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Murine cytomegalovirus reactivation concomitant with acute graft-versus-host disease is controlled by antibodies
Martina Seefried, … , Michael Mach, Thomas H. Winkler
Martina Seefried, … , Michael Mach, Thomas H. Winkler
Published January 31, 2023
Citation Information: JCI Insight. 2023;8(5):e149648. https://doi.org/10.1172/jci.insight.149648.
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Research Article Hematology Immunology

Murine cytomegalovirus reactivation concomitant with acute graft-versus-host disease is controlled by antibodies

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Abstract

Reactivation of human cytomegalovirus (HCMV) from latency is a frequent complication following hematopoietic stem cell transplantation (HSCT). The development of acute graft-versus-host disease (GVHD) is a significant risk factor for HCMV disease. Using a murine GVHD model in animals latently infected with murine CMV (MCMV), we studied preventive and therapeutic interventions in this high-risk scenario of HSCT. Mice latently infected with MCMV experienced reactivated MCMV and developed disseminated MCMV infection concomitant with the manifestations of GVHD. Dissemination was accompanied by accelerated mortality. We demonstrate that MCMV reactivation and dissemination was modulated by MCMV-specific antibodies, thus demonstrating in vivo protective activity of antiviral antibodies. However, the efficacy of serum therapy required repetitive doses of high-titer immune serum secondary to the shortened serum half-life of IgG in animals with GVHD. In a complementary approach, treatment of GVHD by adoptive transfer of donor-derived Tregs facilitated production of MCMV-specific antibodies from newly developing donor-derived B cells. Together, our findings strongly suggest that antibodies play a major role in controlling recurrent MCMV infection that follows GVHD, and they argue for reassessing the potential of antibody treatments as well as therapeutic strategies that enhance de novo antibody development against HCMV.

Authors

Martina Seefried, Nadine Hundhausen, Irena Kroeger, Maike Büttner-Herold, Petra Hoffmann, Matthias Edinger, Evelyn Ullrich, Friederike Berberich-Siebelt, William J. Britt, Michael Mach, Thomas H. Winkler

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Figure 1

GVHD results in recurrent infection in MCMV-infected BMT recipients.

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GVHD results in recurrent infection in MCMV-infected BMT recipients.
MCM...
MCMV-infected BALB/c mice were lethally irradiated and received 5 × 106 T cell-depleted bone marrow cells (BM) ± 6 × 105 to 8 × 105 T lymphocytes from C57BL/6 donors. (A) Bioluminescence imaging of 5 mice per group at 7, 14, 21, and 28 days after BMT. (B) MCMV viral load in mice transplanted with BM (red square) or BM + T cells (red triangle) 25 days after BMT. Median values are depicted as horizontal bars and detection limit as dashed lines. Representative data from 3 experiments. (C) Survival curve of 12–15 infected recipients per group transplanted with BM (red squares) or BM + T cells (red triangles). For comparison of survival, 13 uninfected recipients per group were transplanted in parallel with BM (black squares) or BM + T cells (black triangles). MCMV-infected mice that received BM + T cells showed significantly accelerated mortality compared with uninfected recipients receiving BM + T cells. ***P < 0.001; log-rank test. Results of 2 independent experiments were combined. (D) IHC stainings of sections from rectum (1 and 2) and liver (3 and 4) from BALB/c infected mice 30 days after transplantation without (1 and 3) or with (2 and 4) GVHD. Immediate-early protein 1 (IE) protein from MCMV was detected in the nucleus of infected cells, as labeled by the arrows. (E) Quantification of IE+ nuclei in liver and rectum of transplanted mice. (F) Double stainings of rectum of GVHD mice for glial fibrillary acidic protein (GFAP) in blue and MCMV IE protein in brown showing colocalization as labelled by the arrows.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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