title: Synergistic enhancement of cell-mediated immunity by interleukin-12 plus interleukin-2: basis for therapy of cutaneous T cell lymphoma.
abstract: Cutaneous T cell lymphoma is a clonally derived, skin-invasive malignancy of CD4+ T lymphocytes with the phenotype of mature helper T cells. Previous work has demonstrated that the Sézary form, or typically leukemic form of cutaneous T cell lymphoma, is characterized by prominent immunologic defects, including depressed cell-mediated immunity associated with marked defects in the production of interleukin-12 and other type 1 helper T cell cytokines. Recent clinical trials with recombinant human interleukin-12 for cutaneous T cell lymphoma have demonstrated that it is a potent therapeutic agent, which induces cytotoxic T cell responses. Nevertheless, a high rate of refractoriness to recombinant human interleukin-12 occurred in these studies that may be related to the downmodulation of interleukin-12 receptor expression by chronic interleukin-12 use. In an effort to enhance the overall response rate and to overcome the refractoriness to recombinant human interleukin-12 therapy, we studied the immunologic effects in vitro of adding interleukin-2 to interleukin-12 as a model to achieve these goals. We examined the stimulation of interferon-gamma production, natural killer cell activity and interleukin-12 receptor expression by T cells of cutaneous T cell lymphoma patients. The addition of interleukin-12 to cutaneous T cell lymphoma patient peripheral blood cells resulted in the production of interferon-gamma (mean = 7914 pg per ml +/- 2161, n = 15) as did interleukin-2 alone (mean = 7222 pg per ml +/- 2228, n = 15). Importantly, the addition of interleukin-2 to the interleukin-12 synergistically enhanced the levels of interferon-gamma produced (mean = 16 792 pg per ml +/- 2492 n = 15) (p <0.01). Similarly, addition of interleukin-2 to interleukin-12 synergistically enhanced both the natural killer cell activity of 15 cutaneous T cell lymphoma patients as well as T cell surface interleukin-12 receptor expression in comparison with the effects of interleukin-12 or interleukin-2 alone. Thus, interleukin-2 plus interleukin-12 unequivocally produces the synergistic enhancement of multiple parameters of cell-mediated immunity as well as upmodulating interleukin-12 receptor expression; this indicates that protocols combining these two potent immune enhancing cytokines may have added therapeutic benefit for cutaneous T cell lymphoma.
authors.affiliation: Department of Dermatology, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Zaki
authors.forename: Maria
authors.initials: M
authors.lastname: Wysocka
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Everetts
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Wang
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Alain H
authors.initials: AH
authors.lastname: Rook
mesh_terms: D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D007155:Immunologic Factors / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000502:physiology; D009000:Monocytes / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D053707:Receptors, Interleukin-12; D012751:Sezary Syndrome / Q000097:blood / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D013601:T-Lymphocytes / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D007155:Immunologic Factors; D007376:Interleukin-2; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D007371:Interferon-gamma