title: TET inducible expression of the α4β7-integrin ligand MAdCAM-1 on the blood-brain barrier does not influence the immunopathogenesis of experimental autoimmune encephalomyelitis.
abstract: Inhibiting the α4 subunit of the integrin heterodimers α4β1 and α4β7 with the mab natalizumab is an effective treatment of multiple sclerosis (MS). Which of the two α4 heterodimers is involved in disease pathogenesis has, however, remained controversial. Whereas the development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, is ameliorated in β7-integrin-deficient C57BL/6 mice, neutralizing antibodies against the β7-integrin subunit or the α4β7-integrin heterodimer fail to interfere with EAE pathogenesis in the SJL mouse. To facilitate α4β7-integrin-mediated immune-cell trafficking across the blood-brain barrier (BBB), we established transgenic C57BL/6 mice with endothelial cell-specific, inducible expression of the α4β7-integrin ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 using the tetracycline (TET)-OFF system. Although TET-regulated MAdCAM-1 induced α4β7-integrin mediated interaction of α4β7(+) /α4β1(-) T cells with the BBB in vitro and in vivo, it failed to influence EAE pathogenesis in C57BL/6 mice. TET-regulated MAdCAM-1 on the BBB neither changed the localization of central nervous system (CNS) perivascular inflammatory cuffs nor did it enhance the percentage of α4β7-integrin(+) inflammatory cells within the CNS during EAE. In conclusion, our study demonstrates that ectopic expression of MAdCAM-1 at the BBB does not increase α4β7-integrin-mediated immune cell trafficking into the CNS during MOG(aa35-55)-induced EAE.
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: Axinia
authors.initials: A
authors.lastname: Döring
authors.forename: Friederike
authors.initials: F
authors.lastname: Pfeiffer
authors.forename: Matthias
authors.initials: M
authors.lastname: Meier
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Dehouck
authors.forename: Silke
authors.initials: S
authors.lastname: Tauber
authors.forename: Urban
authors.initials: U
authors.lastname: Deutsch
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009088:Mucoproteins; D010641:Phenotype; D013752:Tetracycline / Q000494:pharmacology
chemical_list: D015815:Cell Adhesion Molecules; D016023:Integrins; D008024:Ligands; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; C071777:integrin alpha4beta7; D013752:Tetracycline