title: Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes.
abstract: Celiac disease (CD) is an autoimmune inflammatory disease with a relatively high prevalence especially in the western hemisphere. A strong genetic component is involved in the pathogenesis of CD with virtually all individuals that develop the disease carrying HLA-DQ alleles that encode specific HLA-DQ2 or HLA-DQ8 heterodimers. Consumption of cereals rich in gluten triggers a chronic intestinal inflammation in genetically susceptible individuals leading to the development of CD. Emerging evidence has implicated a central role for IL-15 in the orchestration and perpetuation of inflammation and tissue destruction in CD. Therefore, IL-15 represents an attractive target for development of new therapies for CD. Transgenic mice that express human IL-15 specifically in enterocytes (T3(b)-hIL-15 Tg mice) develop villous atrophy and severe duodeno-jejunal inflammation with massive accumulation of NK-like CD8(+) lymphocytes in the affected mucosa. We used these mice to demonstrate that blockade of IL-15 signaling with an antibody (TM-beta1) that binds to murine IL-2/IL-15Rbeta (CD122) leads to a reversal of the autoimmune intestinal damage. The present study, along with work of others, provides the rationale to explore IL-15 blockade as a test of the hypothesis that uncontrolled expression of IL-15 is critical in the pathogenesis and maintenance of refractory CD.
authors.affiliation: Department of Allergy and Immunology, Tokyo Metropolitan Institute of Medical Science, Tokyo, 113-8613, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Watanabe
authors.forename: Noriko
authors.initials: N
authors.lastname: Sato
authors.forename: Pin-Yu
authors.initials: PY
authors.lastname: Perera
authors.forename: Lyvouch
authors.initials: L
authors.lastname: Filkoski
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: Takachika
authors.initials: T
authors.lastname: Hiroi
authors.forename: Liyanage P
authors.initials: LP
authors.lastname: Perera
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002446:Celiac Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D020895:Enterocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D019409:Interleukin-15 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*; D053646:Interleukin-2 Receptor beta Subunit / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; C508022:Il2rb protein, mouse; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011994:Recombinant Proteins