免疫介导心脏疾病新策略课件

1、New Strategies for Immune-mediated Heart DiseasesMitsuakiIsobeDepartment of Cardiovascular MedicineTokyo Medical and Dental UniversityChina-Japan Cardiovascular Forum 2019Immune-mediated heart diseasesIschemia-reperfusion injuryAtherosclerosisRestenosisCardiac allograft rejectionCardiac allograft va

2、sculopathyMyocarditisCongestive heart failureArrhythmiaImmune-mediated heart diseasesIschemia-reperfusion injuryAtherosclerosisRestenosisCardiac allograft rejectionCardiac allograft vasculopathyMyocarditisCongestive heart failureArrhythmiaInflammation in coronary arteriosclerosis and atherogenesisPP

3、AR(Peroxisome proliferator-activated receptor-)NFBAcute cardiac allograft rejectionEctopic heart transplantion recipients : C3H/He donors : BALB/c full mismatchAdministration of pioglitazone (3mg/kg/day) to the recipient mice.Murine heart transplantation Survival RatePostoperative DaysPioglitazone(3

4、mg/kg/day)Control chowProlongation of heart graft by pioglitazone10.80.60.40.2010203040506070*p0.05Kosuge, Suzuki, Isobe: Circulation 113: 2613-2622、 20190.80.60.40.20Optical DensityRR + Pio10-6MR + SR + S + Pio10-6MR + S + Pio10-7MR + S + Pio10-5MR: responder (recipient)S: stimulator (donor)Pio: pi

5、oglitazone*p0.05Suppression of T cell Proliferation by Pioglitazone in Mixed Lymphocyte Reaction*Chronic cardiac rejectionGraft arterial disease (GAD)RCALADLCX8-y-o boySmallarteriesMyocardiumAccelerated coronary sclerosisGraft vasculopathyCardiac allograft vasculopathyPathology: Diffuse intimal thic

6、kening of small to large coronary arteriesPathology: Diffuse intimal thickening of small to large coronary arteriesRisk factors: CMV infection episodes of acute rejectionRisk factors: CMV infection episodes of acute rejectionTherapy: ?Therapy: ?Progression: months to yearsProgression: months to year

7、s Chronic cardiac allograft rejectionCardiac allograft vasculopathy recipients : C57BL/6 donors : Bm12 classII mismatch -1 0 7 14 21 28 35 42 49 56 dayssacrificeControl chowPioglitazone(3mg/kg/day)Telmisartan(10mg/kg/day)8 Weeks after TransplantationLuminal occlusion (%)p0.05ControlPioglitazoneAtten

8、uation of Graft Arteriosclerosis by Treatment with Pioglitazone or TelmisartanControlPioglitazoneTelmisartanp0.05ControlTelmisartanKosuge, Suzuki, Isobe: Circulation 2019AortaSMCsactivated splenocytesProliferationSMC Proliferation AssayPioglitazonetelmisartanSuppression of SMC proliferation ?Suppres

9、sion of SMC Proliferation after Interaction with Splenocytes by Pioglitazone or TelmisartanSMCs+Pio10-6MSp+SMCs+Pio10-7M Sp+SMCs+Pio10-6M Sp+SMCs+Pio10-5M 05.04.03.02.01.0Optical DensitySMCsSp+SMCs*00.10.20.30.40.50.60.7SMCsSMCs+Tel 10-6MFBS+SMCs*FBS+SMCs+Tel 10-7M FBS+SMCs+Tel10-6M FBS+SMCs+Tel 10-

10、5M FBS+SMCs+Tel 10-5M+GW Summary 1PPAR is associated with pathophysiology of immune-mediated heart diseases.PPAR- agonists (pioglitazone and telmisartan) are effective in suppressing experimental cardiac allograft rejection (acute rejection and allograft vasculopathy).ReferencesKosuge, Suzuki, Isobe

11、: Circulation 113: 2613-2622, 2019Isobe, Kosuge, Suzuki: ATVB, 26: 1447-1456, 2019 Kosuge, Suzuki, Isobe: ATVB, 26: 2660-2665, 2019 Onai, Suzuki, Maejima: Am J Physiol, 292, H530-538, 2019 Kosuge, Suzuki, Isobe, Transplanation, in pressMaejima, Suzuki, Okada, Isobe: in submissionInflammation in coro

12、nary arteriosclerosis and atherogenesisPPAR(Peroxisome proliferator-activated receptor-) NFBLPSTNFNFBTCRTCellStimuliAnoxiaReactive oxygen speciesLPSCytokines (IL-1, TNF)Re-oxygenationLipoproteinThrombinGene ExpressionCytokines (IL-1, TNF)iNOS, COX-2Adhesion molecules (ICAM-1, VCAM-1)Immunoreceptors

13、(MHC class I, II)IL-6, M-CSF, GM-CSFChemokines (MCP-1, )Acute phase protein (CRP,)Role of NF-kB in Cardiovascular DiseasesHeart failureVascular remodelingAllograft rejectionMyocarditisReperfusion injuryVentricular remodelingNF-B ActivationNF-B decoy - Mechanism of Action -Cell MembraneNucleusCis-Ele

14、mentInflammatory genesDecoyI-Bp50p65 I-kB kinasesk I-B kinasesStimuliDegradationI-BPI-Bp50p65DecoymRNAInflammatorymoleculesp50p65p50p65p50p65XXAcute MyocarditisExperimental Allergic Myocarditis in RatsImmunizationLewis rats were immunized with porcine cardiac myosin.In vivo gene transferInjection of

15、 HVJ-liposome-NFB decoy at coronary cuspDay 0, 7 or 1421 days after transfectionFITC-labeled Decoy in Rat HeartNFkB decoy reduces extent of autoimmune myocariditisControl(injection at day 7)(Yokoseki O, Isobe M, Circ Res 2019)020406080100(%)UTSDday0day7day14Myocarditis-affected area NFkB decoyMethod

16、 of gene transfer to cardiac allograftDonor HeartHVJ-HVJ-liposomeDonorRecipientHistological analysisTransfection: 10 min, 4CIschemic time: 30 minDecoy Transfection28 daysVCAM-1PDGF-B mRNAEvG stainingScramble decoyNFB decoyEffect of NFB decoy on GAD(Suzuki, Isobe, Gene Therapy, 2019)Gene Transfer Sys

17、temDecoy + microbubble complexUltrasound (US)Wire injuryInhibition of intimal hyperplasia by NF-kB decoy transfectionDecoyMicrobubbleUltrasound (-) (+) (+) (+) (-) (-) (+) (+) (-) (+) (-) (+)I/Mp 75% by QCA)PatientsRatesNegative1794.1%Positive15.9%Average % Restenosis（by QCA）Before PCIAfter PCI6 Mo.

18、 Later% Restenosis88.51.539.6Summary of QCAConclusionsPPAR and NFB are good molecular targets for treatment of immune-mediated cardiovascular diseases. Further studies should be conducted to explore the possibility to develop new therapeutic strategies.AcknowledgementTokyo Medical and Dental Univers

19、ityJun-ichi SuzukiHisanori Kosuge Noritaka KogaNoriko TamuraMasahito Ogawa Osaka UniversityRyuichi MorishitaYasufumi KanedaKyushu UniversityKensuke EgashiraAkita UniversityHiroshi Ito IL-10IL-15IL-6IFN-ControlPioglitazoneSuppression of Cytokines Expression in Allografts by Treatment with PioglitazoneRNase protection assay 5 days after transplantationSuppression of T cell Proliferation by Telmisartan in Mixed Lymphocyte Reaction00.20.40.60.8Optical Density*p