title: Sézary syndrome patients demonstrate a defect in dendritic cell populations: effects of CD40 ligand and treatment with GM-CSF on dendritic cell numbers and the production of cytokines.
abstract: Sézary syndrome (SzS) is an advanced form of cutaneous T-cell lymphoma associated with involvement of the peripheral blood by malignant T cells. The disease is defined by impaired cell-mediated immunity and the production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), possibly as a result of deficient IL-12 production. To understand the mechanism of this impairment, we examined the composition and function of dendritic cells and monocytes in the blood of SzS patients with different levels of peripheral blood tumor burden. Consistent with our previous observations, numbers of monocytes in SzS patients were comparable to numbers observed in healthy donors. In contrast, decreased IL-12 production correlated with a decrease in the numbers of CD11c(+) dendritic cells, which was particularly profound among patients with medium (20%-50% circulating malignant T cells) and high (more than 50% circulating malignant T cells) tumor burden. Furthermore, CD123(+) dendritic cells, major producers of IFN-alpha, were significantly diminished in SzS patients, regardless of the level of tumor burden. Granulocyte macrophage-colony-stimulating factor-treated patients experienced an increase in the number of dendritic cells but not in IFN-alpha or IL-12 production. However, in vitro stimulation of peripheral blood mononuclear cells from SzS patients with rCD40L and IFN-gamma significantly increased the production of IL-12. Thus, our results demonstrate a profound defect in circulating dendritic cells in SzS patients that may contribute to the pathogenesis of the cytokine disorders and to the depressed cellular immunity. Importantly, the ability of rCD40L to potently induce IL-12 production from monocytes and residual dendritic cells of SzS patients could potentially serve as an immune-restorative therapeutic agent.
authors.affiliation: Department of Dermatology, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Wysocka
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Zaki
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
authors.forename: Jihed
authors.initials: J
authors.lastname: Chehimi
authors.forename: Michael
authors.initials: M
authors.lastname: Shapiro
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Everetts
authors.forename: Karen S
authors.initials: KS
authors.lastname: McGinnis
authors.forename: Luis
authors.initials: L
authors.lastname: Montaner
authors.forename: Alain H
authors.initials: AH
authors.lastname: Rook
mesh_terms: D017951:Antigen Presentation; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D039521:CD11c Antigen / Q000032:analysis; D023201:CD40 Ligand / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000145:classification / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007111:Immunity, Cellular; D007153:Immunologic Deficiency Syndromes / Q000209:etiology; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D018664:Interleukin-12 / Q000172:deficiency / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053650:Interleukin-3 Receptor alpha Subunit; D009182:Mycosis Fungoides / Q000097:blood / Q000150:complications / Q000276:immunology / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism; D016185:Receptors, Interleukin-3 / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins; D012751:Sezary Syndrome / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000473:pathology
chemical_list: D018122:B7-1 Antigen; D039521:CD11c Antigen; D016207:Cytokines; C115022:IL3RA protein, human; D016898:Interferon-alpha; D007376:Interleukin-2; D053650:Interleukin-3 Receptor alpha Subunit; D016185:Receptors, Interleukin-3; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor