title: Retinoid-related orphan receptor γ (RORγ) adult induced knockout mice develop lymphoblastic lymphoma.
abstract: RORγ is a nuclear hormone receptor which controls polarization of naive CD4+T-cells into proinflammatory Th17 cells. Pharmacological antagonism of RORγ has therapeutic potential for autoimmune diseases; however, this mechanism may potentially carry target-related safety risks, as mice deficient in Rorc, the gene encoding RORγ, develop T-cell lymphoma with 50% frequency. Due to the requirement of RORγ during development, the Rorc knockout (KO) animals lack secondary lymphoid organs and have a dysregulation in the generation of CD4+ and CD8+ T cells. We wanted to extend the evaluation of RORγ deficiency to address the question whether lymphomas, similar to those observed in the Rorc KO, would develop in an animal with an otherwise intact adult immune system. Accordingly, we designed a conditional RORγ knockout mouse (Rorc CKO) where the Rorc locus could be deleted in adult animals. Based on these studies we can confirm that these animals also develop lymphoma in a similar time frame as embryonic Rorc knockouts. This study also suggests that in animals where the gene deletion is incomplete, the thymus undergoes a rapid selection process replacing Rorc deficient cells with remnant thymocytes carrying a functional Rorc locus and that subsequently, these animals do not develop lymphoblastic lymphoma.
authors: Drug Safety and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, , Pepparedsleden 1, Mölndal 431 83, SE, Sweden. Electronic address: maria.liljevald@astrazeneca.com.
authors: Maria
authors: M
authors: Liljevald
authors: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: Maria
authors: M
authors: Rehnberg
authors: Drug Safety and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, , Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: Magnus
authors: M
authors: Söderberg
authors: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: Marie
authors: M
authors: Ramnegård
authors: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SE.
authors: Jenny
authors: J
authors: Börjesson
authors: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: Donatella
authors: D
authors: Luciani
authors: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: Nina
authors: N
authors: Krutrök
authors: Drug Safety and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, , Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: Lena
authors: L
authors: Brändén
authors: Drug Safety and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, , Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: Camilla
authors: C
authors: Johansson
authors: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SE.
authors: Xiufeng
authors: X
authors: Xu
authors: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SE.
authors: Mikael
authors: M
authors: Bjursell
authors: Drug Safety and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, , Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: Anna-Karin
authors: AK
authors: Sjögren
authors: Drug Safety and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, , Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: Jorrit
authors: J
authors: Hornberg
authors: Drug Safety and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, , Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: Ulf
authors: U
authors: Andersson
authors: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: David
authors: D
authors: Keeling
authors: Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SE, Sweden.
authors: Johan
authors: J
authors: Jirholt
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000628:therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D058504:Th17 Cells / Q000276:immunology
chemical_list: D057132:Nuclear Receptor Subfamily 1, Group F, Member 3
keywords: Adult induced knockout mouse model; Lymphoblastic lymphoma; NHR; RORγ; RORγt; Rorc; Th17 cells