title: IL-12/IL-23p40 Is Highly Expressed in Secondary Lymphoid Organs and the CNS during All Stages of EAE, but Its Deletion Does Not Affect Disease Perpetuation.
abstract: BACKGROUND
  Interleukin (IL)-12 and IL-23 are heterodimers that share the p40 subunit, and both cytokines are critical in the differentiation of T helper (Th)1 and Th17 cells, respectively. Th1 and Th17 effector cells have been implicated in the pathogenesis of experimental autoimmune encephalitis (EAE), an animal model of the human central nervous system (CNS) autoimmune demyelinating disorder multiple sclerosis (MS). However, ustekinumab, a monoclonal antibody (mAb) against p40 failed to show efficacy over placebo in a phase II clinical trial in patients with MS. The role of p40 in initial T cell priming and maintenance in secondary lymphoid tissues is not yet well understood.
  
  
  METHODS
  Active EAE was induced in the B6.129-IL12b strain of p40eYFP reporter mice (yet40 mice), and Th1 and Th17 polarized cells were adoptively transferred into p40-deficient mice. Cellular subsets were phenotyped by multi-parameter flow cytometry, and p40 tissue expression was identified by confocal microscopy.
  
  
  RESULTS
  We show that yet40 mice are susceptible to EAE, and that p40 is highly expressed in secondary lymphoid organs and the CNS during all stages of the disease. Interestingly, p40 expression in the recipient is not required for EAE induction after adoptive transfer of activated and differentiated encephalitogenic Th1 and Th17 cells into p40-deficient mice. Peripheral antagonism of T helper cell trophic factors critical for the differentiation and maintenance of Th1 and Th17 cells ameliorates EAE, indicating that p40 may play a critical role in the induction of CNS autoimmunity but not in its perpetuation.
  
  
  CONCLUSIONS
  Our data may explain why ustekinumab did not ameliorate paraclinical and clinical disease in patients with MS. In patients with already established disease, activated antigen-specific encephalitogenic CD4+ T cells are likely already differentiated, and are not dependent on p40 for maintenance. A clinical trial of longer duration with anti-p40 mAbs or other forms of pharmacological p40 antagonism, or sequential anti-p40 therapy following T cell depletion may show a benefit by affecting de novo generation of autoimmune T cells.
authors: Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States of America.
authors: Petra D
authors: PD
authors: Cravens
authors: Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States of America.
authors: Rehana Z
authors: RZ
authors: Hussain
authors: Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States of America.
authors: William A
authors: WA
authors: Miller-Little
authors: Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States of America.
authors: Li-Hong
authors: LH
authors: Ben
authors: Department of Neurology, University of Michigan, Ann Arbor, MI, United States of America.
authors: Benjamin M
authors: BM
authors: Segal
authors: Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States of America.
authors: Emily
authors: E
authors: Herndon
authors: Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States of America.|Neurology Section, VA North Texas Health Care System, Medical Service, Dallas, TX, United States of America.|Department of Neurology, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors: Olaf
authors: O
authors: Stüve
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism*; D008198:Lymph Nodes / Q000276:immunology*; D051379:Mice; D013154:Spleen / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000637:transplantation; D058504:Th17 Cells / Q000276:immunology / Q000637:transplantation; D015854:Up-Regulation
chemical_list: D053762:Interleukin-12 Subunit p40