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Infect Immun. 2017 Aug 18;85(9). pii: e00127-17. doi: 10.1128/IAI.00127-17. Print 2017 Sep.

Genetic Adjuvantation of a Cell-Based Therapeutic Vaccine for Amelioration of Chagasic Cardiomyopathy.

Author information

1
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
2
Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA.
3
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
4
National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, USA.
5
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
6
Laboratorio de Parasitología, Centro de Investigaciones Regionales Dr. Hideyo Noguchi, Universidad Autónoma de Yucatán, Mérida, México.
7
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
8
National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, USA kathrynj@bcm.edu decker@bcm.edu.
9
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA kathrynj@bcm.edu decker@bcm.edu.
10
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.

Abstract

Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi, is a leading cause of heart disease ("chagasic cardiomyopathy") in Latin America, disproportionately affecting people in resource-poor areas. The efficacy of currently approved pharmaceutical treatments is limited mainly to acute infection, and there are no effective treatments for the chronic phase of the disease. Preclinical models of Chagas disease have demonstrated that antigen-specific CD8+ gamma interferon (IFN-γ)-positive T-cell responses are essential for reducing parasite burdens, increasing survival, and decreasing cardiac pathology in both the acute and chronic phases of Chagas disease. In the present study, we developed a genetically adjuvanted, dendritic cell-based immunotherapeutic for acute Chagas disease in an attempt to delay or prevent the cardiac complications that eventually result from chronic T. cruzi infection. Dendritic cells transduced with the adjuvant, an adenoviral vector encoding a dominant negative isoform of Src homology region 2 domain-containing tyrosine phosphatase 1 (SHP-1) along with the T. cruzi Tc24 antigen and trans-sialidase antigen 1 (TSA1), induced significant numbers of antigen-specific CD8+ IFN-γ-positive cells following injection into BALB/c mice. A vaccine platform transduced with the adenoviral vector and loaded in tandem with the recombinant protein reduced parasite burdens by 76% to >99% in comparison to a variety of different controls and significantly reduced cardiac pathology in a BALB/c mouse model of live Chagas disease. Although no statistical differences in overall survival rates among cohorts were observed, the data suggest that immunotherapeutic strategies for the treatment of acute Chagas disease are feasible and that this approach may warrant further study.

KEYWORDS:

Chagas disease; SHP-1; dendritic cell

PMID:
28674032
PMCID:
PMC5563592
DOI:
10.1128/IAI.00127-17
[Indexed for MEDLINE]
Free PMC Article

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