Immunology and Biotherapies

Key Points.Sirolimus and PTCy/MMF GVHD prophylaxis effectively reduce the grade II-IV acute GVHD rates after haplo-HCT.Sirolimus and PTCy/MMF permit hematopoie...

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Key Points Hyperinflammation-associated JAK/STAT pathway signaling decreases the apoptotic potential of immune cells in response to glucocorticoids. JAK/STAT pathway inhibition sensitizes immune cells to glucocorticoid-induced apoptosis in vitro and dampens hyperinflammation in vivo. Subjects: Immunobiology and Immunotherapy, Plenary Papers Topics:apoptosis, cytokine, dexamethasone, mice, t-lymphocytes, glucocorticoids, jak-stat signaling pathway, ruxolitinib, cytokine storm, hemophagocytic lymphohistiocytosis Abstract Cytokine storm syndromes (CSS) are severe hyperinflammatory conditions characterized by excessive immune system activation leading to organ damage and death. Hemophagocytic lymphohistiocytosis (HLH), a disease often associated with inherited defects in cell-mediated cytotoxicity, serves as a prototypical CSS for which the 5-year survival is only 60%. Frontline therapy for HLH consists of the glucocorticoid dexamethasone (DEX) and the chemotherapeutic agent etoposide. Many patients, however, are refractory to this treatment or relapse after an initial response. Notably, many cytokines that are elevated in HLH activate the JAK/STAT pathway, and the JAK1/2 inhibitor ruxolitinib (RUX) has shown efficacy in murine HLH models and humans with refractory disease. We recently reported that cytokine-induced JAK/STAT signaling mediates DEX resistance in T cell acute lymphoblastic leukemia (T-ALL) cells, and that this could be effectively reversed by RUX. On the basis of these findings, we hypothesized that cytokine-mediated JAK/STAT signaling might similarly contribute to DEX resistance in HLH, and that RUX treatment would overcome this phenomenon. Using ex vivo assays, a murine model of HLH, and primary patient samples, we demonstrate that the hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative DEX resistance. Upon exposure to RUX, this apoptotic potential is restored, thereby sensitizing CD8 T cells to DEX-induced apoptosis in vitro and significantly reducing tissue immunopathology and HLH disease manifestations in vivo. Our findings provide rationale for combining DEX and RUX to enhance the lymphotoxic effects of DEX and thus improve the outcomes for patients with HLH and related CSS. Subjects: Immunobiology and Immunotherapy, Plenary Papers Topics:apoptosis, cytokine, dexamethasone, mice, t-lymphocytes, glucocorticoids, jak-stat signaling pathway, ruxolitinib, cytokine storm, hemophagocytic lymphohistiocytosis REFERENCES 1. Canna SW, Behrens EM. Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes. Pediatr Clin North Am. 2012;59(2):329-344. 2. Behrens EM, Koretzky GA. Review: cytokine storm syndrome: looking toward the precision medicine era. Arthritis Rheumatol. 2017;69(6):1135-1143. 3. 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