Increased voluntary exercise in mice deficient for tumour necrosis factor-alpha and lymphotoxin-alpha.

BACKGROUND: The endogenous mediators playing a role in the sensing of fatigue and cessation of exercise are yet to be characterized. We hypothesized that proinflammatory cytokines, in particular tumour necrosis factor-alpha (TNFalpha) and lymphotoxin-alpha (LT) transmit signals leading to fatigue. MATERIALS AND METHODS: Mice were placed in a cage with a freely rotating exercise wheel and allowed to adapt for 24 h. The running distance was measured for two additional periods of 24 h. The effects of the administration of intravenous anti-TNF antibodies, intracerebral recombinant TNF, or intravenous lipopolysaccharide (LPS) were also determined. RESULTS: Compared to normal littermates, the voluntary daily running distance was 1.8-fold greater in mice with a disruption of the gene for TNFalpha, and 3-fold greater in mice with a gene disruption for both TNFalpha and LT. Intravenous administration of a monoclonal antibody against murine TNFalpha did not affect the running distance of wild-type mice, whereas administration of TNF intracerebrally reduced by 4-fold the voluntary running distance of the animals. This demonstrates that fatigue is mediated by TNFalpha expressed in the central nervous system (CNS) and not by increased peripheral TNFalpha concentrations. TNFalpha and LT are strong inducers of prostaglandins, but mice with disrupted prostaglandin or prostacyclin receptors exhibited running distances not significantly different from their wild-type littermates. Thus, signalling molecules other than prostaglandins mediate the effect of TNFalpha and LT on exercise capacity. CONCLUSIONS: Our finding that exercise capacity is controlled by TNFalpha is the first to define the endogenous mediators of fatigue, and may have important implications for diseases with impaired exercise tolerance.

Higher numbers of blood CD14+ cells before starting conditioning regimen correlate with greater risk of acute graft-versus-host disease in allogeneic stem cell transplantation from related donors.

Host antigen-presenting cells (APCs) have been shown to induce acute graft-versus-host disease (aGVHD) in experimental models. In this study, we investigated whether pretransplantation blood levels of host APCs, such as plasmacytoid and myeloid dendritic cells and monocytes, correlate with the development of aGVHD. A total of 89 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched related (n = 48) or unrelated (n = 41) donors were enrolled in the study. Blood samples were analyzed by flow cytometry before initiating the conditioning regimen. In related donor transplants, patient-donor sex mismatch and monocyte levels significantly correlated with aGVHD grade II-IV in both univariate and multivariate analyses. Similar results were not observed in recipients of matched unrelated transplants, possibly due to use of antithymocyte globulin (ATG) or differences in graft source in these patients. In conclusion, pretransplantation recipient monocyte levels are relevant to the development of GVHD in HSCT from related donors.