R Schwinzer

Ludwig-Maximilian-University of Munich, München, Bavaria, Germany

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Publications (107)320.95 Total impact

  • Transplantation 01/2008; 86. · 3.78 Impact Factor
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    ABSTRACT: The C77G polymorphism in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of C77G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, hepatitis C and human immunodeficiency virus (HIV)-1. C77G individuals overexpress CD45RA isoforms on activated/memory T cells. We have shown previously that aberrant expression of CD45RA isoforms enhances the intensity of T cell receptor (TCR) signalling. Here we report that the C77G polymorphism also influences the responsiveness of T cells to cytokines and alters their adhesion properties. When stimulated by interleukin (IL)-2, C77G T cells proliferated more strongly than wild-type controls and showed accelerated phosphorylation of Janus kinase (Jak1). Furthermore, C77G T cells exhibited a higher tendency to form homotypic aggregates in culture which could be enhanced significantly by antibody-mediated triggering of the variant CD45RA molecules. These data indicate that the changes in CD45 isoform combination resulting from C77G may not only affect TCR signalling but also cytokine-driven T cell responses and cellular adhesion. Altered immune responsiveness may enhance susceptibility of C77G carriers for certain diseases.
    Clinical & Experimental Immunology 01/2008; 150(3):509-17. · 3.28 Impact Factor
  • Xenotransplantation 07/2007; 14(4):371 - 371. · 1.78 Impact Factor
  • Annegret Plege, Katja Borns, Reinhard Schwinzer
    Xenotransplantation 07/2007; 14(4):371-371. · 1.78 Impact Factor
  • Xenotransplantation 07/2007; 14(4):371-372. · 1.78 Impact Factor
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    ABSTRACT: CD45, the leucocyte common antigen, is a haematopoietic cell specific tyrosine phosphatase. Human polymorphic CD45 variants are associated with autoimmune and infectious diseases and alter the phenotype and function of lymphocytes, establishing CD45 as an important regulator of immune function. Here we report four patients with diverse diseases with unusual clinical features. All four have the C77G polymorphism of CD45 exon 4, which alters the splicing and CD45RA/CD45R0 phenotype of lymphocytes. We suggest that C77G may be a contributing factor in these unusual cases.
    Clinical & Experimental Immunology 01/2007; 146(3):448-54. · 3.28 Impact Factor
  • Xenotransplantation 11/2006; 13(6):576-587. · 1.78 Impact Factor
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    ABSTRACT: The applicability of tightly regulated transgenesis in domesticated animals is severely hampered by the present lack of knowledge of regulatory mechanisms and the long generation intervals. To capitalize on the tightly controlled expression of mammalian genes made possible by using prokaryotic control elements, we have used a single-step transduction to introduce an autoregulative tetracycline-responsive bicistronic expression cassette (NTA) into transgenic pigs. Transgenic pigs carrying one NTA cassette showed a mosaic transgene expression restricted to single muscle fibers. In contrast, crossbred animals carrying two NTA cassettes with different transgenes, revealed a broad tissue-independent and tightly regulated expression of one cassette, but not of the other one. The expression pattern correlated inversely with the methylation status of the NTA transcription start sites indicating epigenetic silencing of one NTA cassette. This first approach on tetracycline regulated transgene expression in farm animals will be valuable for developing precisely controlled expression systems for transgenes in large animals relevant for biomedical and agricultural biotechnology.
    The FASEB Journal 07/2006; 20(8):1200-2. · 5.48 Impact Factor
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    ABSTRACT: The 77C-->G mutation in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of 77C-->G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, and HIV-1. To investigate the mechanisms by which the variant allele may contribute to disease susceptibility, we compared T cell reactivity in heterozygous carriers of the mutation (healthy individuals and multiple sclerosis patients) and wild-type controls. In vitro-generated T cell lines and freshly isolated CD4+CD45R0+ primed/memory T cells from 77C-->G individuals aberrantly expressed CD45RA isoforms and showed enhanced proliferation and IL-2 production when stimulated with anti-TCR/CD3 mAb or Ag. Mutant T cell lines contained a more active pool of p56lck tyrosine kinase and responded with increased phosphorylation of Zap70 and TCR-zeta and an enhanced Ca2+ flux to TCR/CD3 stimulation. These data suggest that 77C-->G may act as a risk factor for certain diseases by increasing the intensity of TCR signaling.
