title: Interleukin 2 receptor targeted fusion toxin (DAB486-IL-2) treatment blocks diabetogenic autoimmunity in non-obese diabetic mice.
abstract: Insulin-dependent diabetes mellitus (IDDM) is strikingly similar in the non-obese diabetic (NOD) mouse and humans. In IDDM, the systematic autoimmune destruction of insulin-producing beta cells within the pancreas is dependent on autoreactive T cells. This autoimmune process can be accelerated by transferring spleen cells from diabetic donors into irradiated syngeneic NOD mice. In a previous study we established that interleukin 2 receptor (IL 2R)-bearing cells propagated from pre-diabetic NOD mice promote IDDM. Therefore, we reasoned that specific elimination of IL 2R+ T cells should abort the diabetogenic process. T cell expressing IL 2R can be selectively destroyed with a diphtheria toxin-related IL 2 fusion protein (DAB486-IL-2). We set DAB486-IL-2 the challenging task of preventing fulminant IDDM accelerated by the adoptive transfer of diabetic spleen cells. Eight weeks after the adoptive transfer only 10% and 20% of NOD mice treated with 10 and 5 micrograms/day of DAB486-IL-2, respectively, became diabetic while 100% control mice (vehicle buffer) became diabetic within 5 weeks. A dose of 1 microgram/day of DAB486-IL-2 had no protective effect. Although the protection conferred by DAB486-IL-2 is not permanent, it is maintained for at least 4 weeks following cessation of treatment. Furthermore, even though these NOD mice do eventually become diabetic, the tempo of expression and severity of diabetes, as assessed by the level of hyperglycemia, is dramatically reduced. Although histologic examination of pancreas revealed minimal degree of mononuclear infiltrate within the islets in both groups, the vehicle control mice had fewer islets per section indicating many islets had already been destroyed. In addition, spleen cells from diabetic NOD mice which were pre-treated with DAB486-IL-2 (10 micrograms/day) for 1 week lost their ability to transfer disease. Taken together, these studies strongly support the concept that IL 2R-bearing T cells are essential for the induction of IDDM and suggest that DAB486-IL-2 would be a promising therapeutic approach in the treatment of human IDDM.
authors.affiliation: Department of Medicine, Beth Israel Hospital, Boston, MA.
authors.forename: A
authors.initials: A
authors.lastname: Pacheco-Silva
authors.forename: M G
authors.initials: MG
authors.lastname: Bastos
authors.forename: R A
authors.initials: RA
authors.lastname: Muggia
authors.forename: O
authors.initials: O
authors.lastname: Pankewycz
authors.forename: J
authors.initials: J
authors.lastname: Nichols
authors.forename: J R
authors.initials: JR
authors.lastname: Murphy
authors.forename: T B
authors.initials: TB
authors.lastname: Strom
authors.forename: V E
authors.initials: VE
authors.lastname: Rubin-Kelley
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D004167:Diphtheria Toxin / Q000494:pharmacology* / Q000627:therapeutic use; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D015375:Receptors, Interleukin-2 / Q000032:analysis*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*
chemical_list: C054780:DAB(486)-interleukin 2; D004167:Diphtheria Toxin; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins