"Small" Intestinal Immunopathology Plays a "Big" Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor.

Shiv D Kale,Jonathan L Koff,Govindarajan Rajagopalan,Brittney N Mehrkens,Jackie A Fretz,Amy Rizzo,Rachel J Mcneill,Bridget Kastelberg,Saikumar V Karyala,Henry Carnes,Ying Sun,Molly M Stegman,Sheryl Coutermarsh-Ott

doi:10.3389/fimmu.2020.01311

Abstract

Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. As a result, there is no specific treatment available to date for CRS, and it is managed only symptomatically to support the deteriorating organ functions and maintain the blood pressure. Therefore, we used the superantigen-induced CRS model in HLA-DR3 transgenic mice, that closely mimics human CRS, to delineate the immunopathogenesis of CRS as well as to validate a novel treatment for CRS. Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS.

Highlights

With a surge in clinical use of chimeric antigen receptor T cells (CART), T cell agonistic antibodies and immune check point inhibitors, there is a concomitant rise in the incidence of cytokine release syndrome (CRS), a T cell-mediated systemic disease [1]
Given the contrasting roles for IL-17A and IFN-γ in the outcome of CRS, we studied the characteristics of the systemic cytokine/chemokine storm induced by SEB in DR3.WT mice and HLA-DR3 mice lacking these cytokines
The morbidity and mortality associated with CRS following administration of CART therapy, T cell agonistic antibodies, immune check point inhibitors, COVID-19, or other similar conditions is attributed to failure of multiple vital organs mediated by activated T cells and the ensuing cytokine storm [1, 2, 7, 8]

Summary

Introduction

With a surge in clinical use of chimeric antigen receptor T cells (CART), T cell agonistic antibodies and immune check point inhibitors, there is a concomitant rise in the incidence of cytokine release syndrome (CRS), a T cell-mediated systemic disease [1]. In these above therapeutic modalities, T cells get robustly activated by tumor antigens, agonistic antibodies, or by removal of inhibitory signals and produce large amounts of T cell-derived cytokines such as IFN-γ, IL-17, and TNFα. Mortality associated with the ongoing global pandemic coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), is believed to result from serious CRS [7, 8]

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Results

Conclusion