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Abstract Number: 1899

Blockade of Interleukin-33 Signaling Prevents Death in a Mouse Model of Familial Hemophagocytic Lymphohistiocytosis

Julia Rood1, Portia Kreiger2, Erietta Stelekati1, E. John Wherry1 and Edward M. Behrens3, 1Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 2Pathology, Alfred I. duPont Hospital for Children, Wilmington, DE, 3Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: CD8 cells, cytokines and interleukins (IL), Immune Dysregulation, T cells

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Session Information

Session Title: Pediatric Rheumatology - Pathogenesis and Genetics

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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