title: Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and interleukin-10.
abstract: Limited response to idiotype vaccination in patients with myeloma suggests that there is a need to develop better immunotherapy strategies. It has been determined that the number of high-potency CMRF44+CD14-CD19- dendritic cells (DCs) in the blood of patients with myeloma (range, 0.03%-0.8% of mononuclear cells [MNCs]; n = 26) was not significantly different from that in controls (range, 0.05%-0.8% of MNCs; n = 13). Expression of the costimulatory molecules CD80 and CD86 on DCs from these patients (mean, 29%+/-17% of MNCs and 85%+/-10% of MNCs, respectively) was also normal (mean, 29%+/-17% and 86%+/-16% of MNCs, respectively). Up-regulation of CD80 expression in response to stimulation by human huCD40LT + interleukin (IL)-2 was significantly reduced on the DCs of patients with myeloma during stable disease (n = 9) and was absent during progressive stages (n = 7) of disease. Similar effects were seen on B cells but not on monocytes of the same group of patients. CD86 expression on DCs was high before (86%) and after (89%) stimulation. Inhibition of CD80 up-regulation was neutralized by either anti-transforming growth factor (TGF)-beta1 or anti-IL-10. Up-regulation of CD80 on DCs of controls was inhibited by rTGF-beta1 in a dose-dependent manner. Serum TGF-beta1 and IL-10 levels were normal in most patients studied. Cytoplasmic TGF-beta1 was increased in plasma cells during progressive disease. Thus patients with myeloma have normal numbers of DCs, but CD80 expression may fail to be up-regulated in the presence of huCD40LT because of tumor-derived TGF-beta1 or IL-10. Autologous high-potency DCs may have to be tested for CD80 up-regulation and biologically modified ex vivo before idiotype priming for immunotherapy.
authors.affiliation: Institute of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. rbrown@haem.rpa.cs.nsw.gov.au
authors.forename: R D
authors.initials: RD
authors.lastname: Brown
authors.forename: B
authors.initials: B
authors.lastname: Pope
authors.forename: A
authors.initials: A
authors.lastname: Murray
authors.forename: W
authors.initials: W
authors.lastname: Esdale
authors.forename: D M
authors.initials: DM
authors.lastname: Sze
authors.forename: J
authors.initials: J
authors.lastname: Gibson
authors.forename: P J
authors.initials: PJ
authors.lastname: Ho
authors.forename: D
authors.initials: D
authors.lastname: Hart
authors.forename: D
authors.initials: D
authors.lastname: Joshua
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D051940:B7-2 Antigen; D001772:Blood Cell Count; D001773:Blood Cells / Q000378:metabolism; D023201:CD40 Ligand / Q000494:pharmacology*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D007376:Interleukin-2 / Q000494:pharmacology; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D009000:Monocytes / Q000378:metabolism; D009101:Multiple Myeloma / Q000097:blood / Q000276:immunology* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000473:pathology; D010950:Plasma Cells / Q000737:chemistry / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D053773:Transforming Growth Factor beta1
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D007376:Interleukin-2; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D023201:CD40 Ligand