1、Into the Eye of Cytokine Storm cytokine storm and ways of quelling 1ContentIntroduction DefinitionCytokines associated with cytokine stromCytokine dynamicsRegulation of proinflammatory responseCytokine storm pathologyCytokine Gene Expression KineticsQuelling the stormUtilization of sphingosine-1-pho

2、sphate receptor signaling Other Immunomodulatory strategies 2DefinitionA cytokine storm, also known as cytokine cascade and hypercytokinemiaa potentially fatal immune reaction consisting of a positive feedback loop between cytokines and white blood cells, with highly elevated levels of various cytok

3、ines. 3Major types and actions of cytokines TypeActionsInterferons Regulation of innate immunity, activation of antiviral properties, antiproliferative effects Interleukins Growth and differentiation of leukocytes; many are proinflammatory Chemokines （CXC,CC,C CX3C）Control of chemotaxis, leukocyte r

4、ecruitment; many are proinflammatory Colony-stimulating factors Stimulation of hematopoietic progenitor cell proliferation and differentiation Tumor necrosis factor Proinflammatory, activates cytotoxic T lymphocytes 4Cytokine Dynamics Underestimate dynamic nature during acute infection Clinical stud

5、ies using intermittent sampling from one compartment (typically the peripheral blood), although many of the critical responses are likely to be far more localized in tissue The compartmentalization of tissue-specific microenvironments. 5Regulation of Proinflammatory Response Balance between proinfla

6、mmatory cytokines (e.g. TNF and IL- 1 ) and their cognate soluble receptors or inhibitors (TNFR1, TNFR2, and IL-1RA)Regulate the activation of specific cell type(e.g. CD200R)Negative regulation(e.g. SOCS-1,TOLLIP)Production of anti-inflammatory cytokines(e.g. IL-10) 6Cytokine Storm Pathology begins

7、at a local site (or not)spreads throughout the body via the systemic circulation Rubor (redness), tumor (swelling or edema), calor (heat), dolor (pain), and “functio laesa” (loss of function) increase blood flow enable vascular leukocytes and plasma proteins increase local temperatures 7Cytokine Sto

8、rm Pathology 8characteristic plasma cytokine pro files In patients with severe sepsisAcute-response cytokines TNF and IL-1 Chemotactic cytokines IL-8 and MCP-1 appear in the early minutes to hours after infection followed by a more sustained increase in IL-6. The anti-inflammatory cytokine IL-10 app

9、ears somewhat later, as the body attempts to control the acute systemic inflammatory response. 9SIRS in the absence of contaminating pathogensSix healthy young male volunteers first phase 1 clinical trial of TGN1412a rapid induction of proinflammatory cytokines headache, myalgias, nausea, diarrhea,

10、erythema, vasodilatation, and hypotensionpulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. 10Laboratory Results after Infusion 11Suntharalingam G et al. N Engl J Med 2006;355:1018-1028.Laboratory Results after Infusion 12Suntharalingam G et al. N Engl

11、J Med 2006;355:1018-1028.Laboratory Results after Infusion 13Cytokine Gene Expression (H5N1) 14Cytokine Gene Expression (1918 Virus) 15Cytokine Gene Expression (H1N1) 16Key Cytokine Storm Mediators 17Quellling the stormsphingosine-1- phosphate receptor (S1PR) signaling S1P1 agonists chemical tractab

12、le. suppresses cytokine and innate immune cell recruitment 18S1P properties 1920AAL-R treatment blunts the innate immune responses during mouse-adapted and human pathogenic influenza virus infection1*104 PFU of A/WSN/H1N1 influenza virustreated with vehicle or 0.2 mg/kg AAL-R. 1 h post-infection. On

13、 day 2, mice were killed, Innate Immune Response Cause a Cytokine Storm 21AAL-R administration significantly protects against human pathogenic H1N1 2009 influenza virus infection and inhibits immunopathology associated with infection. infectied with 2 105 pfu of A/Wisconsin/WSLH34939/ 09 influenza v

14、irus.Vehicle 21% survived 0.2 mg/kg AAL-R 1 h after i.n. 82%; P 0.00015 mg/kg oseltamivir day 50% (P = 0.010)82% vs. 50%; P = 0.005). combined treatment 96% vs. 21%; P 0.0001schematic cartoon of the effects of AAL-R and oseltamivir1. lung epithelial cells 2. cytokine/chemokine production 3.infiltrat

15、ion and activation of inflammatory cells. 4. DCs (AAL-R impairs surface expression of co-stimulatory and MHC molecules on activated DCs) 22CD8 T Cells Cause a Cytokine Storm 23C57BL/6 mice infected i.n. with 1.5103 PFU of rPVM strain 15. 24Immunomodulatory strategies COX-2 inhibitor: celecoxib CCR2

16、inhibitor: PF-04178903 Anti-TNF agents Statins Glucocorticoids PPARs agonists25Future studiesA combination of knockout mouse models and pharmacological intervention to study the mechanismStrengthen the limited experimental evidence to support the use of immunomodulatory therapyCombine antiviral and

17、immunomodulatory therapy26ReferencesMatheu, M. P., et al. (2013). Three phases of CD8 T cell response in the lung following H1N1 influenza infection and sphingosine 1 phosphate agonist therapy. PLoS One 8(3): e58033.Walsh, K. B., et al. (2011). Quelling the storm: utilization of sphingosine-1-phosph

18、ate receptor signaling to ameliorate influenza virus-induced cytokine storm. Immunol Res 51(1): 15-25Teijaro, J. R., et al. (2014). Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection. Proc Natl Acad Sci U S A 111(10): 3799-3804.Rosenzweig, S. D. and T.

19、 A. Fleisher (2013). Laboratory evaluation for T-cell dysfunction. J Allergy Clin Immunol 131(2): 622-623 e621-624.Tisoncik, J. R., et al. (2012). Into the eye of the cytokine storm. Microbiol Mol Biol Rev 76(1): 16-32.Darwish, I., et al. (2011). Immunomodulatory therapy for severe influenza. Expert Rev Anti Infect Ther 9(7): 807-822.Teijaro, J. R., et al. (2011). Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell 146(6): 980-991.Oldstone, M. B., et al. (2013). D