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

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.

Humanized NOG mice as a model for tuberculosis vaccine‐induced immunity: a comparative analysis with the mouse and guinea pig models of tuberculosis

“…Humanized mice are better suited to study infection with human‐restricted pathogens and the immune responses against them than other small animal models such as mice and rats, which have been traditionally used as hosts to study disease pathogenesis . Accordingly several human‐trophic viruses including human immunodeficiency virus type‐1, Epstein–Barr virus, Kaposi's sarcoma‐associated herpesvirus, herpes simplex virus, human cytomegalovirus, hepatitis C virus and Dengue virus, as well as bacterial pathogens such as Mycobacterium tuberculosis and Salmonella typhi , have been studied in humanized mice primarily to investigate disease pathogenesis and the innate and adaptive immune responses that these pathogens evoke post infection . Additionally, a variety of antigens and human vaccine preparations have been shown to induce innate and adaptive T‐cell‐mediated immune responses in humanized mice, including dinitrophenyl, keyhole limpet haemocyanin antigen, toxic shock syndrome toxin 1, tetanus toxoid, DTaP vaccine and hepatitis B virus vaccine .…”

Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses in HLA-A2.1/Kb Transgenic Mice

“…However, it remains unclear whether the HTNV-NP FA9 epitope can induce a strong CD8 + T-cell immunity against HTNV infection in vivo. Humanized mice, which are mice engrafted with human tissue and/or are engineered to express human genes, are considered powerful tools for studying species-restricted pathogen that can induce in vivo human immunity (29)(30)(31). Therefore, a "humanized" HLA-A2.1/K b transgenic (Tg) mouse model that expresses a chimeric monochain of HLA-A*02 infected with HTNV would be an ideal virus replication model to explore the effect of in vivo responses primed by epitope FA9.…”

Editorship for Medical Microbiology and Immunology: the baton has been passed on

“…In the past five decades, when the field has been divided into bacteriology, parasitology and virology, it occurred that one of the editors-in-chief was a virologist who was either more engaged in clinical virology (Richard Haas) or more in basic virus research (Rudolf Rott). Having worked as a clinical virologist, I was honoured to continue that tradition, which I am now going to pass on to my colleague Matthias J. Reddehase.Being one of the leading scientists in CMV basic research focusing on virus-host interactions in preclinical models of hematopoietic cell transplantation [2][3][4][5][6][7][8][9][10]. Matthias J. Reddehase is more than capable of filling my position as editor of this magazine.…”

“…Being one of the leading scientists in CMV basic research focusing on virus-host interactions in preclinical models of hematopoietic cell transplantation [2][3][4][5][6][7][8][9][10]. Matthias J. Reddehase is more than capable of filling my position as editor of this magazine.…”