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

被引：62

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

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