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Parameters determining the efficacy of adoptive CD8 T-cell therapy of cytomegalovirus infection

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Abstract

Reactivation of latent cytomegalovirus (CMV) in the transient state of immunodeficiency after hematopoietic cell transplantation (HCT) is the most frequent and severe viral complication endangering leukemia therapy success. By infecting the bone marrow (BM) stroma of the transplantation recipient, CMV can directly interfere with BM repopulation by the transplanted donor-derived hematopoietic cells and thus delay immune reconstitution of the recipient. Cytopathogenic virus spread in tissues can result in CMV disease with multiple organ manifestations of which interstitial pneumonia is the most feared. There exists a ‘window of risk’ between hematoablative treatment and reconstitution of antiviral immunity after HCT, whereby timely reconstitution of antiviral CD8 T cells is a recognized positive prognostic parameter for the control of reactivated CMV infection and prevention of CMV disease. Supplementation of endogenous reconstitution by adoptive cell transfer of ‘ready-to-go’ effector and/or memory virus epitope-specific CD8 T cells is a therapeutic option to bridge the ‘window of risk.’ Preclinical research in murine models of CMV disease has been pivotal by providing ‘proof of concept’ for a benefit from CD8 T-cell therapy of HCT-associated CMV disease (reviewed in Holtappels et al. Med Microbiol Immunol 197:125–134, 2008). Here, we give an update of our previous review with focus on parameters that determine the efficacy of adoptive immunotherapy of CMV infection by antiviral CD8 T cells in the murine model.

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Acknowledgments

We thank all current and former members of our group for their contributions made over the past 12 years as well as our collaboration partners Ulrich H. Koszinowski (Munich, Germany), Dirk H. Busch (Munich, Germany), Ann B. Hill and Michael Munks (Portland, Oregon), and Stipan Jonjic (Rijeka, Croatia) for advice, discussion, and tools. This work was funded by the Deutsche Forschungsgemeinschaft, SFB 490, and represents a cooperation between individual projects E3 ‘Persistence of murine cytomegalovirus after modulation of the CD8 T-cell immunome’ (S.E., J.P., D. G.-M., D.T., and R.H.) and E4 ‘Antigen presentation under the influence of murine cytomegalovirus immune evasion proteins’ (A.F., K.F, and M.J.R). K.M.G. and M.J.R. were also supported by a grant from the Deutsche Forschungsgemeinschaft, Clinical Research Group KFO 183, individual project TP8 ‘Establishment of challenge models for optimizing the immunotherapy of cytomegalovirus disease’. J.K.B. received a scholarship from the ‘Forschungszentrum Immunologie’ (FZI) of the Johannes Gutenberg University Mainz, University Medical Center, in the Gender Equality Program.

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  1. Institute for Virology, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Strasse 67, Hochhaus am Augustusplatz, 55131, Mainz, Germany

    Stefan Ebert, Jürgen Podlech, Dorothea Gillert-Marien, Kerstin M. Gergely, Julia K. Büttner, Annette Fink, Kirsten Freitag, Doris Thomas, Matthias J. Reddehase & Rafaela Holtappels

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Ebert, S., Podlech, J., Gillert-Marien, D. et al. Parameters determining the efficacy of adoptive CD8 T-cell therapy of cytomegalovirus infection. Med Microbiol Immunol 201, 527–539 (2012). https://doi.org/10.1007/s00430-012-0258-x

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