Antagonizing the α4β1 Integrin, but Not α4β7, Inhibits Leukocytic Infiltration of the Central Nervous System in Rhesus Monkey Experimental Autoimmune Encephalomyelitis

被引：61

作者：

Haanstra, Krista G. ^{[1
]}

Hofman, Sam O. ^{[1
]}

Estevao, Dave M. Lopes ^{[1
]}

Blezer, Erwin L. A. ^{[2
]}

Bauer, Jan ^{[3
]}

Yang, Li-Li ^{[4
]}

Wyant, Tim ^{[4
]}

Csizmadia, Vilmos ^{[4
]}

't Hart, Bert A. ^{[1
,5
]}

Fedyk, Eric R. ^{[4
]}

机构：

[1] Biomed Primate Res Ctr, NL-2280 GH Rijswijk, Netherlands

[2] Univ Med Ctr, Image Sci Inst, NL-3584 CX Utrecht, Netherlands

[3] Med Univ Vienna, Ctr Brain Res, A-1090 Vienna, Austria

[4] Millennium Pharmaceut Inc, Discovery Drug Safety Evaluat & Translat Med, Cambridge, MA 02139 USA

[5] Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, NL-9700 AB Groningen, Netherlands

来源：

JOURNAL OF IMMUNOLOGY | 2013年 / 190卷 / 05期

关键词：

MYELIN OLIGODENDROCYTE GLYCOPROTEIN; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; CELL-ADHESION MOLECULE-1; PLACEBO-CONTROLLED TRIAL; NONHUMAN PRIMATE MODELS; ACTIVE CROHNS-DISEASE; BLOOD-BRAIN-BARRIER; T-CELLS; MULTIPLE-SCLEROSIS; HUMANIZED ANTIBODY;

D O I：

10.4049/jimmunol.1202490

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The immune system is characterized by the preferential migration of lymphocytes through specific tissues (i.e., tissue tropism). Tissue tropism is mediated, in part, by the alpha(4) integrins expressed by T lymphocytes. The alpha(4)beta(1) integrin mediates migration of memory T lymphocytes into the CNS, whereas the alpha(4)beta(7) integrin mediates migration preferentially into gastrointestinal tissue. This paradigm was established primarily from investigations in rodents; thus, the objective of this investigation was to determine if blocking the alpha(4)beta(7) integrin exclusively would affect migration of T lymphocytes into the CNS of primates. The effects of the dual alpha(4)beta(1) and alpha(4)beta(7) antagonist natalizumab were compared with those of the alpha(4)beta(7) antagonist vedolizumab on experimental autoimmune encephalomyelitis in the rhesus monkey. Animals received an initial i.v. bolus of placebo, natalizumab (30 mg/kg), or vedolizumab (30 mg/kg) before intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein and then Ab once weekly thereafter. Natalizumab prevented CNS inflammation and demyelination significantly (p < 0.05), compared with time-matched placebo control animals, whereas vedolizumab did not inhibit these effects, despite saturating the alpha(4)beta(7) integrin in each animal for the duration of the investigation. These results demonstrate that blocking alpha(4)beta(7) exclusively does not inhibit immune surveillance of the CNS in primates. The Journal of Immunology, 2013, 190: 1961-1973.

引用

页码：1961 / 1973

页数：13

共 51 条

[1] SURFACE EXPRESSION OF ALPHA-4 INTEGRIN BY CD4 T-CELLS IS REQUIRED FOR THEIR ENTRY INTO BRAIN PARENCHYMA [J].

BARON, JL ;

MADRI, JA ;

RUDDLE, NH ;

HASHIM, G ;

JANEWAY, CA .

JOURNAL OF EXPERIMENTAL MEDICINE, 1993, 177 (01) :57-68

[2] β1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity [J].

Bauer, Martina ;

Brakebusch, Cord ;

Coisne, Caroline ;

Sixt, Michael ;

Wekerle, Hartmut ;

Engelhardt, Britta ;

Faessler, Reinhard .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (06) :1920-1925

[3] Natalizumab and progressive multifocal leucoencephalopathy [J].

Berger, J. R. .

ANNALS OF THE RHEUMATIC DISEASES, 2006, 65 :48-53

[4] Increased numbers of circulating hematopoietic stem/progenitor cells are chronically maintained in patients treated with the CD49d blocking antibody natalizumab [J].

Bonig, Halvard ;

Wundes, Annette ;

Chang, Kai-Hsin ;

Lucas, Sylvia ;

Papayannopoulou, Thalia .

BLOOD, 2008, 111 (07) :3439-3441

[5] The human CMV-UL86 peptide 981-1003 shares a crossreactive T-cell epitope with the encephalitogenic MOG peptide 34-56, but lacks the capacity to induce EAE in rhesus monkeys [J].

Brok, Herbert P. M. ;

Boven, Leonie ;

van Meurs, Marjan ;

de Rosbo, Nicole Kerlero ;

Celebi-Paul, Liesbeth ;

Kap, Yolanda S. ;

Jagessar, Anwar ;

Hintzen, Rogier Q. ;

Keir, Geoff ;

Bajramovic, Jeffrey ;

Ben-Nun, Avraham ;

Bauer, Jan ;

Laman, Jon D. ;

Amor, Sandra ;

't Hart, Bert A. .

JOURNAL OF NEUROIMMUNOLOGY, 2007, 182 (1-2) :135-152

[6] Non-human primate models of multiple sclerosis [J].

Brok, HPM ;

Bauer, J ;

Jonker, M ;

Blezer, E ;

Amor, S ;

Bontrop, RE ;

Laman, JD ;

't Hart, BA .

IMMUNOLOGICAL REVIEWS, 2001, 183 :173-185

[7] Cutting Edge: Natalizumab Blocks Adhesion but Not initial Contact of Human T Cells to the Blood-Brain Barrier In Vivo in an Animal Model of Multiple Sclerosis [J].

Coisne, Caroline ;

Mao, Wenxian ;

Engelhardt, Britta .

JOURNAL OF IMMUNOLOGY, 2009, 182 (10) :5909-5913

[8] Rhesus monkeys are highly susceptible to experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein: characterisation of immunodominant T- and B-cell epitopes [J].

de Rosbo, NK ;

Brok, HPM ;

Bauer, J ;

Kaye, JF ;

't Hart, BA ;

Ben-Nun, A .

JOURNAL OF NEUROIMMUNOLOGY, 2000, 110 (1-2) :83-96

[9] Control of α4β7 Integrin Expression and CD4 T Cell Homing by the β1 Integrin Subunit [J].

DeNucci, Christopher C. ;

Pagan, Antonio J. ;

Mitchell, Jason S. ;

Shimizu, Yoji .

JOURNAL OF IMMUNOLOGY, 2010, 184 (05) :2458-2467

[10] Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: reactivity to the extracellular domain of MOG is directed against three main regions [J].

deRosbo, NK ;

Hoffman, M ;

Mendel, I ;

Yust, I ;

Kaye, J ;

Bakimer, R ;

Flechter, S ;

Abramsky, O ;

Milo, R ;

Karni, A ;

BenNun, A .

EUROPEAN JOURNAL OF IMMUNOLOGY, 1997, 27 (11) :3059-3069

← 1 2 3 4 5 6 →