to induce 25% loss of initial weight over 3 weeks. Half the animals from each dietary group were run on a treadmill for 30 min/day, 5 days/week. Exercise had no effect on several measures of nutritional status. Spleen weight and blastogenic response to lipopolysaccharide were significantly increased by exercise in undernourished mice. In vivo antibody response to sheep red blood cells, and in vitro splenic responses to concanavalin A and phytohemagglutin were not significantly affected by exercise. Serum corticosterone level was increased by food restriction and significantly decreased by exercise in the undernourished mice. Within a treatment group there were no significant correlations between serum corticosterone level and any immune system measure. Hypothalamic concentration of uric acid was increased in food restriction groups and concentration of norepinephrine was increased in exercise groups. The results suggest that regular exercise may help prevent undernutrition-induced immunodepression, possibly through modulation of the stress response.