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PLoS Pathog. 2015 Jul 16;11(7):e1005049. doi: 10.1371/journal.ppat.1005049. eCollection 2015 Jul.

Evaluating Human T-Cell Therapy of Cytomegalovirus Organ Disease in HLA-Transgenic Mice.

Author information

1
Department of Internal Medicine III, Hematology and Oncology, University Hospital of Regensburg, Regensburg, Germany; Regensburg Center of Interventional Immunology, University of Regensburg, Regensburg, Germany; Department of Internal Medicine III, Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
2
Department of Internal Medicine III, Hematology and Oncology, University Hospital of Regensburg, Regensburg, Germany; Department of Internal Medicine III, Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
3
Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
4
Department of Internal Medicine III, Hematology and Oncology, University Hospital of Regensburg, Regensburg, Germany; Regensburg Center of Interventional Immunology, University of Regensburg, Regensburg, Germany.
5
Department of Internal Medicine III, Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Abstract

Reactivation of human cytomegalovirus (HCMV) can cause severe disease in recipients of hematopoietic stem cell transplantation. Although preclinical research in murine models as well as clinical trials have provided 'proof of concept' for infection control by pre-emptive CD8 T-cell immunotherapy, there exists no predictive model to experimentally evaluate parameters that determine antiviral efficacy of human T cells in terms of virus control in functional organs, prevention of organ disease, and host survival benefit. We here introduce a novel mouse model for testing HCMV epitope-specific human T cells. The HCMV UL83/pp65-derived NLV-peptide was presented by transgenic HLA-A2.1 in the context of a lethal infection of NOD/SCID/IL-2rg-/- mice with a chimeric murine CMV, mCMV-NLV. Scenarios of HCMV-seropositive and -seronegative human T-cell donors were modeled by testing peptide-restimulated and T-cell receptor-transduced human T cells, respectively. Upon transfer, the T cells infiltrated host tissues in an epitope-specific manner, confining the infection to nodular inflammatory foci. This resulted in a significant reduction of viral load, diminished organ pathology, and prolonged survival. The model has thus proven its potential for a preclinical testing of the protective antiviral efficacy of HCMV epitope-specific human T cells in the evaluation of new approaches to an immunotherapy of CMV disease.

PMID:
26181057
PMCID:
PMC4504510
DOI:
10.1371/journal.ppat.1005049
[Indexed for MEDLINE]
Free PMC Article

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