Interactions involving cyclosporine A, interleukin-6, and Epstein-Barr virus lead to the promotion of B-cell lymphoproliferative disease.
Post-transplant patients undergoing prolonged Cyclosporine A (CsA) immunosuppressive therapy were reported to have an increased incidence of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. EBV-infected B cells cultured with CsA demonstrated increased EBV B-cell out-growth as compared to those cultured without CsA. Peripheral blood mononuclear cells (PBMC), following infection with EBV and CsA treatment, demonstrated increased IL-6 activity in the culture supernatant. The induction of IL-6 appeared to differ within the various lymphocyte populations. In monocytes and B cells, IL-6 expression was preferentially induced by EBV, and initiated by the binding of the two major virion glycoproteins, gp350 and gp220, to CD21, or a CD21-like receptor. Expression of IL-6 in T cells appeared to be due mainly to CsA. B cells also expressed IL-6 following EBV exposure, but not following CsA treatment. EBY-immortalized B-cell lines cultured with CsA exhibited both an increased number of cells expressing viral lytic-cycle antigens and increased amounts of lytic-cycle proteins. IL-6, which was induced by CsA in PBMC, was also capable of inducing the lytic viral cycle in several EBV-immortalized cells. When IL-6 was expressed, it was shown to act as an autocrine growth factor for B cells and to inhibit the immune system allowing for the promotion of B-cell tumors by impairing lymphokine-activated killer cells. Thus CsA treatment, in promoting both increased numbers of lytic EBV B cells and expression of the EBV paracrine growth factor, IL-6, within the microenvironment of EBV B:T cell and EBV B:monocyte interactions, may lead to increased EBV B-cell immortalization and ultimately result in the promotion of B-cell lymphomas in immunosuppressed patients.
Tanner
J E
JE
Laboratory of Virology, Children's Hospital of Eastern Ontario, nd Ottawa, Canada.
Alfieri
C
C
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D003043:Cocarcinogenesis; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005814:Genes, Viral; D006566:Herpesviridae Infections; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008223:Lymphoma / Q000209:etiology / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000276:immunology / Q000821:virology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011183:Postoperative Complications / Q000276:immunology / Q000821:virology; D014180:Transplantation; D014412:Tumor Virus Infections; D014764:Viral Proteins / Q000502:physiology; D014775:Virus Activation / Q000187:drug effects
D007166:Immunosuppressive Agents; D015850:Interleukin-6; D009363:Neoplasm Proteins; D014764:Viral Proteins; D016572:Cyclosporine