Induction of CD95 upregulation does not render chronic lymphocytic leukemia B-cells susceptible to CD95-mediated apoptosis.
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a progressive accumulation of long-lived and well-differentiated clonal B-lymphocytes in peripheral blood, lymphoid tissue and bone marrow. Although B-CLL pathogenesis is not entirely understood, the progressive increase in lymphocyte counts coupled with the very low proportion of proliferating cells suggests that B-CLL may be primarily determined by defective apoptosis. Consistently, freshly analyzed CLL B-cells express very low levels of membrane CD95, one of the best-known receptors involved in triggering apoptosis. In this study, CD95 upregulation on CLL B-cells was induced by culturing clonal B-cells in the presence of supernatants from preactivated autologous T-lymphocytes. Intracellular cytokine staining of preactivated autologous T-lymphocytes using monoclonal antibodies (moAbs) specific for Th1 or Th2 cytokines, namely interleukin (IL)-2, IL-4, IL-5, IL-10 and interferon (IFN)-gamma, showed these cells to be positive for IL-2 and IFN-gamma. Blocking experiments using moAbs specific for IL-2 and/or IFN-gamma revealed that CD95 upregulation on CLL B-cells was mainly driven by IFN-gamma. However, CD95-expressing CLL B-cells were demonstrated to be resistant to CD95-mediated apoptosis, thus arguing against strategies aimed at exploiting CD95-mediated apoptosis for immunotherapy of B-CLL.
Romano
Ciro
C
Division of Internal Medicine, Allergy and Clinical Immunology, Department of Gerontology, Geriatrics, and Metabolic Diseases, Second University of Naples School of Medicine, Naples, Italy. ciro.romano@unina2.it
De Fanis
Umberto
U
Sellitto
Ausilia
A
Chiurazzi
Federico
F
Guastafierro
Salvatore
S
Giunta
Riccardo
R
Tirelli
Angelo
A
Rotoli
Bruno
B
Lucivero
Giacomo
G
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*
D000970:Antineoplastic Agents; D016207:Cytokines; D019014:fas Receptor; D007371:Interferon-gamma