title: Interleukin-2 fusion protein (DAB389IL-2) selectively targets activated human peripheral blood and lamina propria lymphocytes.
abstract: Activated mucosal T lymphocytes correlate with the intestinal inflammation of inflammatory bowel disease. Activated T cells elaborate interferon-gamma (IFN-gamma) and express high-affinity interleukin-2 (IL-2) receptors. The IL-2/diphtheria toxin fusion protein (DAB389IL-2) has been shown to specifically kill high affinity IL-2 receptor-bearing cells. We tested whether DAB389IL-2 could specifically target activated lamina propria lymphocytes. Lymphocytes were activated in vitro with phytohemagglutinin and IL-2 for 24-48 hr. Toxin efficacy was determined by the [14C]leucine incorporation, IFN-gamma ELISA, and flow cytometry. DAB389IL-2 (10(-11) M) inhibited protein synthesis by 80% in activated lamina propria lymphocytes. This inhibition was blocked by coculture of either excess IL-2 or a nonfunctional IL-2 diphtheria toxin mutant protein. DAB389IL-2 (10(-12) M) also significantly reduced the numbers of activated helper T cells and IFN-gamma levels in 24-hr cultures. DAB389IL-2 specifically targets activated IL-2 receptor-positive lamina propria lymphocytes and is a potential new therapeutic agent for patients with active inflammatory bowel disease.
authors.affiliation: Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital, Boston, Massachusetts, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bousvaros
authors.forename: A C
authors.initials: AC
authors.lastname: Stevens
authors.forename: T B
authors.initials: TB
authors.lastname: Strom
authors.forename: J
authors.initials: J
authors.lastname: Murphy
authors.forename: J T
authors.initials: JT
authors.lastname: Lamont
mesh_terms: D004167:Diphtheria Toxin / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D000922:Immunotoxins / Q000494:pharmacology*; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology; D008213:Lymphocyte Activation; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D004167:Diphtheria Toxin; D007166:Immunosuppressive Agents; D000922:Immunotoxins; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox