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24. Jahrestagung der Deutschen Transplantationsgesellschaft

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08:00 - 09:30
Wissenschaftliche Sitzung: Immunologie II

Vorsitz: Constanze Schönemann, Berlin; Gunilla Einecke, Hannover

08:00
V040

Immunologische Herausforderungen am Beispiel der Xenotransplantation

*Jan-Michael Abicht1
1 Klinikum der Universität München, Klinik für Anästhesiologie , München, Deutschland
Abstract-Text :

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08:20
V041

Was bedeutet intelligentes Matching?

*Nils Lachmann1
1 Charité Universitätsmedizin, Gewebetypisierungslabor, Berlin, Deutschland
Abstract-Text :

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08:40
V042

Lymphozytotoxtest vs. Luminex Testung: Der Einfluss auf die Wartezeit

*Ondrej Viklicky1
1 Nephrology Clinic, Transplant Centre, Praha 4, Tschechische Republik
Abstract-Text :

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09:00
V043

C1Q-binding ability of donor-specific Anti-HLA antibodies facilitates the identification of harmful antibodies only pre-transplant

*Teresa Kauke1, Oberhauser Cornelia2, Viviane Lin1, Markus  Guba1, Martin  Angele1, Jens Werner1, Michaela Coenen2, Michael Fischereder3, Bruno  Meiser4, Manfred Stangl1, Antje Habicht4
1 Klinikum der Universität München, Klinik für Allgemein-, Viszeral-, Transplantation-, Gefäß- und Thoraxchirurgie, München, Deutschland
2 Ludwig-Maximilians-Universität München, IBE, München, Deutschland
3 Klinikum der Universität München, Medizinische Klinik V, Nephrologie, München, Deutschland
4 Klinikum der Universität München, Transplantationszentrum, München, Deutschland
Abstract-Text :

Background: The impact of donor-specific (DSA) and non donor-specific (nDSA) anti-HLA antibodies detected only by solid phase assay on graft outcome after renal transplantation is still a matter of debate. Differentiating HLA-antibodies by their ability to bind the complement product C1q might enable a better risk assessment. Therefore we investigated the clinical relevance of pre- and posttransplant C1q binding HLA-antibodies on graft outcome in our center.


Methods: We analyzed the sera of 611 renal allograft recipients who were transplanted between January 2005 and December 2011. The presence of HLA-antibodies and their C1q binding capacity was studied by Luminex Assay prior and after transplantation. Acute rejection (AR) episodes, graft dysfunction (20% increase in creatinine in yearly intervals) and graft survival were assessed within a median follow-up of 4.9 years.


Results: 109/611 (17.9%) patients were immunized at time of transplantation with only 2.6% showing pre-existing DSA und 15.2% nDSA. After transplantation 39/611 (6.4%) recipients developed deNovo DSA and 68/611 (11.1%) deNovo nDSA. While neither pre-existing nor deNovo nDSA significantly influenced the rate of AR, graft function and/or survival, DSA significantly impaired renal function. However, pre-existing DSA influenced AR rates (C1q- vs C1q : 33 vs 40%) and graft survival (C1q- vs C1q : 30 vs 50%) only if they were C1q binding  while the development of deNovo DSA was associated with a significant increase in AR (C1q- vs C1q : 50 vs 63%), and overall graft loss (C1q- vs C1q : 42 vs 55%%) independently of the of their ability to bind C1q.


Conclusion: Distinguishing HLA-antibodies by their C1q-binding ability facilitates the identification of renal transplant recipients at immunologic risk only in DSA, which are pre-existing but not in those which develop deNovo post transplant.



09:10
V044

Non-HLA antibodies targeting Angiotensin II Type 1 receptor and Endothelin-1 Type A receptor induce mTOR signaling and endothelial injury in human microvascular endothelium

*Angelika Kusch1, Rusan Catar1, Oskar Wischnewski1, Duska Dragun1
1 Charité Universitätsmedizin Berlin, , Berlin, Deutschland
Abstract-Text :

