title: Addition of histamine to interleukin 2 treatment augments type 1 T-cell responses in patients with melanoma in vivo: immunologic results from a randomized clinical trial of interleukin 2 with or without histamine (MP 104).
abstract: OBJECTIVE
  Preclinical investigations suggest that histamine dihydrochloride (HDC) protects T cells and natural killer cells from inhibition by monocyte-derived reactive oxygen metabolites and synergizes with interleukin (IL) 2 in inducing T-cell activation. Here, we investigate whether this mechanism is operational in patients with melanoma treated with HDC as an adjunct to IL-2.
  
  
  METHODS
  Melanoma patients having liver metastases were treated with IL-2 with or without HDC within a randomized, multicenter, phase III trial. The effect of HDC on type 1 and type 2 T-cell cytokine production was investigated in peripheral blood samples from 19 patients with the use of intracellular cytokine flow cytometry. Melanoma-specific T-cell responses were analyzed in eight HLA-A2-positive patients.
  
  
  RESULTS
  Frequencies of CD3+ T cells producing IFN-gamma (type 1 T cells) in response to phorbol myristate acetate/ionomycin increased (median, 1.8-fold) in patients receiving IL-2 plus HDC but not in those receiving IL-2 alone (P < 0.01 for comparison between arms). In contrast, the number of IL-13-producing type 2 T cells that increased in patients after treatment with IL-2 was not modulated by HDC. Melanoma- and tyrosinase-specific IFN-gamma and IL-13-producing T cells were detected in two of four HLA-A2-positive patients with melanoma following treatment with HDC + IL-2.
  
  
  CONCLUSIONS
  Treatment of patients with stage IV melanoma with HDC in combination with IL-2 increases type 1 T-cell responses and may promote induction of melanoma-specific T cells. These effects are of relevance for tumor immunotherapy and provide a potential mechanism for the clinical efficacy of HDC added to IL-2.
authors.affiliation: Medizinische Klinik III, Hämatologie, Onkologie und Transfusionsmedizin, Charité Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Asemissen
authors.forename: Carmen
authors.initials: C
authors.lastname: Scheibenbogen
authors.forename: Anne
authors.initials: A
authors.lastname: Letsch
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Hellstrand
authors.forename: Fredrik
authors.initials: F
authors.lastname: Thorén
authors.forename: Kurt
authors.initials: K
authors.lastname: Gehlsen
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmittel
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thiel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keilholz
mesh_terms: D017252:CD3 Complex / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D006632:Histamine / Q000627:therapeutic use*; D006650:Histocompatibility Testing; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism / Q000627:therapeutic use*; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008213:Lymphocyte Activation; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009362:Neoplasm Metastasis; D010455:Peptides / Q000737:chemistry; D017382:Reactive Oxygen Species; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D017252:CD3 Complex; D016207:Cytokines; D018793:Interleukin-13; D007376:Interleukin-2; D010455:Peptides; D017382:Reactive Oxygen Species; D006632:Histamine; D007371:Interferon-gamma