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• infectious disease and the immune system
• cell and developmental biology/regenerative medicine
• bioengineering/medical devices

• Medicine
• Anaesthetics
• Pathology

• Infectious diseases
• Respiratory Medicine
• Other

Intensive Care Medicine

John Laffey is an anaesthetist, an intensive care medicine physician and clinician scientist with a particular interest in cell and gene based therapies Acute Respiratory Distress Syndrome and Sepsis. His team at NUI Galway have characterized the repair process following ventilation induced lung injury (VILI) [Anesthesiology115:1022-32, 2011], and demonstrated that Mesenchymal Stem/Stromal Cells (MSCs) enhance this recovery process [Thorax 67:496-501, 2012]. They showed that MSC therapy is equally effective if given intravenously or intra-tracheally, while the MSC secretome is also effective in enhancing recovery following VILI [Anesthesiology, 2013 Apr;118(4):924-932]. Most compellingly, human MSCs enhance recovery following VILI [Anesthesiology 2015 Feb;122(2):363-73], and also reduce the severity of E. coli induced pneumonia [Thorax 2015 Jul;70(7):625-35].

They have demonstrated that over-expression of genes to augment anti-oxidant activity in the lung can protect against endotoxin induced lung injury [Intensive Care Med 37:1680-7 2011]. Overexpression of genes to inhibit the activity of the transcriptional factor nuclear factor kappa-B attenuates endotoxin injury [Hum Gene Ther 2015; PMID: 25382145], VILI [Br J Anaesth 2014 Dec;113(6):1046-54], and early pneumonia induced lung injury [Critical Care 2013 Apr 27;17(2):R82]. However, this worsens the injury produced by prolonged E. coli bacterial pneumonia [Critical Care 2013 Apr 27;17(2):R82].

ARDS and Sepsis constitute clinical syndromes of life-threatening physiologic, pathologic, and biochemical abnormalities resulting from a disordered immune response to uncontrolled microbial infection. Sepsis is the commonest cause of ARDS, and neither syndrome has a direct treatment. ARDS and Sepsis both have a mortality of 40%. Sepsis is a causative factor in 50% of all in-hospital deaths, ans is increasing in this era of multi-antibiotic resistant bacteria.

Our group has shown that Mesenchymal stem/stromal cells (MSCs) offer considerable promise as a non-antibiotic approach for both ARDS and Sepsis. MSCs assist the immune response in killing bacteria, minimizing/resolving host tissue injury, and restoring homeostasis. While na?ve unmodified MSCs are in early phase clinical testing for sepsis, enhancing MSC immune-modulatory effects may further increase efficacy in sepsis.

Objective: This project will elucidate the effects of MSCs on the innate and adaptive cellular immune response to bacterial infection, develop MSCs with enhanced immune effects, and test these ?immune-enhanced? MSCs in pre-clinical sepsis models.

Hypothesis: Enhancing the effects of MSCs on the innate and adaptive cellular responses to sepsis will increase MSC efficacy for sepsis.

Study Design: In relevant preclinical sepsis models, we will: (1) Optimize the anti-microbial effects of na?ve hMSCs; (2) sevelop and test candidate hMSCs with enhanced effects on the cellular immune response to bacteria; (3) address translational barriers and safety concerns regarding our novel IE-hMSC candidate; and (4) Evaluate effects of ?immune enhanced? hMSCs on the healthy and septic human immune system.

Impact: This project will develop an ?immune-enhanced MSC to be taken forward for testing in patients with sepsis. If effective, an ?immune-enhanced? MSC would save countless lives, reduce disability in survivors, and greatly reduce healthcare costs.