Harnessing the Versatility of Invariant NKT Cells in a Stepwise Approach to Sepsis Immunotherapy

被引:4
作者
Choi, Joshua [1 ]
Mele, Tina S. [2 ,3 ]
Porcelli, Steven A. [4 ]
Savage, Paul B. [5 ]
Haeryfar, S. M. Mansour [1 ,2 ,6 ,7 ]
机构
[1] Western Univ, Dept Microbiol & Immunol, Room SDRI 234,1151 Richmond St, London, ON N6A 5C1, Canada
[2] Western Univ, Dept Surg, Div Gen Surg, London, ON N6A 5A5, Canada
[3] Western Univ, Dept Med, Div Crit Care Med, London, ON N6A 5W9, Canada
[4] Albert Einstein Coll Med, Dept Microbiol & Immunol, New York, NY 10461 USA
[5] Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA
[6] Western Univ, Div Clin Immunol & Allergy, Dept Med, London, ON N6A 5C1, Canada
[7] Western Univ, Ctr Human Immunol, London, ON N6A 5C1, Canada
基金
美国国家卫生研究院; 加拿大健康研究院;
关键词
KILLER T-CELLS; HUMANIZED MOUSE MODEL; ALPHA-GALACTOSYLCERAMIDE; DENDRITIC CELLS; IMMUNE DYSFUNCTION; CUTTING EDGE; INKT CELLS; INNATE; ACTIVATION; INHIBITION;
D O I
10.4049/jimmunol.2000220
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Sepsis results from a heavy-handed response to infection that may culminate in organ failure and death. Many patients who survive acute sepsis become immunosuppressed and succumb to opportunistic infections. Therefore, to be successful, sepsis immunotherapies must target both the initial and the protracted phase of the syndrome to relieve early immunopathology and late immunosuppression, respectively. Invariant NKT (iNKT) cells are attractive therapeutic targets in sepsis. However, repeated treatments with alpha-galactosylceramide, the prototypic glycolipid ligand of iNKT cells, result in anergy. We designed a double-hit treatment that allows iNKT cells to escape anergy and exert beneficial effects in biphasic sepsis. We tested the efficacy of this approach in the sublethal cecal ligation and puncture mouse model, which mirrors polymicrobial sepsis with progression to an immunosuppressed state. Septic mice were treated with [(C2S, 3S, 4R)-1-O-(alpha-D-galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol] (OCH), a T(H)2-polarizing iNKT cell agonist, before they received alpha-galactosylceramide. This regimen reduced the morbidity and mortality of cecal ligation and puncture, induced a transient but robust IFN-gamma burst within a proinflammatory cytokine/chemokine landscape, transactivated NK cells, increased MHC class II expression on macrophages, and restored delayed-type hypersensitivity to a model hapten, consistent with recovery of immunocompetence in protracted sepsis. Structurally distinct TH2-polarizing agonists varied in their ability to replace OCH as the initial hit, with their lipid chain length being a determinant of efficacy. The proposed approach effectively exploits iNKT cells' versatility in biphasic sepsis and may have translational potentials in the development of new therapies.
引用
收藏
页码:386 / 397
页数:12
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