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Selective Enhancement of NOD2 Anti-Bacterial Defenses in the Context of Crohn’s Disease Christine McDonald, PhD Department of Pathobiology Lerner Research.

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Presentation on theme: "Selective Enhancement of NOD2 Anti-Bacterial Defenses in the Context of Crohn’s Disease Christine McDonald, PhD Department of Pathobiology Lerner Research."— Presentation transcript:

1 Selective Enhancement of NOD2 Anti-Bacterial Defenses in the Context of Crohn’s Disease Christine McDonald, PhD Department of Pathobiology Lerner Research Institute Cleveland Clinic

2 DISCLOSURES Nothing to disclose

3 Crohn’s is a Multi-Factorial Disease Inappropriate Immune Response to Microbes in a Genetically Susceptible Individual

4 Current Treatment Options » Anti-Inflammatory » Immune Suppressant » Biologic Therapies » Surgery Do Not Address the Underlying Cause of Disease

5 Crohn’s Associated NOD2 Variants 3 major variants found in or near LRRs Disease prevalence: – 1 variant: 30-50% prevalence, 2-4x increased risk – 2 variants: 10% carry, ~17-40x increased risk Associated with early & aggressive disease Variants result in loss of NOD2 function CARD NODLRR X X  R702W G980R L1007fsinsC

6 PALAPALA Novel Therapeutic Concept NOD2 is defective in many CD patients Restoration of NOD2 function will restore health R702W G908R L1007fs NOD2

7 How Do We Do This? Bacteria (MDP) NF  B RIP2 NOD2 Erk Jnk p38 MAPKs CAD PALA Anti-Bacterial & Pro-Inflammatory Responses Richmond et al., (2012) Gastroenterology

8 PALA Enhances NOD2 Bacterial Killing Mouse Bone Marrow-Derived Macrophages

9 Selective Enhancement of NOD2 Function Bacterial Clearance Pro-Inflammatory Cytokine Secretion Human Blood Monocyte-Derived Macrophages

10 Efficacy of CAD Inhibition in Experimental Colitis 2.5% DSS Day: PALA: * * C57BL/6 or NOD2KO male mice 8-10wks old (n=6)

11 Summary Decreased NOD2 function is linked to CD CAD is a negative regulator of NOD2 CAD inhibitor treatment: – Enhances bactericidal NOD2 functions without increasing inflammation – Protects against experimental colitis – Increases function of CD-associated NOD2 variants – May represent a novel approach to CD therapy

12 Acknowledgements Cleveland Clinic McDonald Lab – Chaorui Tian – Amrita Kabi – Craig Homer – Kourtney Nickerson – Laura Dixon – Amy Richmond IBD Research Group – JP Achkar Keyonna Smith – Claudio Fiocchi – Carol de la Motte Sean Kessler – Eleni Stylianou – Michelle Longworth Imaging & Histology Core University of Michigan Gabriel Nuñez Arul Chinnaiyan Alexey Nesvizhskii Arun Sreekumar Funding Support DoD PRMRP - PR CCFA Career Development Award NIDDK R01 - DK NIDDK T32 Training Grant LRI Chairman’s Innovative Research Award Gerald & Nancy Goldberg Resources George Stark (CCF) Laura Lindsey-Boltz (UNC) NCI / DTP Open Chemical Repository NCI Cooperative Human Tissue Network CCF/CWRU CTSC


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