| 159-Use of human MonoMac6 cells for development of in vitro assay predictive of adjuvant safety in vivo. | |
| | |
MedLine Citation:
|
PMID: 22609036 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
|
Subunit vaccines composed of recombinant or purified antigens have a good safety record but are poorly immunogenic and require adjuvants to activate innate immunity and facilitate antigen specific immune response. Of the many adjuvant formulations that are under development, very few are licensed mainly due to concerns about adverse side effects. The goal of our study was to develop in vitro assays that could predict toxicity of adjuvants in vivo. Pro-inflammatory cytokines IL-β, IL-6, TNF-α, and IL-8 were measured in human primary monocytes and the monocytoid cell line, MonoMac 6 (MM6), activated with a panel of TLR agonists or with adjuvants. A 0.5EU/ml dose of Standard for endotoxin (previously shown to provide a margin between pyrogenic and non-pyrogenic substances in rabbits) was used as a comparator to establish a "safety threshold". FSL-1, Pam3CSK4, flagellin, and R848 TLR agonists but not Alum, MF59, Poly I:C, or MPL adjuvants induced cytokines in MM6 cells above the safety threshold. To confirm the predictive value of the in vitro assays, FSL-1 and flagellin were injected intramuscularly into New Zealand White (NZW) rabbits. Both TLR agonists induced fever within 6-8h post-injection followed 24-48h later by increased C reactive protein (CRP). Importantly, an early peak in plasma prostaglandin E2 (PGE(2)) levels preceded rise in body temperature. In vitro production of PGE(2) in monocytes and MM6 cells was found following treatments with various TLR agonists but not with alum, MF59, MPL, or Poly I:C adjuvants. Together, our studies demonstrated a strong correlation between production of pro-inflammatory cytokines above a "safety threshold" and production of PGE(2)in vitro and an increase in body temperature in rabbits. The developed human cell based assays could provide an important tool for early screening of new molecular moieties and adjuvant formulations and may assist in selection of safer products. |
| | |
Authors:
|
Marina Zaitseva; Tatiana Romantseva; Ksenia Blinova; Joel Beren; Lev Sirota; Debbie Drane; Hana Golding |
Related Documents
:
|
22772316 - Reduced expression of psoriasin in human airway cystic fibrosis epithelia. 1483396 - Planar and vertical signals in the induction and patterning of the xenopus nervous system. 22517116 - Dendritic cell-derived tumor necrosis factor α modifies airway epithelial cell responses. 2041456 - Evidence of immunosuppression in the genetically epilepsy-prone rat. 18056756 - Modulation of established murine collagen-induced arthritis by a single inoculation of ... 12388806 - Natural killer cell activation after infection with lactate dehydrogenase-elevating virus. |
Publication Detail:
|
Type: JOURNAL ARTICLE Date: 2012-5-15 |
Journal Detail:
|
Title: Vaccine Volume: - ISSN: 1873-2518 ISO Abbreviation: - Publication Date: 2012 May |
Date Detail:
|
Created Date: 2012-5-21 Completed Date: - Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 8406899 Medline TA: Vaccine Country: - |
Other Details:
|
Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
|
Copyright © 2012. Published by Elsevier Ltd. |
Affiliation:
|
Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, MD 20892, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Antigenic and immunogenic properties of recombinant hemagglutinin proteins from H1N1 A/Brisbane/59/0...
Next Document: An international opinion research survey of the etiology, diagnosis, therapy and outcome of Kienböc...