title: IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity.
abstract: CD4+CD25+Foxp3+ regulatory T (Treg) cells have been implicated in the lack of effective antitumor immunity. Denileukin diftitox (DAB(389)IL-2), a fusion protein of interleukin 2 (IL-2) and diphtheria toxin, provides a means of targeting Treg cells. In this study, we examined (1) the effect of denileukin diftitox on the deletion of Treg cells in various lymphoid compartments and (2) the dose scheduling of denileukin diftitox in combination with a recombinant poxviral vaccine to enhance antigen-specific immune responses. Treg cells in spleen, peripheral blood, and bone marrow of normal C57BL/6 mice were variously reduced after a single intraperitoneal injection of denileukin diftitox; the reduction was evident within 24 hours and lasted approximately 10 days. Injection of denileukin diftitox 1 day before vaccination enhanced antigen-specific T-cell responses above levels induced by vaccination alone. These studies show for the first time in a murine model (1) the differential effects of denileukin diftitox on Treg cells in different cellular compartments, (2) the advantage of combining denileukin diftitox with a vaccine to enhance antigen-specific T-cell immune responses, (3) the lack of inhibition by denileukin diftitox of host immune responses directed against a live viral vector, and (4) the importance of dose scheduling of denileukin diftitox when used in combination with a vaccine.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mary T
authors.initials: MT
authors.lastname: Litzinger
authors.forename: Romaine
authors.initials: R
authors.lastname: Fernando
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Grosenbach
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: Claudia
authors.initials: C
authors.lastname: Palena
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects*; D000922:Immunotoxins / Q000494:pharmacology; D009980:Influenza A virus / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology*; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011212:Poxviridae / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D004167:Diphtheria Toxin; D000922:Immunotoxins; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D014765:Viral Vaccines; C078456:denileukin diftitox