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Trigger-dependent differences determine therapeutic outcome in murine primary hemophagocytic lymphohistiocytosis |
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| Authors: | Ruth Gather Peter Aichele Nadja Goos Jan Rohr Hanspeter Pircher Tamara Kögl Robert Zeiser Hartmut Hengel Annette Schmitt-Gräff Casey Weaver Stephan Ehl |
| Affiliation: | 1. Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Institute for Immunodeficiency, Medical Center, University of Freiburg, Germany Faculty of Biology, University of Freiburg, Germany;2. Faculty of Medicine, Institute of Immunology, Medical Center, University of Freiburg, Germany;3. Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Institute for Immunodeficiency, Medical Center, University of Freiburg, Germany;4. Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Institute for Immunodeficiency, Medical Center, University of Freiburg, Germany Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Medical Center, University of Freiburg, Germany;5. Department of Hematology and Oncology, Medical Center, University of Freiburg, Germany;6. Faculty of Medicine, Institute of Virology, Medical Center, University of Freiburg, Germany;7. Department of General Pathology, Faculty of Medicine, Institute of Pathology, Medical Center, University of Freiburg, Germany;8. Department of Immunology, School of Medicine, University of Alabama, Birmingham, AL, USA |
| Abstract: | Familial hemophagocytic lymphohistiocytosis (FHL) is a hyperinflammatory syndrome affecting patients with genetic cytotoxicity defects. Perforin-deficient (PKO) mice recapitulate the full clinical picture of FHL after infection with lymphocytic choriomeningitis virus (LCMV). Hyperactivated CD8+ T cells and IFN-γ have been identified as the key drivers of FHL and represent targets for therapeutic interventions. However, the response of patients is variable. This could be due to trigger-dependent differences in pathogenesis, which is difficult to address in FHL patients, since the trigger frequently escapes detection. We established an alternative FHL model using intravenous infection of PKO mice with murine CMV (MCMV)Smith. PKO mice developed acute FHL after both infections and fulfilled HLH diagnostic criteria accompanied by excessive IFN-γ production by disease-inducing T cells, that enrich in the BM. However, direct comparison of the two infection models disclosed trigger-dependence of FHL progression and revealed a higher contribution of CD4 T cells and NK cells to IFN-γ production after MCMV infection. Importantly, therapeutic intervention by IFN-γ neutralization or CD8+ T-cell depletion had less benefit in MCMV-triggered FHL compared to LCMV-triggered FHL, likely due to MCMV-induced cytopathology. Thus, the context of the specific triggering viral infection can impact the success of targeted immunotherapeutic HLH control. |
| Keywords: | hemophagocytic lymphohistiocytosis immunodeficiency immunotherapy lymphocyte cytotoxicity viral infection |