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 transcript:

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

DISCLOSURES Nothing to disclose

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

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

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

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

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

PALA Enhances NOD2 Bacterial Killing Mouse Bone Marrow-Derived Macrophages

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

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

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

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