1、Antibody-mediated rejection in kidney transplantationContents 01History and basic concepts02Pathophysiology and detection03Classification of ABMR04Future History and Basic concepts01The Nobel prizes related to organ transplantation Allo-Allogeneic transplantationAllograftAllogenic antigen1954Joseph

2、MurrayFirst kidney transplantationT or B cell ? Thats a question. ?%T cellmediated rejection (TCMR)CD4+ Th cell Macrophage CD8+ CTL etc.?%Antibody mediated rejection (ABMR) B cellCD4+ Th cell Antibodyetc.Main patternsof ABMR definedHistory of humoral theory acceptance 1960s2002TCMR dominant ABMR dis

3、tinguished from TCMR1990 Recognition of hyperacute rejectionBeforeTBCPathophysiology and detection02Pathophysiology HLA antigenClass I molecules (e.g., HLA-A, HLA-B, HLA-C): on all nucleated cellsClass II molecules (e.g., HLA-DP, HLA-DQ, HLA-DR): only on antigen-presenting cells (APCs)Anti-HLA antib

4、odyDonor-specific antibody (DSA)A recipients anti-HLA antibodies specific to the donors HLAsNon-HLA antigensABO AgmHAEndothelial cell AgMHC class I chain-related proteins A and B (MICA and MICB)Angiotensin II type 1 receptor (AGTR1)Complement systemD: AgR: DSA2FIGURE. Overview of the complement casc

5、ade and its regulators. Schematic representation of the three complement activation pathways, their convergence at the C3 convertase step, the formation of the membrane attack complex and the sites of complement regulation. See text for details. C1-INH, C1 esterase inhibitor; CR1, complement recepto

6、r 1 (CD35); DAF, decay accelerating factor (CD55), fB, factor B; fD, factor D; fH, factor H; fI, factor I; fP, properdin; MAC, membrane attack complex C5b-9; MBL, mannose-binding lectin; MASP, mannan-binding serine peptidase; MCP, membrane cofactor protein.Overview of the complement cascade and its

7、regulatorsEffects of complement activation on allograft injury.Sheen, Joong; Heeger, PeterCurrent Opinion in Organ Transplantation. 20(4):468-475, August 2015.DOI? 10.1097/MOT.0000000000000216PAUL I. TERASAKIHumoral theory of transplantation.Junchao Cai, Paul I. Terasaki. Humoral Theory of Transplan

8、tation: Mechanism, Prevention, and Treatment. Human Immunology, Volume 66, Issue 4, 2005, 334342Advanced immunological detection method123Complement dependent cytotoxicity crossmatch test (CDCC)Flow crossmatch (FXM)Single antigen bead (SAB) assayComplement dependent cytotoxicity crossmatch test (CDC

9、C)Donors lymphocytesRecipient serumRabbit complementStandard method for detecting DSAsRelatively insensitive Sheen, J.H. and P.S. Heeger, Effects of complement activation on allograft injury. Current Opinion in Organ Transplantation, 2015. 20(4): p. 468-475.Flow crossmatch (FXM)Donors cellsRecipient

10、 serumFluorescein labeledanti-human IgG“Channel shift”More sensitiveStandards varyFalse positive Sheen, J.H. and P.S. Heeger, Effects of complement activation on allograft injury. Current Opinion in Organ Transplantation, 2015. 20(4): p. 468-475.Single antigen bead (SAB) assayHLA antigens fixed onto

11、 microbeadsRecipient serumFluorochrome labeled anti-human IgGFlow cytometryHigh sensitivity and specificity Standards varyFalse positive Sheen, J.H. and P.S. Heeger, Effects of complement activation on allograft injury. Current Opinion in Organ Transplantation, 2015. 20(4): p. 468-475.Indirect detec

12、tion C4dA complement split proteinBind to the endothelium or basement membrane collagen of capillary Diagnosing AMRImmunofluorescence(IF) assay Immunohistochemical assayFalsely negativeC4d-negative ABMRC4d-negative aAMRNo influence on short-term outcome2Possible mechanismEffects of complement activa

13、tion on allograft injury. Sheen, Joong; Heeger, PeterCurrent Opinion in Organ Transplantation. 20(4):468-475, August 2015. DOI? 10.1097/MOT.0000000000000216Classificationof abmr03Three kinds of ABMRABMRHyper-acute Chronic Acute Peritubular capillaritis.Another key lesion in antibody-mediated rejecti

14、on.Glomerulitis.One of the key lesions in antibody-mediated rejection.KimSolez and Lorraine CRacusen. The Banff classification revisited. Kidney Int.2013 Feb;83(2):201-6. doi: 10.1038/ki.2012.395. Epub 2012 Dec 12Hyperacute ABMRPre-existing DSA Blood groupHLA incompatibilityWithin minutes to hoursSe

15、vere cortical necrosis and thrombosis in the microvasculatureMostly irreversible, but extremely rareCrossmatch testing Effective immunosuppressive therapyPreformed alloantibodiesBind to HLA antigens on endothelium Activate complementComplement mediated Direct cellular toxicityActivation of the coagu

