Relevance of adenosine deaminase to organ transplantation

We have presented a discussion on the relevance of ADA to organ transplantation with regard to whether or not purine analogue inhibitors of ADA can prevent allograft rejection, and whether or not cells with high ADA activity may be involved in the rejection of allografts. It is clear that ADA inhibitors do have a modest amount of immunosuppressive activity. The potentiation of this modest effect by the addition of a deoxyadenosine analogue supports studies by others suggesting that it is the metabolism of deoxyadenosine and the presence of this compound as a substrate that is biochemically responsible for the immunosuppressive effects observed. In other studies that we are currently conducting, we have found that the ADA inhibitor EHNA causes a rapid and severe depletion of ATP in resting murine lymphocytes and that EHNA potentiates a similar effect of the new immunosuppressive agent cyclosporine in the same model. Investigations are currently underway to see if ADA inhibitors may potentiate the immunosuppressive effect of cyclosporine in vivo. It appears that cells with high ADA activity that are detectable in the peripheral blood mononuclear cells of renal allograft patients may indeed be involved in the rejection of allografts. However, from murine studies allogeneic cells alone do not seem to generate the appearance of these cells nearly as strongly as infection with murine cytomegalovirus. It must be determined if the ADA-rich cells that appear at the time of CMV infection are involved in viral functions or are the ontologic appearance of cytotoxic T cells representing the host's response to the antigens of the virus. The attack of these host cells against allograft cells infected with the virus may then explain the long-standing observation that viral infections seem to trigger allograft rejection responses.