Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Dr. John K. McCormick

2nd Supervisor

Dr. S.M. Mansour Haeryfar

Joint Supervisor

Abstract

Sepsis is characterized by a severe systemic inflammatory response to infection that is associated with high morbidity and mortality despite optimal care. Invariant natural killer T (iNKT) cells are potent regulatory lymphocytes that can produce pro- and/or anti-inflammatory cytokines, thus shaping the course and nature of immune responses; however, little is known about their role in sepsis. We demonstrate here that patients with sepsis/severe sepsis have significantly elevated proportions of circulating iNKT cells in their peripheral blood, as compared to non-septic patients. We therefore investigated iNKT cells in mice with intra-abdominal sepsis (IAS). Our data show that iNKT cells are pathogenic in IAS, and that T helper (Th)2-type polarization of iNKT cells using the synthetic glycolipid OCH significantly reduced mortality from IAS. This reduction in mortality is associated with the systemic elevation of the anti-inflammatory cytokine interleukin (IL)-13, and reduction of several pro-inflammatory cytokines within the spleen, notably IL-17. Finally, we show that administration of OCH in septic mice is associated with significantly reduced apoptosis of splenic T and B lymphocytes, as well as macrophages, but not natural killer cells. We propose that modulation of iNKT cell responses towards a Th2 phenotype may be an effective therapeutic strategy in sepsis.

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