Welche Donor-spezifischen HLA Antikrper sind schdlich? Donor-spezifischen HLA Antikrper . sind...

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Transcript of Welche Donor-spezifischen HLA Antikrper sind schdlich? Donor-spezifischen HLA Antikrper . sind...

  • Welche Donor-spezifischen HLA Antikrper sind schdlich?

    Prof. Dr. med. Caner Ssal Transplantationsimmunologie

    Institut fr Immunologie Universitt Heidelberg

  • Sensitization Alloantibody Production

  • Before Transplantation Hyperacute rejection Accelerated humoral rejection Delayed graft function

    After Transplantation (de novo)

    Chronic rejection

    Alloantibodies

  • Alloantibodies

    HLA (A, B, C, DRB1/3/4/5, DQA1, DQB1, DPA1, DPB1) Non-HLA

    Angiotensin II Typ 1 R MIC-A Endothelial antigens

  • Antibody Specification

    CDC-PRA ELISA-PRA Luminex (PRA, Single Antigen)

  • Ssal et al, Transfus Med Hemother 2013

    Sensitization against HLA-B27 MM from the previous Tx

    CDC-PRA: 1 Specificity

    ELISA-PRA: 6 Specificities

    Luminex-SA: 33 Specificities

  • Ssal, Opelz Transplantation 2002

    Pre-Tx Anti-HLA Antibody Status (ELISA) CDC-PRA

  • Pre-Tx Luminex SA Testing (DSA or Non-DSA) CDC- and ELISA-Negative Kidney Tx Recipients

    cut-off 1,000 MFI

    45%

    66%

    Graft Loss Non-Rejector

    Class I

    31%50%

    Graft Loss Non-Rejector

    Class II

    45%

    55%

    66%

    34%

    31%

    69%

    50%

    50%

    Graft Loss Non-Rejector Graft Loss Non-Rejector

    Class I Class II

    Positive Graft Loss Patients Positive Non-Rejectors

    Ssal et al. Transplantation 2011

  • Disadvantages of Presensitization 1. Prolonged waiting time

    2. Inferior graft survival

  • Morath et al., Transplantation 2010

    1. Pre-Tx identification of high-risk patients

    2. Good HLA-match

    3. ET Acceptable Mismatch Program

    4. Pretreatment with PPh/IA + Rituximab + ATG

    5. Infection prophylaxis

    6. Apheresis after Tx

    7. Post-Tx antibody monitoring

    8. Protocol biopsies on post-Tx days 7 and 90

    9. Desensitization in positive-DSA/XM living-Tx

    Heidelberg Algorithm for Transplantation of High-Risk Sensitized Patients

  • Four High Risk Groups

  • DSA- and XM-Positive Patients

  • Pre-Tx HLA Antibody Status (ELISA) Deceased Donor Kidney Transplants 2003-2008

    CTS Serum Study

    Hum Immunol 70:569-573, 2009

  • Morath Ssal, Transplantation 2010

    1. Pre-Tx identification of high-risk patients

    2. Good HLA-match

    3. ET Acceptable Mismatch Program

    4. Pretreatment with PPh/IA + Rituximab + ATG

    5. Infection prophylaxis

    6. Apheresis after Tx

    7. Post-Tx antibody monitoring

    8. Protocol biopsies on post-Tx days 7 and 90

    9. Desensitization in positive-DSA/XM living-Tx

    Heidelberg Algorithm for Transplantation of High-Risk Sensitized Patients

  • Total Kidney Tx, Heidelberg Tx Center 2001-2013

    18 19 20 2538 30 37

    4357 53

    65 57 54

    6341

    69 54

    8077

    10574

    86 9587

    88 8981

    60

    8979

    118107

    117

    142 143148 152 145

    0

    50

    100

    150

    200

    2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 31.12.2013

    verstorbenen Spende

    Lebendspender143

    Heidelberg Algorithm Since April 2006

  • CTS Serum Study (www.ctstransplant.org)

  • 1. Pre-existing DSA

    2. Loss of pre-existing DSA 3. Persistence of pre-existing DSA 4. Reappearance of pre-existing DSA 5. de novo development of DSA 6. C1q-/C3d-DSA

    Donor-Specific HLA Alloantibodies (DSA)

