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  β1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity

Bauer, M., Brakebusch, C., Coisne, C., Sixt, M., Wekerle, H., Engelhardt, B., et al. (2009). β1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity. Proceedings of the National Academy of Sciences of the United States of America, 106(6), 1920-1925. doi:10.1073/pnas.0808909106.

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 Creators:
Bauer, M.1, Author
Brakebusch, C.2, Author
Coisne, C.2, Author
Sixt, M.1, Author
Wekerle, H.3, Author           
Engelhardt, B.3, Author           
Fässler, R.1, Author
Affiliations:
1Max Planck Society, ou_persistent13              
2[Brakebusch, Cord] Univ Copenhagen, Biotech Res & Innovat Ctr, Inst Biomed, DK-2200 Copenhagen, Denmark.; [Coisne, Caroline; Engelhardt, Britta] Univ Bern, Theodor Kocher Inst, CH-3012 Bern, Switzerland., ou_persistent22              
3Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society, ou_1113547              

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Free keywords: EAE; T lymphocyte; mouse genetics
 Abstract: Inhibiting the alpha(4) subunit of the integrin heterodimers alpha(4)beta(1) and alpha(4)beta(7) with the monoclonal antibody natalizumab is an effective treatment for multiple sclerosis (MS). However, the pharmacological action of natalizumab is not understood conclusively. Previous studies suggested that natalizumab inhibits activation, proliferation, or extravasation of inflammatory cells. To specify which mechanisms, cell types, and alpha(4) heterodimers are affected by the antibody treatment, we studied MS-like experimental autoimmune encephalomyelitis (EAE) in mice lacking the beta(1)-integrin gene either in all hematopoietic cells or selectively in T lymphocytes. Our results show that T cells critically rely on beta(1) integrins to accumulate in the central nervous system (CNS) during EAE, whereas CNS infiltration of beta(1)-deficient myeloid cells remains unaffected, suggesting that T cells are the main target of anti-alpha(4)-antibody blockade. We demonstrate that beta(1)-integrin expression on encephalitogenic T cells is critical for EAE development, and we therefore exclude alpha(4)beta(7) as a target integrin of the antibody treatment. T cells lacking beta(1) integrin are unable to firmly adhere to CNS endothelium in vivo, whereas their priming and expansion remain unaffected. Collectively, these results suggest that the primary action of natalizumab is interference with T cell extravasation via inhibition of alpha(4)beta(1) integrins.

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Language(s): eng - English
 Dates: 2009-02-10
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 429907
ISI: 000263252500046
DOI: 10.1073/pnas.0808909106
 Degree: -

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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : PNAS
  Other : Proceedings of the National Academy of Sciences of the USA
  Abbreviation : Proc. Natl. Acad. Sci. U. S. A.
Source Genre: Journal
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Publ. Info: Washington, D.C. : National Academy of Sciences
Pages: - Volume / Issue: 106 (6) Sequence Number: - Start / End Page: 1920 - 1925 Identifier: ISSN: 0027-8424
CoNE: https://pure.mpg.de/cone/journals/resource/954925427230