title: Signalling molecules and cytokine production in T cells of multiple myeloma-increased abnormalities with advancing stage.
abstract: T-cell immune dysfunction in patients with malignant tumours has been attributed to the altered expression of components of the T-cell receptor (TCR)/CD3 complex and their associated intracellular protein tyrosine kinases. In this study, four-colour flow cytometry was applied to study the surface bound molecules TCRalphabeta, CD28, CD152 and CD154 involved in T-cell signalling and the signal transduction molecules CD3zeta, p56lck, p59fyn, ZAP-70 and phosphatidyl-inositol-3 kinase (PI3-k) as well as the intracellular cytokines interferon-gamma (IFN-gamma), interleukin (IL)-4 and IL-2 as a functional read-out of non-stimulated and superantigen (staphylococcus enterotoxin B)-stimulated blood T cells of multiple myeloma (MM) patients at different stages of the disease. Multiple abnormalities were demonstrated in the CD4 and CD8 populations, both under non-stimulated and superantigen-stimulated conditions. There was a marked reduction, particular in advanced stage MM, in the proportion of CD4 and CD8 cells expressing CD28, CD152, CD3zeta, p56lck, ZAP-70 and PI3-k. The level of intracellular T-cell cytokines (IFN-gamma, IL-2 and IL-4) was normal or increased in non-stimulated cells but activation-induced cytokine production was impaired. These results illustrated profound and multiple T-cell signalling defects, from the surface and down-stream, consistent with involvement of a master T-cell function, especially in advanced stage MM. These data should be taken into consideration when developing immune-based therapeutic approaches and when applying new emerging technologies that aim to restore T-cell functions.
authors.affiliation: Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Fariba
authors.initials: F
authors.lastname: Mozaffari
authors.forename: Lotta
authors.initials: L
authors.lastname: Hansson
authors.forename: Shahryar
authors.initials: S
authors.lastname: Kiaii
authors.forename: Xiuli
authors.initials: X
authors.lastname: Ju
authors.forename: Eva D
authors.initials: ED
authors.lastname: Rossmann
authors.forename: Hodjattallah
authors.initials: H
authors.lastname: Rabbani
authors.forename: Håkan
authors.initials: H
authors.lastname: Mellstedt
authors.forename: Anders
authors.initials: A
authors.lastname: Osterborg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000941:Antigens / Q000032:analysis*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis; D015415:Biomarkers / Q000032:analysis; D018106:CD28 Antigens / Q000032:analysis; D017252:CD3 Complex / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D018089:Superantigens / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015415:Biomarkers; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D007376:Interleukin-2; D018089:Superantigens; D015847:Interleukin-4; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human