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WhenInnateImmunityHurts:
ImplicationsforMedicalDevice
Failure
JoshuaB.Slee,PhD
AssistantProfessorofBiology
DeSalesUniversity
October31,2016
LearningGoals
• Explaininnateimmunity/inflammatory
response
• Relatephagocytosistotheinflammatory
response
• Explainhowtheinflammatoryresponseis
regulated
Immunity
Outside
Inside
Physical&
ChemicalBarriers
(skin&mucus
membranes)
Barrierstoinfection
• Epitheliallayersproduceprotectivesubstances
– AcidicpH
– Enzymes
– Antimicrobialpeptides
• Psoriasin
• Whydoesourskin
secretepsoriasin?
Immunity
Outside
Inside
InnateImmunity
Physical&
ChemicalBarriers
(skin&mucus
membranes)
http://www.republicmortgage.com/wp
-content/uploads/How-To-Keep-YourHome-Germ-Free.jpg
•
•
•
•
Firstlineofdefense
Non-specific
Nomemory
Sameresponseto
repeatinfection
AdaptiveImmunity
•
•
•
•
Maxresponseindays
Specific
Memory
Morerapidresponse
torepeatinfection
PathogenRecognition
WhiteBloodCell
•
•
PAMPs – Pathogen-AssociatedMolecularPatterns
PRRs – PatternRecognitionReceptors
http://mx.itqb.unl.pt/colin_mcvey/images/Projects/immune1.png
•
Inflammation istriggeredwheninnateimmunecellsdetectinfectionor
tissueinjury
http://www.sabiosciences.com/pathwaymagazine/pathways7/toll-like-receptors-and-innate-immunity.php
InflammatoryResponse
LeukocyteRollingandExtravasation
Barreiro& Sánchez-MadridRevEsp Cardiol.2009
Phagocytosis
http://classes.midlandstech.edu/carterp/courses/bio225/chap16/lecture3.htm
Phagocytosis
Bacteriaor
Foreignobject
(splinter)
Inflammatorycellinteracts
withbacteriaorforeignobject
Inflammatorycellengulfs
bacteriaorforeignobject
Modifiedfrom:Wikipedia
PAMP/PRR-orC3b(complementprotein)
- Opsonization
Inflammatorycellmembrane
(neutrophilsandmacrophages)
Phagocytosis
http://classes.midlandstech.edu/carterp/courses/bio225/chap16/lecture3.htm
PhagocytosisVideo1
http://highered.mheducation.com/sites/0072495855/student_
view0/chapter2/animation__phagocytosis.html
PhagocytosisVideo2
https://www.youtube.com/watch?v=Z_mXDvZQ6dU
Inflammation-RelatedDiseases
Inflammation
MedicalDeviceFailure
Implantrejection
http://www.ucdenver.edu/academics/colleges/medicalscho
ol/departments/immunology/faculty/Pages/SAlper.aspx
IssueswithInnateImmunity
Restenosis
Crackedpacemakerlead
insulation
Wiedermanetal
AnnThoracSurg2010
Bioprostheticvalve
calcification
Post-surgicalcomplications
ofcardiopulmonarybypass
Biocompatibility
“Theconditionofbeingcompatible
withlivingtissueoralivingsystem
bynotbeingtoxicorinjuriousand
notcausingimmunologicalrejection”
Merriam-WebsterDictionary
Regulationoftheinflammatory
response
• Underhomeostatic
conditions,responseto
foreignstimuliclosely
regulated
• Inhibitoryimmunecell
surfacereceptors
• Immunoreceptor Tyrosine
InhibitoryMotif(ITIM)
proteinfamily
– SignalRegulatoryProtein
Alpha(SIRPα)
DecreasedImmune
Response
CD47
• Expressedin
virtuallyallcells
• CD47-SIRPα
interaction
inhibitsimmune
response
• Over-expressed
inmostcancer
cells
SleeJBetal.Polymers2014
TheuseofCD47asanantiinflammatoryagentonmedical
devices
•
•
•
•
•
•
Pacemakerleads
Cardiopulmonarybypasstubing
Hemodialysistubing
Vascularstents
Artificialheartvalves
Glucosesensors
DoesCD47preventinvitroblood
cellattachment?
InvitroTHP-1attachmentassay
AttachmentAssay
THP-1=human
monocyte-derived
macrophagecellline
3dayincubation
WashwithPBS
Fixcells
StainwithDAPI
CountadheredCells
Modifiedvs
ControlSurfaces
A.
THP-1AttachmentAssay
Unmodified
recCD47
CD47pep
DIC
B.
AdheredCells/200X
field
DAPI
100
80
60
40
20
0
*
Unmodified Recombinant
recCD47
SleeJBetal.J.Vis.Exp.2014
*
Peptide
CD47pep
DoesCD47preventexvivoblood
cellattachment?
ChandlerLoopApparatus
SleeJBetal.J.Vis.Exp.2014
ChandlerLoopAssay
Unmodified
A.
recCD47
CD47pep
DAPI
AdheredCells/200Xfield
B.
60
50
40
30
20
*
*
Recombinant
recCD47
Peptide
CD47pep
10
0
Unmodified
SleeJBetal.J.Vis.Exp.2014
DoesCD47preventinvivocell
attachment?
VascularStents
http://en.wikipedia.org/wiki/Cardiology
Restenosis
http://www.yoursurgery.com/ProcedureDetails.cfm?BR=5&Proc=33
CD47PreventsCellAttachment InVivo
BareMetalStent
2,000X
10,000X
SleeJBetal.Biomaterials.2016
CD47stent
CD47PreventsRestenosisInVivo
BareMetalStent
*
CD47stent
*
CD47decreasesrestenosismeasuresbyalmost30%
SleeJBetal.Biomaterials.2016
Summary
• Pathogensandforeignobjectstriggeran
inflammatoryresponseinthebody.
• InnateImmunityisthefirstwaythebody
dealswitheliminatingpathogensandforeign
objectsfromthebody.
• CD47isamarkerof“self”toimmunecells.
• CD47canbeusedonmedical
devices/implantablematerialstopreventthe
inflammatoryresponse.
Thank You!
Questions?
JoshuaB.Slee,PhD
AssistantProfessorofBiology
DeSalesUniversity
[email protected]