免疫介导心疾病新策略

1、immune-mediated heart diseases ischemia-reperfusion injury atherosclerosis restenosis cardiac allograft rejection cardiac allograft vasculopathy myocarditis congestive heart failure arrhythmiaimmune-mediated heart diseases ischemia-reperfusion injury atherosclerosis restenosis cardiac allograft reje

2、ction cardiac allograft vasculopathy myocarditis congestive heart failure arrhythmiainflammation in coronary arteriosclerosis and atherogenesisppar(peroxisome proliferator-activated receptor-)nfbacute cardiac allograft rejectionectopic heart transplantion recipients : c3h/he donors : balb/c full mis

3、matchadministration of pioglitazone (3mg/kg/day) to the recipient mice.murine heart transplantation survival ratepostoperative dayspioglitazone(3mg/kg/day)control chowprolongation of heart graft by pioglitazone10.80.60.40.2010203040506070*p0.050.80.60.40.20optical densityrr + pio10-6mr + sr + s + pi

4、o10-6mr + s + pio10-7mr + s + pio10-5mr: responder (recipient)s: stimulator (donor)pio: pioglitazone*p0.05suppression of t cell proliferation by pioglitazone in mixed lymphocyte reaction*chronic cardiac rejectiongraft arterial disease (gad)pathology: diffuse intimal thickening of small to large coro

5、nary 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 years chronic cardiac allograft r

6、ejectioncardiac 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 (%)p0.05controlpioglitazoneattenuation of graft arteriosclero

7、sis by treatment with pioglitazone or telmisartancontrolpioglitazonetelmisartanp0.05controltelmisartanaortasmcsactivated splenocytesproliferationsmc proliferation assaypioglitazonetelmisartansuppression of smc proliferation ?suppression of smc proliferation after interaction with splenocytes by piog

8、litazone 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 10-5m fbs+smcs+tel 10-5m+gw summary 1ppar is associated with pathophysi

9、ology of immune-mediated heart diseases.ppar- agonists (pioglitazone and telmisartan) are effective in suppressing experimental cardiac allograft rejection (acute rejection and allograft vasculopathy). onai, suzuki, maejima: am j physiol, 292, h530-538, 2007 kosuge, suzuki, isobe, transplanation, in

10、 pressmaejima, suzuki, okada, isobe: in submissioninflammation in coronary arteriosclerosis and atherogenesisppar(peroxisome proliferator-activated receptor-) nfblpstnfnfbtcrtcellstimulianoxiareactive oxygen specieslpscytokines (il-1, tnf)re-oxygenationlipoproteinthrombinrole of nf-kb in cardiovascu

11、lar diseasesheart failurevascular remodelingallograft rejectionmyocarditisreperfusion injuryventricular remodelingnf-b activationcell cell membranemembranenucleusnucleuscis-elementcis-elementnf- bnf- binflammatory genesinflammatory genesdecoyi-bp50p50p65p65 i- b kinases i- b kinasesstimulistimulideg

12、radationi-bpi-bp50p50p65p65decoymrnainflammatoryinflammatorymoleculesmoleculesp50p50p65p65p50p50p65p65p50p50p65p65xxday 0, 7 or 14(yokoseki o, isobe m, circ res 2001)donor hearthvj-hvj-liposomehistological analysisvcam-1pdgf-b mrnaevg stainingscramble decoynfb decoyeffect of nfb decoy on gad(suzuki,

13、 isobe, gene therapy, 2001)japan trial to prevent restenosis after stent usingnfkb decoy oligodeoxynucleotides as gene therapy ( j-pranj-pran )clinical trial for prevention of coronary restenosis after angioplastydecoy transfection after stent implantationno virus vectordose trial for safetyevaluati

14、on at 6 months by angiography and ivusthe first clinical trial of gene therapy for heart disease in japancollaboration with kyushu univ, osaka univ, and tokyo med and dent univ.(suzuki, isobe, circ j 2004)123456789101112131415161718patient id (dose)i-001i-002q-001q-002q-004q-005q-007q-009q-012q-013i

15、-003q-017q-018q-019q-022q-028q-032a-001(1mg）(1mg）(1mg）(1mg）(1mg）(1mg）(2mg）(2mg）(2mg）(2mg）(2mg）(2mg）(4mg）(4mg）(4mg）(4mg）(4mg）(4mg）gendermmmmmffmmmmmmmmmmmage44757578477958577066565476665785-53% qca before pci75 90 90 90 90 99 90 90 90 99 99 90 90 90 99 75 90 99 % qca after pci0 0 0 0 0 0 0 0 25 0 0 0

16、 0 0 0 0 0 0 % qca 6 mo later0 25 45 50 25 55 25 47 67 25 50 25 90 25 25 25 *68.9 resultspatientsratesnegative1794.1%positive15.9%before pciafter pci6 mo. later% restenosis88.51.539.6summary of qcaacknowledgementtokyo medical and dental universityjun-ichi suzukihisanori kosuge noritaka koganoriko ta

17、muramasahito 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*p0.05r: responder (recipient)s: stimulator (donor)rr + tel 10-5mr + sr + s + tel 10-5mr + s + tel 10-6mtel: telmisarta