Document 0279
 DOCN  M95A0279
 TI    Implication of cyclosporine in up-regulation of Bcl-2 expression and
       maintenance of CD8 lymphocytosis in cytomegalovirus-infected allograft
       recipients.
 DT    9510
 AU    Labalette M; Queyrel V; Masy E; Noel C; Pruvot FR; Dessaint JP; Service
       d'Immunologie, Faculte de Medecine, Hopital Calmette,; Centre
       Hospitalier et Universitaire de Lille, France.
 SO    Transplantation. 1995 Jun 27;59(12):1714-23. Unique Identifier :
       AIDSLINE MED/95328140
 AB    T cell homeostasis and CD4/CD8 ratios are normally reestablished by
       apoptotic clearance of activated T cells after immune stimulation. In
       allograft recipients with cytomegalovirus infection, CD8 lymphocytosis
       persists after negativation of viral cultures, contrary to
       immunocompetent hosts. We investigated the expression of Bcl-2 protein,
       an intracellular suppressor of apoptosis, and of CD95 (APO-1/Fas), a
       membrane inducer of apoptosis, in peripheral blood lymphocytes from 45
       solid organ recipients. During the viremic phase of CMV infection, we
       found absence or diminished expression of Bcl-2 protein and increased
       expression of CD95 antigen in activated CD8+ T cells. Opposite evolution
       of these molecular regulators of apoptosis was reflected by the presence
       of 10-25% of apoptotic lymphocytes with fragmented DNA, as shown by both
       in situ nick translation and electrophoresis. Normalization of Bcl-2
       expression was progressive over several months but still lower than in
       uninfected allograft recipients. These results suggest that the initial
       evolution of CMV infection in allograft recipients resembles acute viral
       infection in immunocompetent hosts. Conversely, we showed that
       overexpression of Bcl-2 protein in lymphocytes from uninfected allograft
       recipients, and culture of unstimulated normal lymphocytes with 0.5
       micrograms/ml cyclosporine led to an increase in the expression of
       intracellular Bcl-2. This up-regulation of Bcl-2 protein by cyclosporine
       suggests the acquisition of resistance to apoptosis. Thus, the reversion
       of 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
       homeostatic maintenance of the peripheral lymphocyte compartment toward
       persistingly high numbers of CD8+ T cells.
 DE    Adolescence  Adult  Antigens, Surface/BIOSYNTHESIS  Apoptosis/DRUG
       EFFECTS/PHYSIOLOGY  Cyclosporine/*ADVERSE EFFECTS  Cytomegalovirus
       Infections/*BLOOD/*COMPLICATIONS/IMMUNOLOGY  CD4-CD8 Ratio  CD8-Positive
       T-Lymphocytes/*IMMUNOLOGY/METABOLISM/VIROLOGY  Female  Human  Kidney
       Transplantation/*ADVERSE EFFECTS/IMMUNOLOGY  Liver
       Transplantation/*ADVERSE EFFECTS/IMMUNOLOGY  Lymphocyte
       Subsets/IMMUNOLOGY  Lymphocyte Transformation/IMMUNOLOGY
       Lymphocytosis/CHEMICALLY INDUCED/METABOLISM/*VIROLOGY  Male  Middle Age
       Protein p53/BIOSYNTHESIS  Proto-Oncogene Proteins/*PHYSIOLOGY  Support,
       Non-U.S. Gov't  Up-Regulation (Physiology)/*DRUG EFFECTS  JOURNAL
       ARTICLE

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