Deoxycoformycin (DCF) and desoxyadenosine (dADO) in vitro treatment for graft-versus-host disease (GVHD) prevention

Abstract

Dividing as well as resting T cells are sensitive to μM concentrations of dADO in the presence of an adenosine-deaminase (ADA) inhibitor such as DCF. Therefore, this drug combination was investigated for its ability to deplete T cells from allogeneic rat bone marrow (BM) and spleen (SP) cells and for its potential to prevent GVHD in fully allogeneic rat bone marrow transplantation(BMT). - It was found that a concentration of 0.5 μM of DCF was sufficient to block ADA-activity in rat BM and SP cells completely. Concentrations as high as 100 μM were not toxic to in vitro colony forming units (CFU-GM). Increasing dADO concentrations in the presence of DCF led to increasing T cell but also increasing CFU toxicity. However, dADO concentrations below 40 μM had no significant influence on CFU growth but clearly exhibited an effect on T cells. T cell functions, as determined by mitogen and alloantigen stimulated thymidine (3HTdR) uptake, were reduced to 10-30% of normal values. Flowcytometric analysis revealed a significant T cell reduction following in vitro treatment. However, some residual T cells were detectable in treated samples. - In accordance with the described in vitro data, rat-recipients of DCF/dADO treated allogeneic BM and SP cell grafts showed a significantly decreased incidence of acute lethal GVHD. - The results indicate that a significant but incomplete depletion of T cells can be achieved through DCF/dADO in vitro treatment using concentrations which are not toxic for stem cells. Such T cell depletion results in modification of acute lethal GVHD intn a chronic form in fully allogeneic rat BMT.