Abstract 1375: Benefits of adding an exercise intervention to conventional immunosuppression in chronic graft versus host disease: insights from a murine model.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Purpose.- Graft-versus-host-disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and it is associated with high morbimortality and decreased patients’ physical capacity. We determined the effects of an exercise training program performed after allo-HSCT on survival, clinical evolution and physical capacity, using a murine model of chronic GVHD treated with cyclosporine A. Methods.- BALB/C female mice (aged 8 weeks) were randomly assigned to an exercise (n=11) or control group (n=12). Allo-HSCT was performed with donor bone marrow cells and splenocytes from B10.D2 female mice. Mice of the exercise group performed a moderate-intensity treadmill running program, and both groups received Cyclosporine A (15 mg/kg/day) during ∼11wks after transplant. We analyzed survival and total clinical severity score (which is the sum of five individual scores). We measured mice basal heart rate as an indicator of physical fitness status before and after allo-HSCT. We collected blood and serum samples for immune cell reconstitution at days +21 and +82, and for cytokine analysis (IL2, IL4, IL6, IL10, IL17a, IFNγ and TNFα) at days -10 and +82. On sacrifice day, we removed target tissues (liver, intestine, skin) and spleen, for analyzing the GVHD damage and the immune cell reconstitution respectively, and skeletal muscles evaluating the muscle adaptations. Results.- Exercise training resulted in an increased survival (p=0.011) and lesser deterioration of physical capacity after ∼11 weeks (p=0.03 for the between-group comparison) in the exercise group. Regarding disease clinical course/severity, the exercise intervention induced a significant group x interaction effect for total severity score (p=0.002), reflecting a better disease evolution in the exercise group. We found a beneficial effect in three individual scores: weight (a reliable indicator of the severity of the disease, p=0.02), spontaneous activity (p=0.001) and posture (p=0.002). Exercise training reduced blood IL4 and TNFα (p=0.025 and p=0.031, respectively) while increasing circulating B220 (p=0.008) and CD4 lymphocytes (p=0.043). We found no between-group difference in citrate synthase activity (p=0.322), and a trend towards higher muscle anabolism (as determined by the ratio of phospho-p70 S6 kinase / p70 S6 kinase) in the exercise compared with the control group (p=0.083). Conclusion.- A moderate-intensity exercise program mimicking the widely accepted public health recommendations for physical activity in humans (≥ 30min/day) was well tolerated and had significant positive effects on clinical and biological indicators of chronic GVHD, and resulted in better survival. Citation Format: Carmen Fiuza-Luces, Luisa Soares-Miranda, Africa Gonzalez-Murillo, Jesus Martinez Palacio, Isabel Colmenero, Fernando Casco, Gustavo Melen, Maria Moran, Manuel Ramirez, Alejandro Lucia. Benefits of adding an exercise intervention to conventional immunosuppression in chronic graft versus host disease: insights from a murine model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1375. doi:10.1158/1538-7445.AM2013-1375