IMPLICATION OF CYCLOSPORINE IN UP-REGULATION OF BCL-2 EXPRESSION AND MAINTENANCE OF CD8 LYMPHOCYTOSIS IN CYTOMEGALOVIRUS-INFECTED ALLOGRAFTRECIPIENTS

T cell, homeostasis and CD4/CD8 ratios are normally reestablished by a poptotic clearance of activated T cells after immune stimulation, In a llograft recipients with cytomegalovirus infection, CDS lymphocytosis persists after negativation of viral cultures, contrary to immunocompe tent hosts. We investigated the expression of Bcl-2 protein, an intrac ellular suppressor of apoptosis, and of CD95 (APO-1/Fas), a membrane i nducer of apoptosis, in peripheral blood lymphocytes from 45 solid org an recipients. During the viremic phase of CMV infection, we found abs ence or diminished expression of Bcl-2 protein and increased expressio n of CD95 antigen in activated CD8(+) T cells. Opposite evolution of t hese molecular regulators of apoptosis was reflected by the presence o f 10-25% of apoptotic lymphocytes with fragmented DNA, as shown by bot h in situ nick translation and electrophoresis, Normalization of Bcl-2 expression was progressive over several months but still lower than i n uninfected allograft recipients, These results suggest that the init ial evolution of CMV infection in allograft recipients resembles acute viral infection in immuno-competent hosts, Conversely, we showed that overexpression of Bcl-2 protein in lymphocytes from uninfected allogr aft recipients, and culture of unstimulated normal lymphocytes with 0. 5 mu g/ml cyclosporine led to an increase in the expression of intrace llular Bcl-2, This up-regulation of Bcl-2 protein by cyclosporine sugg ests the acquisition of resistance to apoptosis. Thus, the reversion o f balance between T cell death and survival after acute CMV infection might be impeded by cyclosporine, Combination of CMV latent infection and cyclosporine therapy appears therefore critical to shift the homeo static maintenance of the peripheral lymphocyte compartment toward per sistingly high numbers of CD8(+) T cells.