title: Either interleukin-12 or interferon-gamma can correct the dendritic cell defect induced by transforming growth factor beta in patients with myeloma.
abstract: The poor response to immunotherapy in patients with multiple myeloma (MM) indicates that a better understanding of any defects in the immune response in these patients is required before effective therapeutic strategies can be developed. Recently we reported that high potency (CMRF44(+)) dendritic cells (DC) in the peripheral blood of patients with MM failed to significantly up-regulate the expression of the B7 co-stimulatory molecules, CD80 and CD86, in response to an appropriate signal from soluble trimeric human CD40 ligand. This defect was caused by transforming growth factor beta(1) (TGFbeta(1)) and interleukin (IL)-10, produced by malignant plasma cells, and the defect was neutralized in vitro with anti-TGFbeta(1). As this defect could impact on immunotherapeutic strategies and may be a major cause of the failure of recent trials, it was important to identify a more clinically useful agent that could correct the defect in vivo. In this study of 59 MM patients, the relative and absolute numbers of blood DC were only significantly decreased in patients with stage III disease and CD80 up-regulation was reduced in both stage I and stage III. It was demonstrated that both IL-12 and interferon-gamma neutralized the failure to stimulate CD80 up-regulation by huCD40LT in vitro. IL-12 did not cause a change in the distribution of DC subsets that were predominantly myeloid (CD11c+ and CDw123-) suggesting that there would be a predominantly T-helper cell type response. The addition of IL-12 or interferon-gamma to future immunotherapy trials involving these patients should be considered.
authors.affiliation: Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia. rbrown@haem.rpa.cs.nsw.gov.au
authors.forename: Ross
authors.initials: R
authors.lastname: Brown
authors.forename: Allan
authors.initials: A
authors.lastname: Murray
authors.forename: Belinda
authors.initials: B
authors.lastname: Pope
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sze
authors.forename: John
authors.initials: J
authors.lastname: Gibson
authors.forename: P Joy
authors.initials: PJ
authors.lastname: Ho
authors.forename: Derek
authors.initials: D
authors.lastname: Hart
authors.forename: Doug
authors.initials: D
authors.lastname: Joshua
mesh_terms: D018122:B7-1 Antigen / Q000276:immunology; D023201:CD40 Ligand / Q000627:therapeutic use; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D007371:Interferon-gamma / Q000008:administration & dosage* / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000276:immunology; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma