2022-05-31 ISN Webinar DSA negative ABMR .pptx
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In this presentation, given for the ISN-TTS webinar on Antibody-Mediated Rejection after kidney transplantation, I discuss the phenotype of microcirculation inflammation/microvascular rejection/ABMRh in the absence of donor-specific HLA antibodies. Also the potential role of missing self activation of natural killer (NK) cells and non-HLA antibodies.
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2022-05-31 ISN Webinar DSA negative ABMR .pptx
- 1. Microvascular rejection in the absence of anti-HLA DSAs Maarten Naesens, MD PhD KU Leuven, Belgium ISN webinar May 31st 2022
- 2. 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017 2019 2022 1. Tissue injury 2. Antibody interaction 3. Serological evidence Microvascular inflammation Microvascular inflammation C4d deposition C4d deposition HLA-DSA
- 3. Not considered as sABMR or ABMR in any Banff update n=3171 Banff’01 Banff’13 Banff’17 DSA+ C4d- MVI+ DSA- C4d- MVI+ DSA+/C4d+ v > 0 ABMR n=199 sABMR n=292 ABMR n=237 No ABMR n=254 DSA- C4d+ 1st/MVI+ DSA- C4d- MVI+ DSA+ C4d- 1st+ Isolated ptc Callemeyn, al. Am J Transplant 2021. ABMR n=74 sABMR n=238 No ABMR n=179
- 4. N=935 No ABMRh (N=727; 78%) ABMRh (N=208; 22%) HLA-DSA positive ABMRh (N=85; 41%) HLA-DSA negative ABMRh N=123 (59%) We observed a very high percentage of patients with ABMRh without HLA-DSA Senev et al. Am J Transplant 2019 . . Ba
- 5. Coemans et al. Transplant Int 2021 Absolute number of cases B. Histological picture of antibody-mediated rejection D. Transplant glomerulopathy N = 1000 transplants; 3594 posttransplant biopsies There is a high number of cases with ABMR histology without HLA-DSA
- 6. DSAneg ABMRh differs from DSApos ABMRh (97% MVI) HISTOLOGICAL PICTURE OF ABMR (Banff criteria 1 and 2) N=208 patients HLA-DSA positive N=85 HLA-DSA negative N=123 More graft failure (33%) Less graft failure (15%) Time after transplantation (< 1y) Light microscopic appearance More Repeated (52%) More transient (27% repeat) More C4d positivity (55%) Less C4d positivity (38%) C4d p<0.001 p<0.001 p<0.01 First clinical presentation Equal Senev et al. Am J Transplant 2019
- 7. DSAnegABMRh DSAposABMRh Senev et al. Am J Transplant 2018 Outcome of HLA-DSA negative ABMRh is better than in HLA-DSA positive ABMRh
- 8. Outcome of HLA-DSA negative ABMRh is better than in HLA-DSA positive ABMRh Bestard & Grinyo, Am J Transplant 2018 Koenig et al Nat Comm 2019
- 9. ABMRh -> transplant glomerulopathy: one entity! Logit (ABMR) Time post-transplant First occurrence cg • Highly significant in entire cohort (HR 1.19, p<0.001) • And even in the DSA negative group (HR 1.16, p<0.001) ABMRh/cg ‘Exposure to’ ABMRh Joint modeling Coemans et al. Transplant Int., 2021
- 10. Association between time-dependent aABMRh, cg and aABMRh/cg and death-censored graft failure (N=837 HLA-DSA negative patients; 3140 biopsies) Coemans et al. Transplant Int., 2021 Parameters in the survival sub-modela # phenotype occurrences HR (95% CI) P-value aABMRh 205 1.17 (0.97 – 1.43) 0.10 cg 79 1.25 (1.08 – 1.55) 0.004 aABMRh/cg 268 1.32 (1.07 – 1.61) 0.008
- 11. Halloran et al. Am J Transplant, May 2022 Association between molecular ABMR and death-censored graft failure is independent of the HLA-DSA status (N=268) Callemeyn et al. J Am Soc Nephrol 2020 (N=224)
- 12. Callemeyn et al. Kidney Int 2022 The cellular infiltrates of kidney transplant rejection HLA antigen mismatch “Missing Self”
- 13. NK cells are kept in balance by inhibitory and activating receptors KIR
- 14. Tumoral NK cells activate by “absence of self” (missing self)
- 15. NK cells activate by “absence of self” (missing self)
- 16. The concept of missing self requires NK cell education Callemeyn et al. J Am Soc Nephrol 2021
- 17. Missing self, direct NK cell activation and MicroVascular Inflammation Koenig et al. Nature Commun 2019 A B C
- 18. Missing self associates with microvascular inflammation (MVI) “high” missing self Callemeyn et al. J Am Soc Nephrol 2021
- 19. Missing self independently increases risk of MVI Pretransplant HLA-DSA Callemeyn et al. J Am Soc Nephrol 2021 Koenig et al. J Am Soc Nephrol 2021
- 20. Callemeyn et al. JASN 2021 Koenig et al. Nat Commun 2020 102/222 of MVI (46%) not yet explained 15/44 of MVI (34%) not yet explained Not all MVI is explained by DSA or by missing self
- 21. There are many pathways of NK cell activation Hamada et al. HLA 2021
- 22. Non-HLA Ab detection immunoassay (NHADIA) to detect non-HLA DSA Lamarthée et al JASN 2021
- 23. MICA is confirmed as minor histocompatilibty antigen in kidney transplantation leading to anti-MICA DSA and microvascular rejection Carapito et al Nat Med 2022
- 24. N=935 No ABMRh (N=727; 78%) ABMRh (N=208; 22%) HLA-DSA positive ABMRh (N=85; 41%) HLA-DSA negative ABMRh N=123 (59%) CONCLUSION: DSA-negative Microvascular Rejection is common and further research is needed Senev et al. Am J Transplant 2019
- 25. Not considered as sABMR or ABMR in any Banff update n=3171 Banff’01 Banff’13 Banff’17 DSA+ C4d- MVI+ DSA- C4d- MVI+ DSA+/C4d+ v > 0 ABMR n=199 sABMR n=292 ABMR n=74 sABMR n=238 No ABMR n=179 ABMR n=237 No ABMR n=254 DSA- C4d+ 1st/MVI+ DSA- C4d- MVI+ DSA+ C4d- 1st+ Isolated ptc Callemeyn, al. Am J Transplant 2021. ABMR (HLA-DSApos) MVR (HLA-DSAneg) (MVI based on restricted definition) No ABMR (DSA+) New proposal
- 27. Thank you!
Editor's Notes
- 15 minutes
- Theoretically, a similar situation can arise in organ transplantation. If the organ that is transplanted has a different MHC class I repertoire than the recipient. This could lead to disinhibition of the NK cells, which get activated and degranulate cytotoxic molecules ultimately killing the target donor cells, thus damaging the transplanted organ.