Possible association of the immunosuppressive and B cell lymphoma-promoting properties of cyclosporine.
Central to the immunosuppressive properties of cyclosporine is a drug imposed blockade of the interleukin-2 gene activation. As IL-6 stimulates antigen-activated T cells to release IL-2, we examined the influence of CsA on IL-6 gene expression and IL-6-supported T cell proliferation. Northern blot analysis revealed that CsA failed to abolish IL-6 gene expression in mitogen-activated peripheral blood mononuclear cells. In fact, increased IL-6 gene transcription and increased release of IL-6 bioactivity were detected using mitogen-activated PBMCs cultured with CsA doses (200-800 ng/ml) only slightly in excess of the minimal antiproliferative dose. CsA completely abrogated the IL-6-stimulated proliferative responses of macrophage-depleted T cells stimulated with polyvalent anti-CD3 monoclonal antibodies. It is interesting that CsA-treated patients evidence an increased incidence of polyclonal lymphoproliferative disorders and B cell lymphomas. As IL-6 fosters B cell activation and growth of EBV-transformed B cells, excessive CsA doses may support development of EBV-transformed B cell lymphomas via superinduction of the IL-6 gene.
Walz
G
G
Charles A. Dana Research Institute, Boston, Massachusetts 02215.
Zanker
B
B
Melton
L B
LB
Suthanthiran
M
M
Strom
T B
TB
D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D001402:B-Lymphocytes; D017252:CD3 Complex; D003524:Cyclosporins / Q000009:adverse effects*; D005784:Gene Amplification / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008223:Lymphoma / Q000209:etiology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D003524:Cyclosporins; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell