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Stem cells translational medicine2016; 5(8); 1026-1035; doi: 10.5966/sctm.2015-0341

Engineered Mesenchymal Cells Improve Passive Immune Protection Against Lethal Venezuelan Equine Encephalitis Virus Exposure.

Abstract: : Mesenchymal stromal cells (MSCs) are being exploited as gene delivery vectors for various disease and injury therapies. We provide proof-of-concept that engineered MSCs can provide a useful, effective platform for protection against infectious disease. Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne pathogen affecting humans and equines and can be used in bio-warfare. No licensed vaccine or antiviral agent currently exists to combat VEEV infection in humans. Direct antibody administration (passive immunity) is an effective, but short-lived, method of providing immediate protection against a pathogen. We compared the protective efficacy of human umbilical cord perivascular cells (HUCPVCs; a rich source of MSCs), engineered with a transgene encoding a humanized VEEV-neutralizing antibody (anti-VEEV), to the purified antibody. In athymic mice, the anti-VEEV antibody had a half-life of 3.7 days, limiting protection to 2 or 3 days after administration. In contrast, engineered HUCPVCs generated protective anti-VEEV serum titers for 21-38 days after a single intramuscular injection. At 109 days after transplantation, 10% of the mice still had circulating anti-VEEV antibody. The mice were protected against exposure to a lethal dose of VEEV by an intramuscular pretreatment injection with engineered HUCPVCs 24 hours or 10 days before exposure, demonstrating both rapid and prolonged immune protection. The present study is the first to describe engineered MSCs as gene delivery vehicles for passive immunity and supports their utility as antibody delivery vehicles for improved, single-dose prophylaxis against endemic and intentionally disseminated pathogens. Direct injection of monoclonal antibodies (mAbs) is an important strategy to immediately protect the recipient from a pathogen. This strategy is critical during natural outbreaks or after the intentional release of bio-weapons. Vaccines require weeks to become effective, which is not practical for first responders immediately deployed to an infected region. However, mAb recipients often require booster shots to maintain protection, which is expensive and impractical once the first responders have been deployed. The present study has shown, for the first time, that mesenchymal stromal cells are effective gene delivery vehicles that can significantly improve mAb-mediated immune protection in a single, intramuscular dose of engineered cells. Such a cell-based delivery system can provide extended life-saving protection in the event of exposure to biological threats using a more practical, single-dose regimen.
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Publication Date: 2016-06-22 PubMed ID: 27334491PubMed Central: PMC4954456DOI: 10.5966/sctm.2015-0341Google Scholar: Lookup
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  • Comparative Study
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research study demonstrates how genetically engineered cells from the human umbilical cord can provide long-lasting protection against lethal exposure to Venezuelan equine encephalitis virus. The results offer potential implications for developing protection methods against infectious diseases, especially in instances of bio-warfare.

Background and Aim of Study

  • Venezuelan equine encephalitis virus (VEEV) is a potentially lethal mosquito-borne pathogen that can affect both humans and horses.
  • As yet, no approved vaccine or antiviral agent is available to combat VEEV infection in humans.
  • This research aimed to investigate the effectiveness of Mesenchymal stromal cells (MSCs) as gene delivery vectors for disease protection, specific to VEEV.

Approach and Findings

  • The researchers used human umbilical cord perivascular cells (HUCPVCs), a rich source of MSCs. These cells were engineered with a gene encoding a humanized antibody capable of neutralizing VEEV.
  • Compared to the purified antibody, these engineered HUCPVCs generated protective anti-VEEV serum levels for 21-38 days after a single intramuscular injection, with 10% of mice having circulating anti-VEEV antibodies up to 109 days after transplantation.
  • This contrasts to the direct delivery of the antibody, which had a half-life of 3.7 days, meaning its protective effect only lasted 2 to 3 days post-administration.
  • The mice were effectively protected against lethal doses of VEEV when pre-treated with an intramuscular injection of the engineered HUCPVCs 24 hours or 10 days prior to exposure.

Significance and Implications

  • This research represents the first study demonstrating the effectiveness of engineered MSCs as gene delivery vehicles for passive immunity.
  • As such, these cells hold promise as antibody delivery vehicles for improving prophylaxis against endangered and deliberately disseminated pathogens, offering extended protection or even potentially life-saving effects.
  • This strategy could be particularly important for providing immediate protection during natural outbreaks or bio-weapon release events, offsetting the impracticalities and costs associated with regular injections of monoclonal antibodies (mAbs).
  • Applications could extend to first responders and those deployed to infected regions, who require immediate, long-lasting protection against infectious diseases.

Cite This Article

APA
Braid LR, Hu WG, Davies JE, Nagata LP. (2016). Engineered Mesenchymal Cells Improve Passive Immune Protection Against Lethal Venezuelan Equine Encephalitis Virus Exposure. Stem Cells Transl Med, 5(8), 1026-1035. https://doi.org/10.5966/sctm.2015-0341

Publication

Stem cells translational medicine
ISSN: 2157-6564
NlmUniqueID: 101578022
Country: England
Language: English
Volume: 5
Issue: 8
Pages: 1026-1035

Researcher Affiliations

Braid, Lorena R
  • Bio-Threat Defence Section, Defence Research and Development Canada, Suffield Research Centre, Ralston, Alberta, Canada Aurora BioSolutions Inc., Medicine Hat, Alberta, Canada.
Hu, Wei-Gang
  • Bio-Threat Defence Section, Defence Research and Development Canada, Suffield Research Centre, Ralston, Alberta, Canada wei-gang.hu@drdc-rddc.gc.ca.
Davies, John E
  • Institute of Biomaterials and Bioengineering, University of Toronto, Toronto, Ontario, Canada Tissue Regeneration Therapeutics, Inc., Toronto, Ontario, Canada.
Nagata, Les P
  • Bio-Threat Defence Section, Defence Research and Development Canada, Suffield Research Centre, Ralston, Alberta, Canada.

MeSH Terms

  • Animals
  • Antibodies, Monoclonal, Humanized / biosynthesis
  • Antibodies, Monoclonal, Humanized / genetics
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Neutralizing / biosynthesis
  • Antibodies, Neutralizing / genetics
  • Antibodies, Neutralizing / immunology
  • Cells, Cultured
  • Encephalitis Virus, Venezuelan Equine / immunology
  • Encephalitis Virus, Venezuelan Equine / pathogenicity
  • Encephalomyelitis, Venezuelan Equine / immunology
  • Encephalomyelitis, Venezuelan Equine / prevention & control
  • Encephalomyelitis, Venezuelan Equine / virology
  • Female
  • Genetic Therapy / methods
  • Genotype
  • Half-Life
  • Host-Pathogen Interactions
  • Humans
  • Injections, Intramuscular
  • Mesenchymal Stem Cells / immunology
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / virology
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phenotype
  • Protein Stability
  • Transfection
  • Umbilical Cord / cytology
  • Viral Vaccines / administration & dosage
  • Viral Vaccines / genetics
  • Viral Vaccines / immunology
  • Viral Vaccines / pharmacokinetics

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