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Selective Enhancement ofNOD2 Anti-Bacterial Defenses
in the Context ofCrohn’s Disease
Christine McDonald, PhDDepartment of Pathobiology
Lerner Research InstituteCleveland Clinic
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DISCLOSURES
• Nothing to disclose
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Crohn’s is a Multi-Factorial Disease
Inappropriate Immune Response to Microbesin a Genetically Susceptible Individual
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Current Treatment Options
»Anti-Inflammatory»Immune Suppressant»Biologic Therapies»Surgery
Do Not Address the Underlying Cause of Disease
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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
1 28 220 273 577 744 10401020
CARD NOD LRR
X X
R702W G980R L1007fsinsC
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PALA
Novel Therapeutic Concept
NOD2 is defective in many CD patients
Restoration of NOD2 function will restore health
R702WG908R
L1007fs
NOD2
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How Do We Do This?Bacteria (MDP)
NFB
RIP2
NOD2
ErkJnkp38
MAPKs
CADPALA
Anti-Bacterial&
Pro-InflammatoryResponses
Richmond et al., (2012) Gastroenterology
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PALA Enhances NOD2 Bacterial Killing
Mouse Bone Marrow-Derived Macrophages
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Selective Enhancement of NOD2 FunctionBa
cter
ial C
lear
ance
Pro-Inflamm
atory Cytokine Secretion
Human Blood Monocyte-Derived Macrophages
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Efficacy of CAD Inhibition inExperimental Colitis
2.5% DSS-1 -2 0-3 1 2 3 4 5 6 7Day:
PALA:
* *
C57BL/6 or NOD2KO male mice 8-10wks old (n=6)
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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
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AcknowledgementsCleveland 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 - PR110887• CCFA Career Development Award• NIDDK R01 - DK082437• 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