Functional non-HLA antibodies targeting G protein-coupled receptors (GPCR) Angiotensin II Type 1 receptor (AT1R) and Endothelin-1 Type A receptor (ETAR) are implicated in the pathogenesis of renal and cardiac transplant vasculopathy. Both antibodies activate canonic G-protein related ERK 1/2. While ERK signaling may represent general cellular response to agonist stimulation, the molecular link between receptor stimulation and development of vascular obliterative lesion has not been fully established yet. We hypothesized the involvement of PI3K/Akt downstream signaling target mammalian target of rapamycin (mTOR) and assessed functional consequences of AT1R- and ETAR-activation by non-HLA antibodies. Human microvascular endothelial cells (HMEC) with reliable expression of target antigens were stimulated with AT1R-Ab and ETAR-Ab containing IgG from patients with obliterative vasculopathy. Phospho-specific antibodies against ERK and mTOR downstream targets were used to assess activation of mTORC1 (pp70S6K at Thr389) and mTORC2 (pAkt at Ser473). Scratch assay was employed to study effect of non-HLA-antibodies on wound healing. Involvement of AT1R/ETAR activation in non-HLA antibody downstream signaling was addressed by use of specific inhibitors for AT1R (Valsartan) and ETAR (Sitaxentan). Signaling activity of both, mTORC1 and mTORC2, was increased after short and long term treatment with patient IgG compared to cells treated with IgG from healthy controls. This effect could be inhibited by preincubating the cells with specific inhibitors of AT1R and ETAR. Both, activation of mTORC1 and mTORC2 were PI3K-dependent and independent from ERK-activation. mTOR inhibitor rapamycin completely abolished non-HLA antibodies induced activation of mTORC1 and in addition mTORC2 after long term treatment. Impaired wound healing by non-HLA antibodies could be restored by either use of specific AT1R or ETAR inhibitors. We provide evidence that functional targeting AT1R and ETAR auto-antibodies induce mTORC1 and mTORC2 signalling which is independent of canonic ERK 1/2 activation in human microvascular endothelium. Our data on impaired AT1R and ETAR-dependent wound healing induced by non-HLA antibodies may provide a translational rationale for therapeutic AT1R and mTOR inhibitors in patients with non-HLA antibodies.



09:20
V045

Biopsy-proven rejection in children after liver transplantation is associated by an IL-12p40-mediated innate immune response followed by Th1 T cell activation 

*Christine Falk1, Imeke Goldschmidt2, Frauke Mutschler2,3, Eva Pfister2, Frank Lehner4, Christine Neudörfl1, Jana Keil1, Kerstin Daemen1, Andre Karch5, Rafael Mikolajczyk5, Ulrich Baumann2
1 Medizinische Hochschule Hannover, Institut für Transplantationsimmunologie, Hannover, Deutschland
2 Medizinische Hochschule Hannover, Pädiatrische Nieren- und Stoffwechselerkrankungen, Hannover, Deutschland
3 Medizinische Hochschule Hannover, , Hannover, Deutschland
4 Medizinische Hochschule Hannover, Abteilung Viszeral-, Transplantationschirurgies, Hannover, Deutschland
5 Helmholtz-Zentrum für Infektionsforschung, Epidemiologie, Braunschweig, Deutschland
Abstract-Text :

Background: The concept of a coordinated immune response initiated by innate and sustained by adaptive immune cells and their soluble mediators is well established for infection but it has not been demonstrated for solid organ transplantation in humans. Therefore, we wanted to identify a sequence of innate and adaptive immune reactions in children after liver transplantation that correlated with rejection as clinical outcome.   


Subjects and methods: In the frame of the CHILSFree study, 32 children, aged 3 months to 16 years, were liver transplanted at MHH for end stage liver disease. Lymphocyte subsets as well as cytokines and chemokines in peripheral blood were quantified by flow cytometry and multiplex technique before, weekly up to 4 weeks after LTx.


Results: Three major patterns could be identified among T, B and NK cell subsets correlating with their respective cytokines and chemokines. A first innate response wave by IL-12p40, sCD25, TRAIL and NK cells was identified in 50% of patients. However, only if this 1st wave was followed by a 2nd wave of adaptive response, i.e. T cell expansion and elevated levels of IFN-g, IL-1RA, IL-13, IL-17, CCL5 and CXCL10, clinically relevant rejection was associated in form of biopsy-proven acute rejection (PBAR). In contrast, if all cellular and soluble parameters remained silent, this non-reactive status was associated with a stable transplant which was presumably achieved by sufficient immunosuppressive treatment.


Conclusion: The quantification of a panel of cellular and soluble immune markers during the first weeks after pediatric liver Tx may provide relevant information for an early detection of the risk of rejection and enable us to identify markers that allow an optimization of immunosuppressive treatment.