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Microvascular inflammation and endothelial cell activation in kidney antibody mediated rejection 

Microvascular inflammation and endothelial cell activation in kidney antibody mediated rejection . Michael Mengel Department of Laboratory Medicine and Pathology University of Alberta, Edmonton, Canada. Three Pathways to Antibody-Mediated Injury. Cell Mediated ( FcR ). Complement

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Microvascular inflammation and endothelial cell activation in kidney antibody mediated rejection 

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  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

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

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

  4. Detection of C4d is crucial for diagnosing antibody mediated rejection

  5. Microcirculation inflammation in AMR Kidney Heart CD68 CD3

  6. Phenotype of glomerulits CD15 – early AMR CD68 – late AMR

  7. Diagnosis of AMR Mengel M et al. Transpl Int. 2012 Jun;25(6):611-22

  8. Regele et al. 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)

  9. Pathogenesis of Capillaropathy

  10. Transplant-Capillaropathy

  11. antibody-mediated injury and microcirculation inflammation glomerulitis glomerulopathy

  12. Sequential development of CHR in non-human primates No CHR Stage I Stage II Stage III Stage IV 106 182 225 352 371 Days post-transplant Smith et al (Boston) AJT 8:1662, 2008

  13. C4d versus microcirculation inflammation in biopsies prior to AMR treatment (1996-2001) Verghese et al. Clin. Transplant 2013 in press

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

  15. Graft Survival Banff lesions unsupervised Principal Component Analysis

  16. Limited specificity of microcirculation inflammation Fahim et al. Am J Transplant. 2007 Feb;7(2):385-93. Gibson et al. Am J Transplant. 2008 Apr;8(4):819-25. % cases with capillaritis

  17. The association of TG (D) (n=44) with antibody (A), PTCBMML (B), and C4d (C). 73% of Tg cases show some signs of humoral rejection Sis et al. AJT 2007; 7: 1743-1752

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

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

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

  21. endothelial genes are increased in AMR Also not in our strict definition of ENDAT list, but increased in ABMR: CDH13 Duffy blood group SOX7 THBD MALL Welch t test FDR 0.05 Red arrows indicate genes that are known to be involved in endothelial cell activation Sis et al. AJT 2009;9:2312-23

  22. Endothelial Cell-Associated Transcripts correlate with pathologic features of AMR (in 173 biopsies) Sis et al. AJT 2009;9:2312-23

  23. C4d is negative in 60% of chronic active ABMR biopsies n=81 p=0.01 score ( cg, mean + 95% CI) n=81 Incidence of transplant glomerulopathy (*%) p=0.53 Glomerulopathy 43% 19% Transplant No Ab Ab with no E Ab with E 6.7% n=30 n=21 n=30 or No Ab Ab with no E No Ab n=30 Ab with no E n=21 Ab with E n=30 Ab with E C4d+ Transplant Glomerulopathy C4d Negative Transplant Glomerulopathy Cumulative Survival 60% C4d negative No Ab No Ab Ab with no E Ab with no E Ab with E Ab with E p=0.001 p=0.001 Sis et al. Am J Transplant. 2009 Oct;9(10):2312-23. Post - biopsy time (months)

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

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

  26. Role of complement and NK cells in antibody mediated rejection AMR AMR + anti NK NK cell stain Akiyoshi and Colvin at al. Human Immunology Volume 73, Issue 12 2012 1226 - 1232 Hirohashi and Colvin et al. Am J Transplant. 2012 Feb;12(2):313-21. 

  27. A molecular classifier for diagnosing AMR • Classifier score correlates with: • Pathology (ptc, g, cg, I, cv, ah, ct, ci) • Consensus amongst pathologists • Presence of DSA • outcome Sellares et al. Am J Transplant. 2013 Apr;13(4):971-83.

  28. Sellares et al. Am J Transplant. 2013 Apr;13(4):971-83.

  29. * * * * * * * * * * * * * * * * * * * * * * * * * * * Dean et al. Am J Transplant 2012; 12:1551-1563

  30. 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, g-interferon), endothelial, and NK cell associated transcripts as the molecular correlate

  31. C4d C4d 30 minutes

  32. 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. 

  33. Intragraft gene expression in positive crossmatch kidney allografts • Class – Comparisons: • A and B: no significant differences in gene expression • C and D: over-expression of inflammatory transcripts (T cells, macrophages, g-interferon) in XM+ biopsies Dean et al. Am J Transplant 2012; 12:1551-1563

  34. Limited specificity of capillaritis Gibson et al. Am J Transplant. 2008 Apr;8(4):819-25. % cases with capillaritis

  35. AMR and vasculopathy

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