Serial Expressions of Toll Like Receptors Pathways and Regulatory B and T Cells at Different Time Points of Childhood Sepsis and Analysis of the Immunomodulatory Effects on Murine Polymicrobial Sepsis Treated with Mesenchymal Stem Cells from Differen

Sepsis is an overwhelming systemic inflammatory response to infection that remains the leading cause of death among patients in intensive care units (ICUs). To survey a serial change of proinflammatory biomarkers in innate immunity is important and useful to manage patients with sepsis and to predict clinical outcomes. Toll-like receptors (TLRs) can activate immune responses by recognizing a foreign microbe’s product. The stimulation of TLRs by agonists can trigger the activation of two downstream signaling pathways: the myeloid differentiation factor 88 (MyD88) dependent and independent pathways. In addition, regulatory B (Breg) and regulatory T (Treg) cells are more and more important because they can exert the immunosuppressive function during sepsis. Based on our prelimiting data, the expressions of MyD88 dependent and independent pathways revealed significant difference, and Treg and Breg cells showed different role in murine sepsis. Furthermore, mesenchymal stem cells (MSCs) from different sources have been shown to have immunosuppressive properties based on our initial study results. The results support us to further investigate the effects of MSCs on treatments for sepsis. Moreover, MSCs are safe in human clinical application. Therefore, the following Specific Aims are planned in this Project to illustrate the role of innate immunity in human sepsis and murine sepsis immunemodulatory effects of MSCs on sepsis. 1. To confirm the predictive values of serum proinflammatory biomarkers in the different time courses of sepsis and clinical outcomes in children admitted to the ICUs 2. To evaluate the change of the TLRs pathways and Breg and Treg cells for the different progression of sepsis for the potential clinical application. 3. To identify the roles of MyD88-dependent and independent signaling pathways and Breg and Treg cells in the early and later stages of murine sepsis induced by cecal ligation and puncture (CLP) 4. To survey the change of these immune biomarkers in an experimental murine polymicrobial sepsis model to gain insight into serial changes of pro-inflammatory markers in innate immune response to sepsis and septic peritonitis and to provide evidence for clinical application. 5. To confirm the effect of the immunomodulatory properties of MSCs on TLRs pathways, and Breg and Treg cells in murine sepsis. We investigate the mechanisms of MSC-mediated immunomodulation in this project by determining the time course of TLRs activation, and Breg and Treg functions after MSC administration in rats receiving CLP-induced polymicrobial sepsis. Importance and Novelty: This project serves as a helpful investigation to evaluate the role of TLRs singaling pathways, and Breg and Treg biomarkers in the prediction of patients with sepsis. Based on our prelimiting data, MyD88 dependent and independent pathway revealed significant difference of both protein and mRNA expressions with different severity of sepsis. This project will use different sources of MSCs via intraperitoneal injection for treating sepsis in our animal CLP model, and prove the immunomodulatiory effect of MSCs on sepsis. Human clinical trials thereafter can be rapidly proceeded on the basis of the results from this Project, especially when we understand that MSCs have a potential value to treat patients with sepsis.

Project ID:PC10608-1488
External Project ID:MOST106-2314-B182-054