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Microvascular inflammation and endothelial cell activation in kidney antibody mediated rejection Michael Mengel Department of Laboratory Medicine and Pathology.

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Presentation on theme: "Microvascular inflammation and endothelial cell activation in kidney antibody mediated rejection Michael Mengel Department of Laboratory Medicine and Pathology."— Presentation transcript:

1 Microvascular inflammation and endothelial cell activation in kidney antibody mediated rejection Michael Mengel Department of Laboratory Medicine and Pathology University of Alberta, Edmonton, Canada

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4 Three Pathways to Antibody-Mediated Injury Antibody Alone Complement Mediated Cell Mediated (FcR) Farkash and Colvin, Nat Rev Nephrol 8:255, 2012

5 Classical complement pathway activation: Antibody + Antigen C1 C4 C4a + C4b  C4d binds covalently to local site Helmut Feucht Clin Exp Immunol 86:464, 1991 Mannose binding lectin/MASP1 Role of C4d in antibody-mediated rejection

6 Detection of C4d is crucial for diagnosing antibody mediated rejection

7 Microcirculation inflammation in AMR CD3 CD68 HeartKidney

8 Phenotype of glomerulits CD15 – early AMR CD68 – late AMR

9 Diagnosis of AMR Mengel M et al. Transpl Int Jun;25(6):611-22

10 Follow up of C4d positive biopsies and the development of TX-Glomerulopathy Significant more often associated with Transplant Glomerulopathy (53% vs. 14%) Significant more often associated with Transplant Capillaropathy (71% vs. 13%) Significantly associated with progression of Transplant Glomerulopathy in follow-up biopsy (82% vs. 27%, median after 23 months) Regele et al.

11 Pathogenesis of Capillaropathy

12 Transplant-Capillaropathy

13 icrocirculation inflammation antibody-mediated injury and microcirculation inflammation glomerulitisglomerulopathy

14 Sequential development of CHR in non-human primates No CHR Stage I Stage II Stage III Stage IV Days post-transplant Smith et al (Boston) AJT 8:1662, 2008

15 C4d versus microcirculation inflammation in biopsies prior to AMR treatment ( ) Verghese et al. Clin. Transplant 2013 in press

16 Gaston et al Transplant 90:68,2010 C4d - DSA - C4d - DSA + C4d + DSA - C4d + DSA + N=173 DeKAF Study Biopsies for late graft dysfunction Months post-bx

17 unsupervised Principal Component Analysis Banff lesions Graft Survival

18 Limited specificity of microcirculation inflammation Fahim et al. Am J Transplant Feb;7(2): % cases with capillaritis Gibson et al. Am J Transplant Apr;8(4):

19 The association of TG (D) (n=44) with antibody (A), PTCBMML (B), and C4d (C). TG phenotype*ABCDn (%) “ABCD” (27) “ABD” (32) “ACD”+-++2 (5) “AD”+--+1 (3) “BCD”-+++1 (3) “BD”-+-+9 (24) “CD”--++1 (3) “D”---+1 (3) Sis et al. AJT 2007; 7: % of Tg cases show some signs of humoral rejection

20 Loupy et al: Subclinical progressive microcirculation injury in presensitized patients, despite C4d negativity

21 Potential causes for C4d negativity C4d+ ABMR C4d negative ABMR Complement activationComplement dependent cell injuryEndothelial activationRecruitment and activation of leukocytes Is C4d deposited in low amounts (Thus not detectable by current methods) Treatment effects? Do HLA antibodies in a complement- independent way cause EC activation and subsequent inflammation and Fc receptor mediated graft injury? ? ?

22 Three Pathways to Antibody-Mediated Injury Antibody Alone Complement Mediated Cell Mediated (FcR) Farkash and Colvin, Nat Rev Nephrol 8:255, 2012

23 endothelial genes are increased in AMR Red arrows indicate genes that are known to be involved in endothelial cell activation Welch t test FDR 0.05 Sis et al. AJT 2009;9: Also not in our strict definition of ENDAT list, but increased in ABMR: CDH13 Duffy blood group SOX7 THBD MALL

24 Endothelial Cell-Associated Transcripts correlate with pathologic features of AMR (in 173 biopsies) Endothelial Transcripts Correlation coefficientp C4d deposition.376p<0.001 Peritubular capillaritis PTCBMML g i.358p<0.001 t.135NS v.092NS cg mm ci.330p<0.001 ct.286p<0.001 cv.014NS ah-.050NS Sis et al. AJT 2009;9:

25 n=81 Incidence of transplant glomerulopathy (*%) No Ab n=30 Ab with no E n=21 Ab with E n=30 C4d+ Transplant Glomerulopathy C4d Negative Transplant Glomerulopathy 6.7% 19% 43% C4d is negative in 60% of chronic active ABMR biopsies Sis et al. Am J Transplant Oct;9(10): NoAb n=30 Abwith no E n=21 Abwith E n=30 Transplant Glomerulopathy score ( cg, mean + 95% CI) n=81 p=0.01 p=0.53 Cumulative Survival No Ab with no E Ab with E Post-biopsy time (months) p=0.001 Abwith E No Ab or AbAbwith no E 60% C4d negative

26 Transcripts selectively associated with DSA: Endothelial and NK cell transcripts Hidalgo et al. AJT 2010; 10: 1812–1822 NK endothelial

27 A. B. C.D.D. E. C4d+ ABMR C4d- ABMR TCMR CD56+ CD68+ CD3+ Mean number of positive cells in five peritubular capillaries p=0.006 p=0.03 p=0.09 CD3CD68CD56 NK cells and macrophages in antibody mediated peritubular capillaritis Hidalgo et al. AJT 2010; 10: 1812–1822

28 Hirohashi and Colvin et al. Am J Transplant Feb;12(2): Akiyoshi and Colvin at al. Human Immunology Volume 73, Issue Role of complement and NK cells in antibody mediated rejection NK cell stain AMRAMR + anti NK

29 A molecular classifier for diagnosing AMR Sellares et al. Am J Transplant Apr;13(4): Classifier score correlates with: Pathology (ptc, g, cg, I, cv, ah, ct, ci) Consensus amongst pathologists Presence of DSA outcome

30 Sellares et al. Am J Transplant Apr;13(4):

31 Dean et al. Am J Transplant 2012; 12: * * * * * * * * * * * * * * * * * * * * * * * * * * *

32 Summary Donor-specific antibody acting on the allograft is associated with endothelial cell and local complement activation [ in most cases] DSA acting on the allograft is associated with microcirculation inflammation as the morphological correlate [notion: the antigen is expressed in the microcirculation] DSA acting on the allograft is associated with increased expression of inflammation (T cells, macrophages,  - interferon), endothelial, and NK cell associated transcripts as the molecular correlate

33 C4d 30 minutes

34 Objective To review the current knowledge of mechanisms, diagnostics and clinical management of patients with antibody- mediated rejection. Since the vast majority of experience in this area has been accumulated in renal transplant patients, this group of patients will be the main focus of the presentation, but relevant lessons applicable to other types of organ transplants will be discussed as well.

35 Intragraft gene expression in positive crossmatch kidney allografts Dean et al. Am J Transplant 2012; 12: Class – Comparisons: A and B: no significant differences in gene expression C and D: over-expression of inflammatory transcripts (T cells, macrophages,  interferon) in XM+ biopsies

36 Limited specificity of capillaritis % cases with capillaritis Gibson et al. Am J Transplant Apr;8(4):

37 AMR and vasculopathy


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