Reduced levels of hsp70 result in a therapeutic effect of 15-deoxyspergualin on acute graft-versus-host disease in (DAxLEW)F1 rats

We have shown previously that increased levels of hsp70, and antibodies rea ctive with hsp70 parallel the onset and severity of graft-versus-host disea se (GVHD) in a parent --> (DA x LEW)F1 rat model. In this study we have ass essed the effect of reducing the levels of the 70 kDa heat shock protein (h sp70), on the morbidity and mortality of acute GVHD in (DA x LEW)F1 rats. T he reduction was accomplished by the administration of 15-deoxyspergualin ( DSG), an immunosuppressive agent which binds to a constitutively expressed member of the 70 kDa heat shock protein Family. DSG administered via three different protocols reduced GVHD-associated morbidity. One of the regimens, which consisted of intermittent DSG administration, also significantly red uced GVHD associated mortality. This DSG treatment reduced hsp70 levels in spleen and lymph nodes, inhibited anti-hsp70 antibody production, and dimin ished the serum levels of IL-2, IFN-gamma, TNF-alpha, and IL-10. IL-4 level s sis in the serum did nor change during GVHD and were nor effected by DSG. These results show chat the mechanism of DSG immunosuppressive effect in r at GVHD may involve DSG's capacity to bind to hsp70, which in turn may lead to a decrease In levels or circulating anti-hsp70 antibodies, and reduced production of cytokines.