    The Journal of Immunology 01/2006; 176(2):931-8. · 5.36 Impact Factor
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    ABSTRACT: Major histocompatibility complex class II (MHC II) peptide complexes can associate with lipid rafts, and this is a prerequisite for their recruitment to the immunological synapse and for efficient T cell stimulation. One of the most often used criterion for raft association is the resistance to extraction by the detergent Triton X-100 (TX-100) at low temperature. For MHC II, a variety of detergents have been used under different conditions, leading to variable and often conflicting conclusions about the association of MHC II with detergent-resistant membranes (DRMs). To clarify whether these inconsistencies were caused by variations in the isolation protocols or reflect different biochemical properties of MHC II lipid complexes, we used two standardized procedures for the isolation of membranes resistant to TX-100, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), or Brij 98. Our results suggest that some of the reported variations in the association of MHC II with DRMs are caused by differences in the methods. We also show that in our hands, specific and efficient flotation of MHC II and the MHC II-associated invariant chain from mouse B-lymphoma cells was only achieved with Brij 98, but not with TX-100 and CHAPS. We furthermore used DRMs prepared from hen egg lysozyme-fed B-lymphoma cells to activate the T cell hybridoma 3A9. In agreement with our biochemical data, T cell activation could only be achieved with Brij 98- but not with TX-100-resistant membranes. Thus, MHC II and also the invariant chain belong to a set of proteins comprising the T cell receptor, prominin, and the prion protein, which reside in membrane environments distinct from conventional lipid rafts.
    Journal of Leukocyte Biology 12/2005; 78(5):1097-105. · 4.30 Impact Factor
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    ABSTRACT: Xenotransplantation of porcine organs into human recipients is a potential option for overcoming the dramatic shortage of suitable donor organs. To date, transgenic modification of pig organs has achieved partial or temporal reduction of xenograft rejection by inhibition of hyperacute rejection. Expression of human tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) in transgenic pigs might be a strategy for controlling posthyperacute rejection mechanisms mediated by cellular components of the immune system. The objective of this study was generation of a transgenic pig model to evaluate the potential of this strategy for xenotransplantation. Transgenic pigs were generated by microinjection of an expression vector for human TRAIL under control of the murine H-2K promoter. Expression of the transgene was analyzed by Western blot and immunohistochemistry. Biologic activity of TRAIL on transgenic porcine lymphocytes was evaluated in co-culture experiments using Jurkat and Hut 78.2 cells as targets. In three lines of transgenic pigs, human TRAIL protein was detected in the membrane fractions of various tissues. Highest expression levels were observed in spleen and lung. Human TRAIL expression on porcine lymphocytes was augmented on activation of cells. Transgenic pig lymphoblasts induced apoptosis in Jurkat and Hut 78.2 cells, which was inhibited by neutralizing anti-TRAIL antibodies, demonstrating a TRAIL-specific effect. Ubiquitous expression of human TRAIL was achieved in transgenic pigs without detrimental side effects. Pigs expressing biologically active human TRAIL will be used for future xenotransplantation experiments to modulate primate anti-pig cellular immune responses.
    Transplantation 08/2005; 80(2):222-30. · 3.78 Impact Factor
  • H-T Do, W Baars, R Schwinzer
    Transplantation Proceedings 01/2004; 37(1):51-2. · 0.95 Impact Factor
  • T Bedke, W Baars, K Borns, R Schwinzer
    Transplantation 01/2004; 78. · 3.78 Impact Factor
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    ABSTRACT: A point mutation in exon A (C to G transversion at position 77) of human PTPRC (CD45) has recently been associated with the development of multiple sclerosis (MS) for at least a subgroup of patients. In the present report, we studied the frequency of the 77C-->G transversion in two other autoimmune diseases namely systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). The mutation was found with significantly enhanced frequency in patients suffering from SSc suggesting that PTPRC could play a role as susceptibility gene not only in MS but also in other autoimmune diseases. Further understanding of the mode of interaction of mutant PTPRC with other susceptibility genes may uncover mechanisms common in various autoimmune disorders.
    Genes and Immunity 03/2003; 4(2):168-9. · 3.79 Impact Factor
  • Tanja Bedke, Wiebke Baars, Reinhard Schwinzer
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    ABSTRACT: Antibody-mediated targeting of pig costimulatory molecules is assumed to be a possible strategy to achieve donor-specific tolerance after xenotransplantation. However, porcine molecules of the B7 family (e.g. CD86) are expressed on typical antigen presenting cells (APC) and also on vascular endothelial cells. Thus, in vascularized porcine xenografts the usage of therapeutic anti-B7 monoclonal antibodies (mAb) might be associated with damage of the endothelium. In the present study we asked whether modulation of human T cell reactivity can be obtained by targeting molecules selectively expressed on pig leucocytes. MAb directed to pig CD45 were tested for their capacity to modulate the in vitro activation of human T cells induced by porcine peripheral blood mononuclear cells. Porcine stimulatory cells induced significant proliferation of human T cells. In the presence of porcine CD45 mAb human T cell responses were reduced by 30-40%. The inhibitory effects were most pronounced when CD45RA mAb were used whereas mAb directed to CD45RC isoforms only moderately inhibited human T cell activation. The tested antibodies had no effects on human T cell activation induced by mitogens or by alloantigen. Manipulation of CD45 molecules on pig leucocytes may reduce their potential to stimulate human T cells. In recipients of vascularized porcine xenografts the usage of anti-pig CD45 mAb could be an approach to block the direct pathway of T cell activation initiated by porcine APC without affecting the endothelium of the graft.
    Annals of transplantation: quarterly of the Polish Transplantation Society 02/2003; 8(3):35-8. · 1.43 Impact Factor
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    ABSTRACT: Graft-versus-host disease (GVHD) after liver transplantation is uncommon, and the outcome is almost always fatal. Since 1987, about 30 cases have been described, and patient survival is mostly exceptional. A 29-year-old man underwent retransplantation due to chronic cholestatic syndrome, 5 years after his first liver transplantation. Indication for the first liver transplantation was acute liver failure caused by exsiccosis. After the second transplantation, the patient had an initially uneventful course, developing thrombocytopenia at day 21 followed by skin rash and septic complications. Diagnosis of acute GVHD was made by using serological techniques for HLA-A and HLA-DRB and subsequently by fluorogenic sequence-specific primed polymerase chain reaction. In addition, donor lymphocytes were marked by immunohistochemical methods via biopsies of the skin. Immunosuppressive therapy was withdrawn to allow the patient's own immune system to eliminate donor cells. By withdrawing the immunosuppressive therapy, clinical and morphological signs of GVHD vanished. The patient is doing well without recurrence 13 months after transplantation. Withdrawal of immunosuppressive therapy is a promising approach in the treatment of acute GVHD to allow the patient's immune system to reconstitute itself, reject offending lymphocytes, and avoid lethal septic complications.
    Transplantation 02/2002; 73(2):307-10. · 3.78 Impact Factor
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    ABSTRACT: The critical shortage of human donor organs has generated growing interest for porcine to human xenotransplantation. The major immunological barrier to xenotransplantation is the hyperacute rejection (HAR) response that is mediated by preformed xenoreactive antibodies and complement. A promising strategy to control the complement activation, is the expression of human complement regulatory proteins in transgenic animals. We have used the human early cytomegalovirus (CMV) promoter to drive expression of the human complement regulatory protein CD59 (hCD59) in transgenic pigs. A total of eight live transgenic founder animals was born from which five transgenic lines could be established. mRNA analysis and Western blotting revealed high expression of hCD59 in heart, kidney, skeletal muscle, and skin in animals of lines 1 and 5, as well as in the pancreas of four lines. This pattern of expression was confirmed by immunhistological staining. A cell-specific expression in heart and kidney tissue of transgenic lines 1 and 5 was determined. Primary fibroblasts and endothelial cell cultures derived from the aorta of transgenic pigs showed a significantly diminished sensitivity against the challenge with xenoreactive human antibodies and complement whereas non-transgenic control cells were highly susceptible to complement mediated lysis. Ex vivo perfusion of kidneys with pooled human blood revealed a significant protective effect of hCD59 against HAR. The average survival of transgenic kidneys was significantly extended (P<0.05) over nontransgenic controls (207.5+/-54.6 vs. 57.5+/-64.5 min). These data support the concept that hCD59 protects nonprimate cells against human complement mediated lysis and suggest that donor pigs transgenic for hCD59 could play a crucial role in clinical xenotransplantation. Two of five hCD59 transgenic lines showed strong hCD59 expression in several organs relevant for xenotransplantation and a protective effect against HAR. This indicates that the use of the CMV-promoter can facilitate the selection process for optimized transgene expression.
    Transplantation 12/2001; 72(12):1898-906. · 3.78 Impact Factor
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    ABSTRACT: Transgenic expression of apoptosis-inducing molecules could be a strategy to protect cells and tissues from destruction by apoptosis-susceptible effector T cells. Some evidence for the potency of this approach has been obtained in mouse and rat transplantation models. However, limited data are available on the capacity of apoptosis-inducing molecules to modulate human alloimmune responses. In this study we analyzed the in vitro consequences of an interaction of human T cells with allogeneic 293 cells and 293 transfectants stably expressing high levels of the apoptosis-inducing CD95 ligand (CD95L). Both, CD95L(-) and CD95L(+) 293 cells were able to activate allogeneic T cells as demonstrated by comparable CD25 expression at day 2 of culture. The analysis of viable T cells at day 7, however, revealed anti-293 cytotoxic activity only in cultures that had been stimulated with CD95L(-) 293 cells. Alloactivated effector T cells lysed CD95L(-) and CD95L(+) 293 targets with similar efficiency when tested in a 4-h 51Cr-release assay. Prolongation of the effector phase to 20 h resulted in a further increase in the destruction of CD95L(-) target cells, whereas lysis of CD95L(+) targets remained low. These data suggest that genetically engineered expression of CD95L on cells or tissues could be an approach to control human T cell reactivity towards allografts. During the induction of an alloimmune response depletion of cytotoxic precursor cells may be obtained by overexpressing CD95L on stimulatory cells; CD95L expression on graft tissue might limit T cell-mediated destruction of the transplant during the effector phase of the response.
    European Journal of Immunology 08/2001; 31(7):2217-26. · 4.52 Impact Factor
  • H J Dulat, W Baars, K Wonigeit, R Schwinzer
    Transplantation Proceedings 02/2001; 33(1-2):262-3. · 0.95 Impact Factor
  • R Schwinzer, W Baars, R Siefken
    Transplantation Proceedings 02/2001; 33(1-2):433-4. · 0.95 Impact Factor

Publication Stats

1k Citations
320.95 Total Impact Points


  • 2005–2012
    • Ludwig-Maximilian-University of Munich
      • • Department of Molecular Animal Breeding and Biotechnology
      • • Chair for Molecular Animal Breeding and Biotechnology
      München, Bavaria, Germany
  • 2008–2011
    • Friedrich Loeffler Institute
      • Institute of Farm Animal Genetics
      Griefswald, Mecklenburg-Vorpommern, Germany
  • 1987–2011
    • Hannover Medical School
      • • Clinic for General, Abdominal and Transplant Surgery
      • • Department of Gastroenterology, Hepatology and Endocrinology
      Hanover, Lower Saxony, Germany
  • 1989–1991
    • Hochschule Hannover
      Hanover, Lower Saxony, Germany