  • Donor-Specific HLA Alloantibodies (DSA)

    Zecher et al, NDT, 2017

  • Morath Ssal, Transplantation 2010

    1. Pre-Tx identification of high-risk patients

    2. Good HLA-match

    3. ET Acceptable Mismatch Program

    4. Pretreatment with PPh/IA + Rituximab + ATG

    5. Infection prophylaxis

    6. Apheresis after Tx

    7. Post-Tx antibody monitoring

    8. Protocol biopsies on post-Tx days 7 and 90

    9. Desensitization in positive-DSA/XM living-Tx

    Heidelberg Algorithm for Transplantation of High-Risk Sensitized Patients

  • 1. International CTS Serum Project

    2. Heidelberg Pediatric Cohort

    3. Heidelberg High-Risk Population

    Clinical Relevance of Post-Tx DSA Monitoring

  • Association of de novo DSA and Non-DSA with Graft Loss

  • Association of de novo DSA and Non-DSA with Graft Loss cut-off 500 MFI

    P

  • P

  • Association of C1q-DSA at the Time of Kidney Transplant Biopsy with Late Graft Failure in

    Pediatric Renal Transplant Recipients

    DSA

    DSA+

    p=0.002

    DSA DSA+, C1q

    DSA+, C1q+ p

  • Heidelberg Adult High-Risk Collective Tx: 2006-2011; Follow up: 09.2013

    Apheresis + Rituximab

    Schfer et al, HLA 2016

    N=74; 16 AMR; 6 AMR-GL; All 6 were post-Tx C1q-DSA-pos.

  • Pre- and post-transplant DSA status and sCD30

    Pre-Tx DSA neg

    Pre-Tx DSA pos C1q-DSA neg Pre-Tx C1q-DSA pos Pre-Tx DSA neg

    Post-Tx DSA neg.

    Post-Tx C1q-DSA neg

    Post-Tx C1q-DSA neg

    Post-Tx C1q-DSA pos De novo C1q-DSA pos

    Number (N) 18 38 11 2 6

    Pre-Tx sCD30 3 (17%) 9 (24%) P=0.73 3 (27%) P=0.65 2 (100%) P=0.05 4 (66%) P=0.04

    Post-Tx sCD30 2/16 (13%) 9/38 (24%) P=0.47 3/10 (30%) P=0.34 1/2 (50%) P=0.31 4/4 (100%) P=0.003

    Heidelberg High-Risk Collective Tx: 2006-2011; Follow up: 09.2013

    Schfer et al. 2015

  • Donor-specific antibodies require preactivated immune system to harm renal transplant

    Caner Ssal1, Bernd Dhler1, Andrea Ruhenstroth1, Christian Morath2, Antonij Slavcev3, Thomas

    Fehr4, Eric Wagner5, Bernd Krger6, Margaret Rees7, Sanja Balen8, Stela ivi-osi8, Douglas

    J. Norman9, Dirk Kuypers10, Marie-Paule Emonds11, Przemyslaw Pisarski12, Claudia

    Bsmller13, Rolf Weimer14, Joannis Mytilineos15 Sabine Scherer1, Thuong H. Tran1, Petra

    Gombos1, Peter Schemmer16, Martin Zeier2, and Gerhard Opelz1

    A Collaborative Transplant Study Report

    EBioMedicine 2016

  • Pre-Tx DSA (Luminex-SA) CDC-/ELISA-Positive Presensitized Recipients

    Ssal et al, EBioMedicine 2016

  • HR=2.95 P

  • 205 patients with AMR in indication biopsy Graft Survival 8 years after AMR:

    Pre-existing DSA: 63% vs. De novo DSA: 34%

    (P

  • www.efi2017.org

  • a) 3.000 MFI fr Hoch-Risiko (Re-Tx oder Klasse I und II AK im Screening) b) 5.000 MFI fr mittelgradiges Risiko (Erst-Tx Empfnger mit nur Klasse I oder II

    AK) c) Bereich zwischen 500/1.000 und 3.000 bzw. 5.000 bleibt Spielraum des

    Zentrums d) Spielraum: Desensibilisierung, Induktion oder Eingabe als NAHA e) Abweichungen sind mglich, mssen allerdings begrndet werden

  • Ssal et al EBioMedicine 2016