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.
Highlights
Reactivation of latent human cytomegalovirus (HCMV) infection is a frequent complication in patients after allogeneic hematopoietic stem cell transplantation (HSCT)
NSG/HHD mice are deficient in natural killer (NK) cell activity due to lack of the interleukin-2 receptor (IL-2R) common γ chain (CD132) causing deficient IL-2/4/7/9/15/21 signaling [28,29], murine CMV (mCMV)-Δm157 was chosen as parental virus to formally exclude activation of the Ly49H+ subset of murine NK cells by m157-Ly49H interaction, a feature that is only valid in the C57BL/6 genetic background and might interfere with a broader application of the model
The model is based on HLA-A2.1 transgenic NSG/HHD mice that are first infected with chimeric virus mCMV-NLV and are subsequently infused with human T cells specific for the immunodominant HLA-A2.1-restricted NLV epitope of HCMV pp65 (UL83)
Summary
Reactivation of latent human cytomegalovirus (HCMV) infection is a frequent complication in patients after allogeneic hematopoietic stem cell transplantation (HSCT). The feasibility of HCMV-specific immunotherapy is currently impeded in clinical routine due to technical restrictions. It has limitations in case the donor is HCMV-seronegative or carries only low frequencies of HCMV-specific memory T cells. In this situation, transduction of non-cognate T cells with virus specific T-cell receptors (TCR) may be an alternative means to transfer HCMV-specific T-cell function into HSCT recipients [15,16]. To allow for a more reliable analysis of HCMV immunotherapies (e.g. adoptive T-cell therapy, therapeutic vaccination) animal models that mimic HCMV infections are needed
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