Selective Enhancement of NOD2 Anti-Bacterial Defenses in the Context of Crohn’s Disease Christine...
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Transcript of Selective Enhancement of NOD2 Anti-Bacterial Defenses in the Context of Crohn’s Disease Christine...
Selective Enhancement ofNOD2 Anti-Bacterial Defenses
in the Context ofCrohn’s Disease
Christine McDonald, PhDDepartment of Pathobiology
Lerner Research InstituteCleveland Clinic
DISCLOSURES
• Nothing to disclose
Crohn’s is a Multi-Factorial Disease
Inappropriate Immune Response to Microbesin 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
1 28 220 273 577 744 10401020
CARD NOD LRR
X X
R702W G980R L1007fsinsC
PALA
Novel Therapeutic Concept
NOD2 is defective in many CD patients
Restoration of NOD2 function will restore health
R702WG908R
L1007fs
NOD2
How Do We Do This?Bacteria (MDP)
NFB
RIP2
NOD2
ErkJnkp38
MAPKs
CADPALA
Anti-Bacterial&
Pro-InflammatoryResponses
Richmond et al., (2012) Gastroenterology
PALA Enhances NOD2 Bacterial Killing
Mouse Bone Marrow-Derived Macrophages
Selective Enhancement of NOD2 FunctionBa
cter
ial C
lear
ance
Pro-Inflamm
atory Cytokine Secretion
Human Blood Monocyte-Derived Macrophages
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)
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
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