Antagonizing the α4β1 integrin, but not α4β7, inhibits leukocytic infiltration of the central nervous system in rhesus monkey experimental autoimmune encephalomyelitis.
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 α(4) integrins expressed by T lymphocytes. The α(4)β(1) integrin mediates migration of memory T lymphocytes into the CNS, whereas the α(4)β(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 α(4)β(7) integrin exclusively would affect migration of T lymphocytes into the CNS of primates. The effects of the dual α(4)β(1) and α(4)β(7) antagonist natalizumab were compared with those of the α(4)β(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 α(4)β(7) integrin in each animal for the duration of the investigation. These results demonstrate that blocking α(4)β(7) exclusively does not inhibit immune surveillance of the CNS in primates.
Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands. haanstra@bprc.nl
Krista G
KG
Haanstra
Sam O
SO
Hofman
Dave M
DM
Lopes Estêvão
Erwin L A
EL
Blezer
Jan
J
Bauer
Li-Li
LL
Yang
Tim
T
Wyant
Vilmos
V
Csizmadia
Bert A
BA
't Hart
Eric R
ER
Fedyk
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects*; D002464:Cell Migration Inhibition / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007157:Immunologic Surveillance / Q000187:drug effects; D007275:Injections, Intravenous; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008253:Macaca mulatta; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000008:administration & dosage / Q000276:immunology; D000069442:Natalizumab; D009928:Organ Specificity; D010919:Placebos; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
D061067:Antibodies, Monoclonal, Humanized; D039041:Integrin alpha4beta1; D063308:Myelin-Oligodendrocyte Glycoprotein; D000069442:Natalizumab; D010919:Placebos; D020033:Protein Isoforms; D011994:Recombinant Proteins; C543529:vedolizumab