Trigger‐dependent differences determine therapeutic outcome in murine primary hemophagocytic lymphohistiocytosis

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.

Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity

“…Perforin-deficient (PKO) mice fail to control infection with lymphocytic choriomeningitis virus (LCMV), murine cytomegalovirus (MCMV), Theiler's Murine Encephalomyelitis or ectromelia virus (39)(40)(41)(42)(43). However, apart from these prominent examples, cytotoxicity is redundant for the elimination of a large number of other murine host-specific viruses (pneumonia virus of mice, murine gammaherpesvirus 68, JHMV strain of mouse hepatitis virus) (44)(45)(46) and viruses not restricted to mice (Vesicular stomatitis virus, Semliki Forest virus, vaccinia virus, cowpox virus, influenza virus, respiratory syncytial virus, Rotavirus) (39,43,(47)(48)(49).…”

Immunopathology caused by impaired CD8+ T‐cell responses

“…But why does impaired lymphocyte cytotoxicity lead to uncontrolled immune responses, hyperinflammation, and severe immunopathology? Preclinical animal models were of great value for the current understanding of HLH pathogenesis [19][20][21][22][23]. After infection with LCMV as trigger, perforin-deficient mice recapitulate the clinical picture of FHL, as seen in patients [20][21][22].…”

“…Preclinical animal models were of great value for the current understanding of HLH pathogenesis [19][20][21][22][23]. After infection with LCMV as trigger, perforin-deficient mice recapitulate the clinical picture of FHL, as seen in patients [20][21][22]. Typically, LCMV infection induces a strong CD8 + Tcell response in WT mice, which eliminates the virus within 8-10 days.…”

Is neutralization of IFN‐γ sufficient to control inflammation in HLH?

“…Finally, the particular biology of LCMV infection may overemphasize the role of IFN‐γ in murine HLH. Indeed, a recent study revealed that anti‐IFN‐γ treatment attenuated disease in LCMV‐infected, but not murine cytomegalovirus‐infected, perforin‐deficient mice 20 …”

“…Indeed, a recent study revealed that anti-IFN-γ treatment attenuated disease in LCMV-infected, but not murine cytomegalovirus-infected, perforin-deficient mice. 20 Taking these and other factors into consideration, 21 Kim E. Nichols https://orcid.org/0000-0002-5581-6555…”