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Novel non-HLA antibodies and rejection Duska Dragun

Novel non-HLA antibodies and rejection Duska Dragun Nephrology, Charité Campus Mitte, Humboldt University Berlin. Antibody mediated acute rejection. The issue is not trivial, humoral rejection causes 30% of acute rejections and 10% of graft failures Pathogenesis

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Novel non-HLA antibodies and rejection Duska Dragun

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  1. Novel non-HLA antibodies and rejection Duska Dragun Nephrology, Charité Campus Mitte, Humboldt University Berlin

  2. Antibody mediated acute rejection • The issue is not trivial, humoral rejection causes 30% of acute rejections and 10% of graft failures • Pathogenesis • donor-specific antibodies against HLA class I and class antigens (C4d+) • „non-HLA“ antibodies against unknown targets

  3. Subpopulation of patients with „unclear“ rejection • severe pathology: endarteritis or fibrinoid necrosis • 16/16 cases negative for HLA class I and class II DSA • no hereditary or autoimmune thrombophilia • negative serology for autoimmune disorders

  4. Inferior survival in patients with non-HLA antibody rejection Dragun, D. et al. N Engl J Med2005;352:558-569

  5. HLA DSA- HLA DSA+ n 16 13 Living donor 7/16 5/13 Male 8/16 4/13 First kidney graft 7/16 5/13 Cold ischemia [h] 10.3 (1.6 – 13.3) 13.2 (1.8 – 16.2) HLA-mismatches 3 (0 – 5) 3 (2 – 6) Age at transplantation [years] 34.8 (27.9-48.4) 43.6 (20.1-59.8) Time transplantation to rejection [days] 4 (2-1217) 9 (3-680) Demographic data

  6. HLA DSA- HLA DSA+ Severe hypertension 16/16 0/13 5/16 13/13 Clinical manifestations and biopsies Histology: C4d positive

  7. Our index case 50-years old female recipient of the first, zero mismatch “full-house” kidney transplant with primary graft function (creatinine 1.0 mg/dl at postoperative day 3) develops refractory vascular rejection with BP 240/160 mm Hg. Autoimmune serology is negative; CMV negative No hereditary thrombophilia. Why is this patient rejecting? Interesting detail from patients´medical history: „During my pregnancy, 25 years ago, I also had very high blood pressure and I almost lost my baby.“

  8. J Clin Invest 103: 945-952, 1999

  9. Patients´IgG Bioassay for Ang II Typ1–Rezeptor (AT1R) agonistic antibodies

  10. HLAneg(before Tx) HLA neg(rejection) HLA pos(before Tx) HLA pos (rejection) Bioassay results for Ang II type 1–receptor (AT1R) activity C4d+

  11. 30 20 10 0 Ang II AT1R-AA +Losartan +PD 123319 IgG activate Angiotensin II Type 1 Receptor Increase in BPM

  12. 30 20 10 0 AT1R-AA Serum AT1R-AA Niere + Losartan + Losartan AT1R agonistic activity in transplant nephrectomies Increase in BPM

  13. Losartan + PPH improve graft survival in AT1R-AA+ patients Dragun, D. et al. N Engl J Med2005;352:558-569

  14. Influence of losartan + PPH on AT1R activity Dragun, D. et al. N Engl J Med2005;352:558-569

  15. 30 20 Increase in beat number/min 10 0 IgG1 IgG2 IgG3 IgG4 AT1R IgG subclass activity

  16. Binding sites of AT1R activating IgG1 and IgG3 Ang II type 1 receptor Ingelfinger, J. R. N Engl J Med 2005;352:617-619

  17. Incidence of AT1R-AA positive rejection 279 kidney transplantations in 4.5 years(Jan 1st 2000 – July 31st 2004) 119 rejection episodes in 83 patients 23 refractory to steroids (19.3% of all rejections)

  18. Incidence of AT1R-AA positive rejection 23 refractory to steroids (19.3% of all rejections) 9 episodesHLA-DSA pos39.1% of refract. rejections 10 episodesAT1R-AA pos43.5% of refract. rejections 4 HLA-DSA neg/AT1R-AA neg 7.6% of all rejections 8.4% of all rejections

  19. ECs, VSMCs Interdisciplinary „bedside to bench“ approach

  20. ERK ½ phosphorylation coronary endothelial cells coronary VSMC

  21. NF-kB

  22. Cell promoter transfection experiments Tissue factor is a target of NF-kB and AP-1 C4d+ AT1R-AA+ Mutant promoter

  23. Tissue Factor expression in patients´ biopsies TF vor PPH + Losartan TF nach PPH + Losartan

  24. Kochs´postulate study to investigate pathogenic role of AT1R-AA in transplant vascular pathology passive transfer of human IgG with AT1R agonistic activity

  25. Orthotopic life-supporting functional NTx rat model Control IgG Lew recipient F344 donor AT1-AA 7 d. pre NTx 7 d. post NTx c allograft morphology telemetry device implant. NTx, osmotic mini-pump Telemetry follow-up

  26. AT1R-AA induce vascular rejection AT1R-AA+ human IgG AT1R-AA- human IgG

  27. Colocalization of AT1R-AA (human IgG) with AT1R AT1R-AA+ human IgG AT1R-AA- human IgG AT1R human IgG

  28. AT1R-AA induce hypertension Dragun, D. et al. N Engl J Med2005;352:558-569

  29. Do AT1R-AA fulfill Koch´s postulates? • The agent (AT1-AA) should be present in all cases but not in controls • The agent (AT1-AA) must be isolated from the cases and studied in cells • The agent (AT1-AA) transferred into a healthy laboratory animal, should cause the disease • The agent should be re-isolated from the experimental disease

  30. Putative mechanism of action of AT1R-AA Apoptosis? Permeability? Mø CTL AT1R-AA AT1R-AA AT1R-AA AT1R AT1R AT1R ECs MAPKs (Erk 1/2) AT1R-AA AT1R-AA AT1R-AA AT1R AT1R MAPKs (Erk 1/2) NF-kB, AP-1 RANTES VSMCs TF MCP-1 TF Thrombotic Angiopathy! Effector cell infiltration!

  31. AT1R-AA collaborators Max-Delbrück-Centre Berlin Gerd Wallukat Nephrology, Charité Campus Buch Ralf Dechend Dominik N. Müller Ralph Plehm Jan Hinrich Bräsen Friedrich C. Luft Pharmacology, Charité Campus Mitte Ulrich Kintscher Thomas Unger Nephrology, Charité Campus Mitte Diana Eckert Melina Nieminen-Kelhä Lutz Fritsche Klemens Budde Hans-H. Neumayer HLA Laboratory Charité Constanze Schönemann Pathology, Charité Campus Mitte Birgit Rudolph CNRS, Strasbourg Johan Hoebeke

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