Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose
Cytokine storm syndromes, such as macrophage activation syndrome and familial hemophagocytic lymphohistiocytosis (FHL), represent important causes of mortality in pediatric rheumatology. Studies of a mouse model of FHL, in which lymphocytic choriomeningitis virus (LCMV) infection of perforin knockout (PKO) mice triggers the disease, have demonstrated that FHL is driven by an excess of LCMV-specific CD8+T cells and their overproduction of interferon-γ (IFNγ). This over-exuberant T cell response is thought to arise from excess antigen stimulation through the T cell receptor (TCR). However, data from our lab and others suggest that other receptors may play an additional role, as mice deficient in both perforin and MyD88, a critical adaptor protein in non-TCR signaling, are protected from FHL.
Interleukin-33 receptor (IL-33R) is one of the receptors upstream of MyD88 and generates pro-inflammatory signals in response to the tissue damage-associated cytokine IL-33. Recent work has suggested that IL-33 signaling is necessary for mounting an effective anti-viral CD8+ T cell response to LCMV in wildtype mice. However, the role of IL-33 signaling in FHL has not been investigated. In this study, we sought to determine whether blockade of IL-33 signaling in the LCMV/PKO model of FHL would sufficiently limit the CD8+T cell response to prevent the development of disease.
Methods
PKO mice were infected i.p. with 2×105 PFU LCMV-Armstrong and received 150 μg i.p. of either IL-33R-blocking antibody or isotype control every 2 days, beginning on day 3 post-infection. Mice were monitored for weight loss, survival, complete blood count, serum cytokines, spleen and liver histology, LCMV titers, frequency of antigen-specific CD8+T cells, and T cell cytokine production.
Results
LCMV-infected PKO mice receiving IL-33R blocking antibody (IL-33RB) showed reduced weight loss (P=0.0170) and highly reduced mortality (HR =11.79, P=0.0021). IL-33R blockade reduced levels of serum IFNγ 16-fold (P=0.0005) and lowered frequencies of IFNγ-producing CD8+ T cells (P=0.0003). Additionally, IL-33RB mice had reduced hepatic parenchymal damage, although leukopenia, anemia, and thrombocytopenia were not improved. Despite the reduced inflammation in IL-33RB mice, they maintained similar frequencies of LCMV-specific CD8+T cells compared to isotype-treated controls and showed equivalent titers of LCMV in the spleen.
Conclusion
IL-33R blockade improves morbidity and mortality in a mouse model of FHL without exacerbating viral infection. Our results identify signaling via the tissue damage-associated cytokine IL-33 as an additional pathway contributing to disease and suggest blockade of this pathway as a viable treatment strategy for FHL.
Disclosure:
J. Rood,
None;
P. Kreiger,
None;
E. Stelekati,
None;
E. J. Wherry,
None;
E. M. Behrens,
Amgen,
2.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/blockade-of-interleukin-33-signaling-prevents-death-in-a-mouse-model-of-familial-hemophagocytic-lymphohistiocytosis/