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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]