Cytokine profile of macrophage activation syndrome associated with Kawasaki disease

Jinkawa, Asumi; Shimizu, Masaki; Nishida, Keigo; Kaneko, Shuya; Usami, Mihoko; Sakumura, Naoto; Irabu, Hitoshi; Takakuwa, Maiko; Inoue, Natsumi; Mizuta, Mao; Ikawa, Yasuhiro; Fujita, Shuhei; Yachie, Akihiro

doi:10.1016/j.cyto.2019.03.001

Cited by 35 publications

(21 citation statements)

References 22 publications

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“…Nonetheless, our AML xenografts showed undoubted differences from studies of CRS triggered by CD19-CARs in both murine and human disease. We detected a rapid rise in TNFα and elevation of IL2 rather than of IL1 and IL6, a pattern that more closely mimics macrophage activation syndrome (MAS) than T cell-related CRS, 38 although TNFα can also be a component of the pro-inflammatory cascade in severe CRS.…”

Section: Discussionmentioning

confidence: 78%

Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia

Atilla

McKenna

Tashiro

et al. 2020

J Immunother Cancer

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BackgroundC-type lectin-like molecule 1 (CLL-1) is highly expressed in acute myeloid leukemia (AML) but is absent in primitive hematopoietic progenitors, making it an attractive target for a chimeric antigen receptor (CAR) T-cell therapy. Here, we optimized our CLL-1 CAR for anti-leukemic activity in mouse xenograft models of aggressive AML.MethodsFirst, we optimized the CLL-1 CAR using different spacer, transmembrane and costimulatory sequences. We used a second retroviral vector to coexpress transgenic IL15. We measured the effects of each construct on T cell phenotype and sequential (recursive) co culture assays with tumor cell targets to determine the durability of the anti tumor activity by flow cytometry. We administered CAR T cells to mice engrafted with patient derived xenografts (PDX) and AML cell line and determined anti tumor activity by bioluminescence imaging and weekly bleeding, measured serum cytokines by multiplex analysis. After euthanasia, we examined formalin-fixed/paraffin embedded sections. Unpaired two-tailed Student’s t-tests were used and values of p<0.05 were considered significant. Survival was calculated using Mantel-Cox log-rank test.ResultsIn vitro, CLL-1 CAR T cells with interleukin-15 (IL15) were less terminally differentiated (p<0.0001) and had superior expansion compared with CD28z-CD8 CAR T cells without IL15 (p<0.001). In both AML PDX and AML cell line animal models, CLL-1 CAR T coexpressing transgenic IL15 initially expanded better than CD28z-CD8 CAR T without IL15 (p<0.0001), but produced severe acute toxicity associated with high level production of human tumor necrosis factor α (TNFα), IL15 and IL2. Histopathology showed marked inflammatory changes with tissue damage in lung and liver. This acute toxicity could be managed by two strategies, individually or in combination. The excessive TNF alpha secretion could be blocked with anti-TNF alpha antibody, while excessive T cell expansion could be arrested by activation of an inducible caspase nine safety switch by administration of dimerizing drug. Both strategies successfully prolonged tumor-free survival.ConclusionCombinatorial treatment with a TNFα blocking antibody and subsequent activation of the caspase-9 control switch increased the expansion, survival and antileukemic potency of CLL-1 CAR T-cells expressing transgenic IL15 while avoiding the toxicities associated with excessive cytokine production and long-term accumulation of activated T-cells.

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Section: Discussionmentioning

confidence: 78%

Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia

Atilla

McKenna

Tashiro

et al. 2020

J Immunother Cancer

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“…Briefly, nine studies included MAS patients [15,16,18,20,23–27], eight included patients with sHLH of other causes [15,17,20,24,28–31] and six studies included pHLH [15,16,23,29–31]. Other inflammatory conditions included were EBV infection ( n = 5) [20,24,29–31], Kawasaki’s disease ( n = 2) [20,28], sJIA/AOSD ( n = 4) [18,20,25,26] and patients with other infectious, inflammatory or malignant disorders [15,17,23]. Seven studies included healthy controls [15–17,20,23,29,30].…”

Section: Resultsmentioning

confidence: 99%

“…Seven studies compared serum IL‐18 between HLH patients and patients with inflammatory conditions other than sJIA/AOSD; these were Kawasaki’s disease [20,28], EBV infection [29–31] and unspecified inflammatory, infectious or malignant disorders [17,23]. In all studies, IL‐18 was significantly increased in HLH/MAS compared to other inflammatory disorders [17,20,23,28–31], with IL‐18 levels generally above 1000 pg/ml in HLH (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome – a systematic review

Krei

Møller

Larsen

2020

Clinical and Experimental Immunology

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Summary Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory disorder, characterized by multiorgan failure, fever and cytopenias. The diagnosis of HLH and its subtype Macrophage Activation Syndrome (MAS) remains a challenge. Interleukin 18 (IL-18) is emerging as a potential biomarker for HLH/MAS but is currently not a part of diagnostic criteria. This systematic review aimed to assess the potential role of IL-18 in the diagnosis and monitoring of HLH and MAS, and was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase were searched on 30 January 2020. Studies included all subtypes of HLH and a range of underlying disorders in both children and adults. A total of 14 studies were included. Generally, serum IL-18 was elevated in both primary and secondary HLH (> 1000 pg/ml) compared with other inflammatory conditions and with healthy individuals; thus, serum IL-18 may be able to discriminate between HLH and other inflammatory conditions. Significantly increased IL-18 (> 10 000 pg/ml) was also consistently described in MAS compared with other subtypes of HLH. The ability of IL-18 to distinguish MAS from systemic juvenile idiopathic arthritis (JIA) is less unambiguous, as IL-18 levels > 100 000 pg/ml were described in sJIA patients both with and without MAS. IL-18 may help to differentiate between HLH subtypes and other inflammatory conditions. As HLH and MAS are rare disorders, only few and relatively small studies exist on the subject. Larger, prospective multi-center studies are called for to assess the diagnostic precision of IL-18 for HLH and MAS.

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“…Differences between our cohort and previously published cohorts must be interpreted with caution due to methodologic differences such as differences in platform, substrates used, and timing of collection in disease course. However, TNF-α appears to play a key role in the pathogenesis of both MIS-C and KD (19,20). Levels of IFN-γ, a cytokine not strongly associated with KD, were very high in many patients with SARS-CoV-2 infections, including children with minimal disease.…”

Section: Discussionmentioning

confidence: 99%

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS–CoV-2

Diorio¹,

Henrickson²,

Vella³

et al. 2020

Journal of Clinical Investigation

368

409

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BACKGROUND. Initial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology. METHODS. We prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data. RESULTS. Twenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C. CONCLUSION. Pediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.

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Cytokine profile of macrophage activation syndrome associated with Kawasaki disease

Cited by 35 publications

References 22 publications

Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia

Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia

The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome – a systematic review

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS–CoV-2

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