16、lation cascadeVascular thrombosisAn influx of immune cells including macrophages and NK cellsRapid destruction of allograftSimplified mechanism Acute ABMRPhenotype 1 (early/acute) Pre-sensitized, but de-sensitized patient Usually days to weeksPhenotype 2 (late/chronic) De novo DSA 12 monthsHistologi

17、c findings similar to hyperacute rejectionSeverity lower, mostly manageable Frequently accompanied by cellular rejectionCD4+Th1 (delayed-type hypersensitivity)CD8+CTL, CD4+CTLRobert B. Colvin & R. Neal Smith. Antibody-mediated organ-allograft rejection. Nature Reviews Immunology5,807-817(October 200

18、5)Alloantibodies Positive final CDCC ?Positive final FXM ?Preconditioning (“Desensitization) strategiesSplenectomyIVIG infusionsPlasmapheresisAnti-CD20 monoclonal antibody (rituximab) Cellular proteosome toxin (bortezomib)The protocol used for desensitization at Johns Hopkins hospital which has a 98

19、% success rate for progressing to transplantation.Montgomery, Robert A. etc. HLA incompatible renal transplantation. Current Opinion in Organ Transplantation: August 2012 - Volume 17 - Issue 4 - p 386392Chronic ABMRSlowly over months to yearsIrreversible allograft damage with a low graft survival ra

20、teDe novo DSAsSlowly activate the complement system and eventually cause histologic changesProgressive interstitial fibrosis and tubular atrophyPossible mechanisms of chronic antibody-mediated injuryStegall, M. D. et al. (2012) The role of complement in antibody-mediated rejection in kidney transpla

21、ntationNat. Rev. Nephrol. doi:10.1038/nrneph.2012.212Source of dnDSAs An episode of early acute rejectionPrevious or ongoing subclinical rejectionPatient noncomplianceRecipients of kidneys from deceased donorsThose with Class II HLA mismatchesClassification of dnDSAsIgG dnDSAA major risk factorDSA I

22、gG1 and IgG3 isotypes to fix complementIgM dnDSAAlone no risk With IgG more severe, often vasculitisClass switchingPrevention of dnDSAImproved HLA matchingClass II matches at the DR, DQ and DP regionsImmunosuppressive strategiesMedication dosingNoncompliance or planned drug minimizationLymphocyte de

23、pleting agentsAnti-thymocyte globulin or anti-CD20 monoclonal antibodiesInhibiting second signaling pathways BelataceptBelataceptA molecularly engineered soluble form of CTLA-4 (CTLA4-Ig)Binds to CD80 and CD86 on APC Inhibit T cell activationModulating T-cell costimulation as new immunosuppressive c

24、oncept in organ transplantation.Pilat, Nina; Schwarz, Christoph; Wekerle, ThomasCurrent Opinion in Organ Transplantation. 17(4):368-375, August 2012.DOI? 10.1097/MOT.0b013e328355fc94Future04Acute and chronic ABMR: Banff 2013Haas, M., et al., Banff 2013 meeting report: inclusion of c4d-negative antib

25、ody-mediated rejection and antibody-associated arterial lesions. Am J Transplant, 2014. 14(2): p. 272-83.2FIGURE. Mechanisms through which complement mediates transplant injury.Effects of complement activation on allograft injury.Sheen, Joong; Heeger, PeterCurrent Opinion in Organ Transplantation. 2

26、0(4):468-475, August 2015.DOI? 10.1097/MOT.0000000000000216ABMR: an expanding spectrumC4d-negative AMRSubclinical ABMRArterial intimal fibrosisIntimal arteritisUnder-treatment Over-treatment Haas M. Pathologicfeaturesofantibody-mediatedrejectioninrenalallografts: anexpandingspectrum. Curr Opin Nephr

27、ol Hypertens.2012 May;21(3):264-71. doi: 10.1097/MNH.0b013e3283520efa. THANKSHe Xuxia 201201027References (including but not limited to)1. Sheen, J.H. and P.S. Heeger, Effects of complement activation on allograft injury. Current Opinion in Organ Transplantation, 2015. 20(4): p. 468-475.2. Filippone

28、, E.J. and J.L. Farber, Humoral Immune Response and Allograft Function in Kidney Transplantation. Am J Kidney Dis, 2015. 66(2): p. 337-47.3. Baldwin, W.M., 3rd, A. Valujskikh, and R.L. Fairchild, Mechanisms of antibody-mediated acute and chronic rejection of kidney allografts. Curr Opin Organ Transplant, 2015.4. Pankewycz, O., K. Soliman, and M.R. Laftavi, The increasing clinical importance of alloantibodies in kidney transplantation. Immunol Invest, 2014. 43(8): p. 775-89.5. Kim, M., et al., Antibody-mediated rejection in kidney transplantation: a review of pathophysiology,