Claudin-1 induced sealing of blood-brain barrier tight junctions ameliorates chronic experimental autoimmune encephalomyelitis

In experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), loss of the blood-brain barrier (BBB) tight junction (TJ) protein claudin-3 correlates with immune cell infiltration into the CNS and BBB leakiness. Here we show that sealing BBB TJs by ectopic tetracycline-regulated expression of the TJ protein claudin-1 in Tie-2 tTA//TRE-claudin-1 double transgenic C57BL/6 mice had no influence on immune cell trafficking across the BBB during EAE and furthermore did not influence the onset and severity of the first clinical disease episode. However, expression of claudin-1 did significantly reduce BBB leakiness for both blood borne tracers and endogenous plasma proteins specifically around vessels expressing claudin-1. In addition, mice expressing claudin-1 exhibited a reduced disease burden during the chronic phase of EAE as compared to control littermates. Our study identifies BBB TJs as the critical structure regulating BBB permeability but not immune cell trafficking into CNS during EAE, and indicates BBB dysfunction is a potential key event contributing to disease burden in the chronic phase of EAE. Our observations suggest that stabilizing BBB barrier function by therapeutic targeting of TJs may be beneficial in treating MS, especially when anti-inflammatory treatments have failed.

TET inducible expression of the α4β7-integrin ligand MAdCAM-1 on the blood-brain barrier does not influence the immunopathogenesis of experimental autoimmune encephalomyelitis

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.

Vorsorglicher Rechtsschutz. Vorsorgliche Massnahmen im internationalen Kontext, offene Fragen im neuen Arrestrecht und Sicherungsmassnahmen der ZPO, mit Beiträgen von Dr. Isabelle Chabloz, Dr. Richard Gassmann, PD Dr. Pascal Grolimund, Dr. Jürg Roth, Prof. Dr. Daniel Staehelin

Am 9. September 2011 führte das Institut für Verfahrensrecht und Internationales Privatrecht (CIVPRO) der Universität Bern in bewährter Zusammenarbeit mit der schweizerischen SchKG-Vereinigung die zweite Schweizer Tagung für Internationales Zivilverfahrensrecht durch. Im Mittelpunkt der Tagung standen vorsorgliche Massnahmen im internationalen Kontext vor dem Hintergrund der neuesten Entwicklungen, namentlich (aber nicht nur) des neuen Lugano-Übereinkommens. Der Tagungsband enthält die auf den Vorträgen basierenden, überarbeiteten und erweiterten Beiträge namhafter Autorinnen und Autoren zum vorsorglichen Rechtsschutz im neuen IZPR (Pascal Grolimund). Besondere Aufmerksamkeit gilt dem neuen Arrestrecht sowohl im als auch ausserhalb des Anwendungsbereichs des Lugano-Übereinkommens (Richard Gassmann und Jürg Roth). Ebenso enthält der Band Beiträge zu den Sicherungsmassnahmen in der Realvollstreckung (Daniel Staehelin) sowie zur Anerkennung ausländischer vorsorglicher Massnahmen (Isabelle Chabloz).