dc.contributor.author | Kalailingam, P | |
dc.contributor.author | Mohd-Kahliab, K-H | |
dc.contributor.author | Ngan, SC | |
dc.contributor.author | Iyappan, R | |
dc.contributor.author | Melekh, E | |
dc.contributor.author | Lu, T | |
dc.contributor.author | Zien, GW | |
dc.contributor.author | Sharma, B | |
dc.contributor.author | Guo, T | |
dc.contributor.author | MacNeil, AJ | |
dc.contributor.author | MacPherson, RE | |
dc.contributor.author | Tsiani, EL | |
dc.contributor.author | O'Leary, DD | |
dc.contributor.author | Lim, KL | |
dc.contributor.author | Su, IH | |
dc.contributor.author | Gao, Y-G | |
dc.contributor.author | Richards, AM | |
dc.contributor.author | Kalaria, RN | |
dc.contributor.author | Chen, CP | |
dc.contributor.author | McCarthy, NE | |
dc.contributor.author | Sze, SK | |
dc.date.accessioned | 2024-01-02T14:37:31Z | |
dc.date.available | 2023-10-31 | |
dc.date.available | 2024-01-02T14:37:31Z | |
dc.date.issued | 2023-11-16 | |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/93254 | |
dc.description.abstract | Aging results from the accumulation of molecular damage that impairs normal biochemical processes. We previously reported that age-linked damage to amino acid sequence NGR (Asn-Gly-Arg) results in "gain-of-function" conformational switching to isoDGR (isoAsp-Gly-Arg). This integrin-binding motif activates leukocytes and promotes chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy mitigates lifespan reduction of Pcmt1-/- mouse. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1-/- and naturally aged WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1 mg/kg) was sufficient to significantly reduce isoDGR-protein levels in body tissues, decreased pro-inflammatory cytokine concentrations in blood plasma, improved cognition/coordination metrics, and extended the average lifespan of Pcmt1-/- mice. Mechanistically, isoDGR-mAb mediated immune clearance of damaged isoDGR-proteins via antibody-dependent cellular phagocytosis (ADCP). These results indicate that immunotherapy targeting age-linked protein damage may represent an effective intervention strategy in a range of human degenerative disorders. | en_US |
dc.format.extent | e18526 - ? | |
dc.language | eng | |
dc.publisher | Wiley | en_US |
dc.relation.ispartof | EMBO Mol Med | |
dc.rights | Attribution 3.0 United States | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | * |
dc.subject | Pcmt1 | en_US |
dc.subject | immunotherapy | en_US |
dc.subject | inflammation | en_US |
dc.subject | isoDGR | en_US |
dc.subject | lifespan | en_US |
dc.title | Immunotherapy targeting isoDGR-protein damage extends lifespan in a mouse model of protein deamidation | en_US |
dc.type | Article | en_US |
dc.identifier.doi | 10.15252/emmm.202318526 | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37971164 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published online | en_US |
dcterms.dateAccepted | 2023-10-31 | |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |