@article{UlrichsNoethlingKelleretal.1987,
  author    = {Ulrichs, Karin and N{\"o}thling, R. and Keller, R. and Heusermann, U. and M{\"u}ller-Buchholtz, W.},
  title     = {Genetically determined variation of constitutive major histocompatibility complex class II antigen expression in various rat strains and cell types},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-44769},
  year      = {1987},
  abstract  = {No abstract available},
  subject      = {Chirurgie},
  language  = {en}
}
@article{EcksteinUlrichsMeinckeetal.1992,
  author    = {Eckstein, V. and Ulrichs, K. and Meincke, G. and M{\"u}ller-Ruchholtz, W.},
  title     = {Natural xenophile antibodies from sera of type I diabetic patients differ strongly in their reactivity against various porcine pancreatic cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45277},
  year      = {1992},
  abstract  = {No abstract available},
  subject      = {Chirurgie},
  language  = {en}
}
@article{DeltzMuellerHermelinkUlrichsetal.1981,
  author    = {Deltz, E. and M{\"u}ller-Hermelink, HK and Ulrichs, Karin and Thiede, A. and M{\"u}ller-Ruchholtz, W.},
  title     = {Development of graft-versus-host reaction in various target organs after small intestine transplantation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45459},
  year      = {1981},
  abstract  = {The GVHRIL foHowing transplantation of small intestine are different from those found after bone marrow transplantation or spleen cell injections in that they show a remarka ble, significant prevalence of lesions within the intestinal mucosa. These findings are consistent with the observation that jntestinal lymphocytes newly formed in mesenteric lymph nodes predominantly home in on the intestine again.\& The degree of histologic alteration within different tissues indicates that the graft and the host may survive the lesions of the lymphatic tissues, whereas the severe intestinal lesions following GVHR may easily cause death of the recipient. With regard to clinical sman bowel transplantation two statements can be made: (l) GVHRIL play a significant role in small bowel trans~ plantation. (2) To minimize their biologic importance, a selective elimination of the graft's Jymph nodes by irradiation or surgical resection should be considered in view of the remarkable difference between GVHRIL in lymph nodes and in the graft's intestinal wall itself.},
  subject      = {Chirurgie},
  language  = {en}
}
@article{WaagaKrzymanskiUlrichsetal.1993,
  author    = {Waaga, AM and Krzymanski, M. and Ulrichs, Karin and Wierusz-Wysocka, Bogna and M{\"u}ller-Buchholtz, Wolfgang},
  title     = {Hematological effects of the new immunosuppressive drug 15-deoxyspergualin},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-44701},
  year      = {1993},
  abstract  = {Since systematic hematological studies on blood and bone marrow changes after treatment with 15-Deoxyspergualin (DOS) are lacking, a quantitative assessment was performed fourteen or twenty eight days after intraperitoneal application of DOS to rats. Further observations done 7 and 14 days after discontinuation of DOS administration allowed analysis of banc marrow regeneration. DOS induced lymphocytopenia, granUlocytopenia and anemia with a decrease of bone marrow cellularity due to suppression of cell maturation. The effect was dose-dependent and bone marrow as well as blood changes were observed in animals treated with doses from 0.5 to 10.0 mg/kg DOS. Within 14 days after termination of the treatment, rapid recovery with normalization of all hematological parameters was observed. In the light of our data, these hematological side effects may not be a major disadvantage, if DOS is used in doses below 2.5 mg/kg, and for a course of therapy which is limited to 7 to 14 days.},
  subject      = {Chirurgie},
  language  = {en}
}
@article{HeiserUlrichsMuellerBuchholtz1994,
  author    = {Heiser, Axel and Ulrichs, Karin and M{\"u}ller-Buchholtz, Wolfgang},
  title     = {Isolation of porcine pancreatic islets: low trypsin activity during the isolation procedure guarantees reproducible high islet yields},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-44719},
  year      = {1994},
  abstract  = {During the past few years, interest in xenotransplantation of porcine islets of Langerhans for the future therapy of type I diabetes has Increased markedly. Therefore, we established a semiautomated digestion method for isolating islets from the porcine pancreas. However, although the isolation technique was standardized and collagenase of controlled quality was used, we were unable to attain high islet yields with a satisfactory degree of reproducibility. One hypothesis was that varying degrees of interference by donor pancreatic enzymes were responsible for this failure. The aim of this stUdy was to examine the kinetics of four types of enzymatic activity during the isolation procedure, as well as their effects on islet yield: collagenase, trypsin, neutral protease, and clostripaln. Our results indicate that while exogenous collagenase activity decreases slightly during the isolation procedure, the activity of the pancreas enzymes neutral protease and trypsin increases. In some cases, trypsin activity increases very strongly. A strong increase in trypsin activity correlates with poor islet yield, whereas low trypsin activity always correlates with high islet yield. Addition of the protease inhibitor Pefabloc to the isolation medium results in low trypsin activity and reproducible high islet yields.},
  subject      = {Langerhans-Inseln},
  language  = {en}
}
@article{WinotoMorbachUlrichsHeringetal.1990,
  author    = {Winoto-Morbach, S. and Ulrichs, Karin and Hering, BJ and Leyhausen, G. and M{\"u}ller-Ruchholtz, W.},
  title     = {Lectins for electromagnetic purification of islets from humans and large mammals},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45430},
  year      = {1990},
  abstract  = {No abstract available},
  subject      = {Chirurgie},
  language  = {en}
}
@article{UlrichsMuellerRuchholtz1990,
  author    = {Ulrichs, Karin and M{\"u}ller-Ruchholtz, W.},
  title     = {Mixed lymphocyte islet culture (MLIC) and its use in manipulation of human islet alloimmunogenicity},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45515},
  year      = {1990},
  abstract  = {No abstract available},
  language  = {en}
}
@article{UlrichsKuhlencordtMuellerRuchholtz1979,
  author    = {Ulrichs, Karin and Kuhlencordt, KM and M{\"u}ller-Ruchholtz, W.},
  title     = {Plating inhibition assay (PIA): a new test for cell mediated cytotoxicity},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45443},
  year      = {1979},
  abstract  = {No abstract available},
  language  = {en}
}
@article{UlrichsDeltzThiedeetal.1982,
  author    = {Ulrichs, Karin and Deltz, E. and Thiede, A. and M{\"u}ller-Ruchholtz, W.},
  title     = {Lymphoid tissue transplantation in rats leads to a GVHR, inducing a specific T-cell mediated autoreactivity against MHC-antigens},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45420},
  year      = {1982},
  abstract  = {No abstract available},
  language  = {en}
}
@article{UlrichsMuellerBuchholtz1985,
  author    = {Ulrichs, Karin and M{\"u}ller-Buchholtz, W.},
  title     = {MHC class II antigen expression on the various cells of normal and activated isolated pancreatic islets},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-44722},
  year      = {1985},
  abstract  = {It is the aim of this study to characterize and quantify the cells within isolated rat islets that express MHC class 11 antigens. A set of five monoelonal antibodies and two polyclonal antisera of defined specificlty were used in combination with a newly devised procedure for three·dimensional immunofluorescence evaluation of intact islets. It is shown that in addition to passen· ger cells, such as Iymphocytes, macro· phages, and dendrlticlike cells, vascular endothelial and endocrine cells are also capable of expressing class 11 antigens. This expression Is strongly influenced by in vitro culture. pregnancy, streptozotocin- induced diabetes, transplantation trauma, and alloantigenic stimuli. The pos· sible role of the above cells in antigen presentation related to islet transplantation is discussed.},
  language  = {en}
}
@article{UlrichsSchangKelleretal.1984,
  author    = {Ulrichs, Karin and Schang, T. and Keller, R. and M{\"u}ller-Ruchholtz, W.},
  title     = {Reactivity of pancreas islet cells with antisera of known specificity},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45466},
  year      = {1984},
  abstract  = {No abstract available},
  language  = {en}
}
@article{HeiserUlrichsMuellerRuchholtz1994,
  author    = {Heiser, A. and Ulrichs, Karin and M{\"u}ller-Ruchholtz, W.},
  title     = {Prophylactic trypsin inhibition during the isolation procedure guarantees reproducible, high porcine islet yields},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45531},
  year      = {1994},
  abstract  = {Abstract: For isolating islets from the porcine pancreas, we established a semiautomated digestion method. Although the isolation technique was standardized and collagenase of controlled quality was used, until now the reproducibility of high islet yields was unsatisfactory. Our hypothesis was that pancreatic trypsin was responsible for this failure. The aim of this study was to investigate the effect of endogenous trypsin on islet yield. Our results demonstrate that a high trypsin level correlates with poor islet yield, whereas low trypsin activity always correlates with high islet yield. Specific inhibition of trypsin results in low trypsin activity and reproducible, high islet yields.},
  language  = {en}
}
@article{EngemannUlrichsThiedeetal.1990,
  author    = {Engemann, R. and Ulrichs, Karin and Thiede, A. and M{\"u}ller-Ruchholtz, W. and Hamelmann, H.},
  title     = {Value of a physiological liver transplant model in rats. Induction of specific graft tolerance in a fully allogeneic strain combination},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45622},
  year      = {1990},
  abstract  = {No abstract available},
  language  = {en}
}
@article{UlrichsYuDunckeretal.1984,
  author    = {Ulrichs, Karin and Yu, MY and Duncker, D. and M{\"u}ller-Ruchholtz, W.},
  title     = {Immunosuppression by cytostatic drugs?},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45574},
  year      = {1984},
  abstract  = {In the present study, an attempt was made to characterize the immunomodulating abilities of the cytostatic drugs cydophosphamide, ifosfamide, vinblastine, vincristine, procarbazine, dacarbazine, 6-mercaptopurine, methotrexate, 5-f/uor-uracil and adriamycine in a defined experimental model. Varying combinations of drug plus transplantation alloantigen, (C3H-lymphocytes) were injected into Balb/c mice at different time intervals in vivo. The resulting T-effector cell reactivity was determined in vitro with the microcytotoxicity assay on day + 5 for primary (r) and day + 7 for secondary (2°) sensitized mice. According to the type of drug (alkylating agent vs. vinca alkaloid vs. antimetabolite vs. cytostatic antibiotic), the dosage (20\% LD50 vs. 60\% LD50), the state of sensitization (r vs. 2° sensitized recipients), and the time of drug application in relation to the antigen treatment on day 0 (in varying steps from day -6 to day +4), so-called "pharmaconantigen- variation-effects" (PA VE) were established for each of the investigated drugs in form of reaction profiles. The results were as folIows: (1) For almost alt substances, characteristic reaction profiles involving immunostimulation and/or immunosuppression could be established. Similarities in the profiles of different substances made it possible to classify the drugs according to different reaction types. The reaction type however is not definitely correlated to the biochemical mechanism of drug action. (2) The PA VE are decisively inf/uenced by so me of the biological parameters, such as the time of drug application in relation to the antigen treatment and the state of sensitization but relatively !ittle by the dosage of the drug. (3) Considering the different processes occurring du ring primary and secondary immune responses, the PAVE may give hints for a distinct manipulation of the immunoregulation and thus information on the immunobiological mechanism of drug action.},
  subject      = {Immunologie},
  language  = {en}
}
@inproceedings{KaitschickUlrichsMuellerRuchholtz1991,
  author    = {Kaitschick, J. and Ulrichs, K. and M{\"u}ller-Ruchholtz, W.},
  title     = {The New Immunosuppressant Leflunomide Appears To Be a Potent Inhibitor of Humoral Xeno Sensitization},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45727},
  year      = {1991},
  abstract  = {No abstract available},
  subject      = {Immunbiologie},
  language  = {en}
}
@inproceedings{WinotoMorbachUlrichsMuellerRuchholtz1991,
  author    = {Winoto-Morbach, S. and Ulrichs, Karin and M{\"u}ller-Ruchholtz, W.},
  title     = {New Developments in Biodegradable Microspheres For Magnetic Separation Techniques},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45712},
  year      = {1991},
  abstract  = {No abstract available},
  subject      = {Immunbiologie},
  language  = {en}
}
@inproceedings{EcksteinUlrichsMeinckeetal.1991,
  author    = {Eckstein, V. and Ulrichs, Karin and Meincke, G. and M{\"u}lller-Ruchholtz, W.},
  title     = {Transplantation of Diabetic Patients With Xenogeneic Pancreatic Islets Has to Consider Natural Xenophile Antibodies (NXA) In Patients Sera As a Major Obstacle to Success},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45707},
  year      = {1991},
  abstract  = {No abstract available},
  subject      = {Immunbiologie},
  language  = {en}
}
@misc{UlrichsMuellerRuchholtz1989,
  author    = {Ulrichs, Karin and M{\"u}ller-Ruchholtz, W.},
  title     = {Identification and Manipulation of Human Islet Alloimmunogenicity: Morphologic and Functional in Vitro Studies with Various Islet Preparations},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45584},
  year      = {1989},
  abstract  = {No abstract available},
  subject      = {Immunbiologie},
  language  = {en}
}
@inproceedings{HeiserUlrichsMuellerRuchholtz1994,
  author    = {Heiser, A. and Ulrichs, Karin and M{\"u}ller-Ruchholtz, W.},
  title     = {Enzyme Activities in Commercial Collagenase Preparations and Their Kinetics During Islet Isolation Procedure},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45633},
  year      = {1994},
  abstract  = {No abstract available},
  subject      = {Transplantation},
  language  = {en}
}
@inproceedings{WangUlrichsMuellerRuchholtz1993,
  author    = {Wang, HY and Ulrichs, Karin and M{\"u}ller-Ruchholtz, W.},
  title     = {Down-Regulation of Xenophile Antibodies by Specific Immunosuppressive Protocols to Facilitate Xenogeneic Organ Transplantation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45669},
  year      = {1993},
  abstract  = {No abstract available},
  subject      = {Immunbiologie},
  language  = {en}
}
@inproceedings{UlrichsEcksteinKorsgrenetal.1993,
  author    = {Ulrichs, Karin and Eckstein, V. and Korsgren, O. and M{\"u}ller-Ruchholtz, W.},
  title     = {Expression of Porcine Pancreatic Islet Antigens Varies and Determines Binding of Human Natural Xenophile Antibodies (NXA)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45655},
  year      = {1993},
  abstract  = {No abstract available},
  subject      = {Immunbiologie},
  language  = {en}
}
@inproceedings{HedkeEcksteinMayetal.1993,
  author    = {Hedke, K. and Eckstein, V. and May, G. and Kaden, J. and M{\"u}ller-Ruchholtz, W. and Ulrichs, Karin},
  title     = {Production of Xenophile Antibodies (XA) in Type I Diabetic Patients is Strongly Influenced by Diabetes and/or Dialysis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45642},
  year      = {1993},
  abstract  = {No abstract available},
  language  = {en}
}
@inproceedings{HeiserUlrichsEcksteinetal.1992,
  author    = {Heiser, A. and Ulrichs, Karin and Eckstein, V. and M{\"u}ller-Ruchholtz, W.},
  title     = {The Human Cell Mediated Response to Xenogeneic (Porcine) Transplantation Antigen Depends on the Stimulator Cell Compartment},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45670},
  year      = {1992},
  abstract  = {No abstract available},
  language  = {en}
}
@inproceedings{UlrichsEulerMuellerRuchholtz1991,
  author    = {Ulrichs, Karin and Euler, HH and M{\"u}ller-Ruchholtz, W.},
  title     = {A Clinically Successful Protocol to Suppress Autoantibody Production in SLE Patients Is Analyzed For Its Efficacy To Inhibit Natural Xenophile Antibodies (NXA)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45693},
  year      = {1991},
  abstract  = {No abstract available},
  language  = {en}
}
@article{WinotoMorbachUlrichsLeyhausenetal.1989,
  author    = {Winoto-Morbach, Supandi and Ulrichs, Karin and Leyhausen, Gaby and M{\"u}ller-Ruchholtz, Wolfgang},
  title     = {New principle for large-scale preparation of purified human pancreas islets},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45600},
  year      = {1989},
  abstract  = {Because successful human islet transplantation requires large quantities of viable islets that must be separated from the highly immunogenic exocrine tissue and because handpicking is too time-consuming and laborious to be clinically relevant, a new approach for solving this problem has been established in rat models. It is based on the principle that magnetic microspheres (MMSs) coupled to lectins with binding specificity for the exocrine tissue portion are trapped in an electromagnetic field, thus providing effluent islets of a high degree of purity. In this study our aim was to adapt this princip'le to human islet preparations. In this context our prime interest was focused on a lectin suitable for human pancreatic tissue. Of 19 different lectins tested, only 1, Wisteria floribunda agglutinin (WFA), is suitable, as shown by immunofluorescence, MMS-Iectin binding, and magnetic separation},
  subject      = {Immunbiologie},
  language  = {en}
}
@article{VonGaudeckerUlrichsMuellerRuchholtz1989,
  author    = {Von Gaudecker, Brita and Ulrichs, Karin and M{\"u}ller-Ruchholtz, Wolfgang},
  title     = {Immunoelectron microscopic localization of MHC structures in isolated pancreatic rat islets},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45596},
  year      = {1989},
  abstract  = {An immunogold-silver enhancement technique, which combines effective labeling of viable isolated islets with the ultrastructural resolution of cytological details, was applied in electron microscopy to identify major histocompatibility complex (MHC) structures on islet cells. Incubation of freshly isolated islets from CAP (RT1C) and LEW (RT1') rats with OX18, an MHC class I antibody, showed strong positive reactivity in macrophages and/or dendritic-like cells (M0-DCs) and vascular endothelial cells (VEs) and a comparatively weaker reactivity in endocrine a-, p-, and 8-ce"s. With MHC class" antibody OX6 (anti-I-A), M0-DCs were strongly labeled in both rat strains on the surface and on internal structures. Three of five particularly high titered batches of OX6 revealed MHC class" expression on VE and p-ce"s. Four days of in vitro culture in combination with a high concentration of glucose and interferon-'Y induced strong enhancement of MHC class I structures and, to a lesser extent, class " structures on p-ce"s.},
  subject      = {Immunbiologie},
  language  = {en}
}
@article{KekowUlrichsMuellerRuchholtzetal.1988,
  author    = {Kekow, J{\"o}rn and Ulrichs, Karin and M{\"u}ller-Ruchholtz, Wolfgang and Gross, Wolfgang L.},
  title     = {Measurement of rat insulin. Enzyme-linked immunosorbent assay with increased sensitivity, high accuracy, and greater practicability than established radioimmunoassay},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45543},
  year      = {1988},
  abstract  = {Total immunoreactive insulin (IRI) is conventionally determined by radioimmunoassays. IR! measurement in rats can be made more sensitive, accurate, and practical, as demonstrated by a new modified enzyme-linked immunosorbent assay (ELlSA). It is characterized by indirect binding of an anti-insulin antibody by an antiglobulin antibody and uses the principle of competitive saturation. In this ELlSA, IRI can be determined in a wide range of concentrations, corresponding to the standards. The standard curve ranges from 100 to 0.049 ng/mllRI (1 ng/ml - 23.4 JLU/ml - 172 pM rat insulin). The statistical analysis shows between- and within-assay coefficients of variation of :515\%. Diabetes 37:321-26,1988},
  subject      = {Chirurgie},
  language  = {en}
}
@inproceedings{HeiserUlrichsEcksteinetal.1992,
  author    = {Heiser, A. and Ulrichs, Karin and Eckstein, V. and M{\"u}ller-Ruchholtz, W.},
  title     = {Xenogeneic Cellular Response of Human Lymphocytes Against Porcine Lymphocytes and Isolated Pancreatic Islets},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45479},
  year      = {1992},
  abstract  = {no abstract available},
  language  = {en}
}
@inproceedings{HeiserUlrichsMuellerRuchholtz1994,
  author    = {Heiser, A. and Ulrichs, Karin and M{\"u}ller-Ruchholtz, W.},
  title     = {Enzyme Kinetics of Commercial Collagenases and their Influence on Porcine Islet Isolation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-45488},
  year      = {1994},
  abstract  = {No abstract available},
  subject      = {Heterotransplantation},
  language  = {en}
}
@phdthesis{Tiurbe2006,
  author    = {Tiurbe, George Christian},
  title     = {Characterization of immature rat bone marrow-derived dendritic cells : Evaluation of their phenotype and immunomodulatory properties in vitro and after organ transplantation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-21429},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2006},
  abstract  = {Solid organ transplantation is an established therapeutic approach in modern medicine to extend and to improve the life of patients in the final stages of organ failure. Transplantation between genetically non-identical individuals leads to the activation of the transplant recipient's immune system. This alloimmune response is a consequence of the recognition of foreign MHC molecules by alloreactive host T cells. To prevent their activation and the subsequently induced activation of further cell subsets (e.g. B cells, cytotoxic T cells, macrophages)immunosuppressive drugs are absolutely necessary in the clinic. However,permanent immunosuppression leads to severe side effects such as nephrotoxicity, diabetes and hyperlipidaemia, and a reduced immunity to infections and malignant diseases. At the moment, there is no real alternative to immunosuppression. The purpose of this study was to analyse the importance of rat dendritic cells with immune inhibitory properties to prevent the immune activation after experimental transplantation. The rat is one of the most important animal models for experimental organ transplantation in a clinic-relevant procedure. In order to modulate the immune response after transplantation in an antigenspecific manner, the strategy should include the alloantigens. These antigens have to be presented by immature dendritic cells in the absence of costimulatory signals in order to turn alloreactive T cells into anergic or regulatory T cells instead of effector T cells. For a certain rat model of allograft rejection,the immunodominant peptide P1 was identified as an important alloantigen which accelerates graft rejection. Such a model offers an attractive and practical approach to analyse the potential of host tolerogeneic dendritic cells pulsed with P1 to suppress the allograft-induced immune response in an antigen-specific manner without the need of chronic immunosuppression. A homogenous population of rat immature dendritic cells was generated from bone marrow precursors cultured with GM-CSF and IL-4 (= IL-4 DCs) or GM65 CSF and IL-10 (= IL-10 DCs). These cells with an identical immature phenotype showed no or a very low surface expression of costimulatory molecules like CD80 and CD86 and a 10-fold reduced expression of MHC class II molecules in comparison to mature splenic DCs. No obvious difference was observed between the phenotype of the IL-4 DCs and the IL-10 DCs. Neither IL-4 DCs nor IL-10 DCs were able to activate na{\"i}ve T cells or to restimulate antigen-specific T cells. This strong inhibitory effect, mediated within 24 hours, was dependent on the number of immature dendritic cells added to the proliferation assay. Antigen-specific T cells pre-incubated with IL-4 DCs and IL-10 DCs, respectively, were not able to proliferate in the presence of P1-pulsed mature DCs. This anergic state was reversible with the addition of exogenous IL-2. T cells incubated with IL-4 DCs (= IL-4 DC-Ts) were able to inhibit the T cell proliferation in a cell number dependent manner. In contrast, antigen-specific T cells pre-incubated with P1-pulsed IL-10 DCs (= IL-10 DC-Ts)showed no effect on the proliferation assay. This was the unique difference between IL-4 DCs and IL-10 DCs found in the present study. Immature DCs influenced also the immune response after transplantation. Different numbers of P1-loaded immature IL-4 DCs and IL-10 DCs were transferred intravenously into Lewis rats one day before transplantation. The best results were obtained with 30 million P1-pulsed immature DCs which prolonged the survival time to a median of 11.2 ± 1.6 days. In addition, the antigen specificity of this effect was demonstrated with a third-party graft from Brown Norway donors. These findings suggest that an antigen-specific modulation of the immune response is possible using immature dendritic cells loaded with the allogeneic antigens. Even more, the protocols described in the present study show that the immune system can be, at least temporarily, controlled after transplantation without the use of immunosuppressive drugs.},
  language  = {en}
}
@phdthesis{Sitaru2003,
  author    = {Sitaru, Ana Gabriela},
  title     = {Modulation of the T cell response with MHC class I peptides and their analogues},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-4561},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2003},
  abstract  = {Transplantation is now firmly established as a therapeutic approach to extend and improve the life of patients in the final stages of organ failure. It has been demonstrated that transplantation between genetically non-identical individuals leads to the activation of the recipient's alloimmune response as a major determinant of transplant outcome. T cell recognition of foreign MHC molecules plays a key role in initiating and sustaining allograft rejection. To prevent the risk of rejection, patients are given immunosuppressive drugs, which are non-specific and have major side-effects (infections, malignancies). It has been shown that the alloreactive T cells specifically recognize donor MHC-derived peptides. This implies that it may be possible to develop antigen-specific strategies in order to modulate the alloimmune response by peptide analogues and specifically altered peptide ligands. The purpose of this study was to explore the potential of "recipient-adapted" analogues from the dominant MHC class I peptide to modulate the alloimmune response. Beside the significant role of donor dominant determinants in the rejection process, we tested seven 13-to-24-mer peptides from the Wistar-Furth MHC class I molecule (WF, RT1.Au) for their possible immunogenicity in a fully MHC-mismatched WF to Lewis (LEW, RT1l) rat strain combination. Secondly, the immunodominant allopeptide was selected to generate analogues in order to investigate their modulatory capacity. All peptides were tested in vitro in a standard proliferation assay and in vivo using a heterotopic heart transplantation model. Our findings show that five peptides (P1-P5) were able to induce specific T cell proliferation in LEW responders. Furthermore, we found a hierarchical distribution of the determinants: peptide P1 as a good candidate for the immunodominant determinant, while P2, P3, P4, and P5 as subdominant epitopes and the other two peptides, P6 and P7, as non-immunogenic determinants of WF MHC class I molecule. Furthermore, the dominance of P1 was confirmed by the strong proliferation induced after immunization with a mixture of peptides in the presence of P1. This hierarchical distribution of the proliferative response correlated with the cytokine production. Peptide P1, comprising only 3 allogeneic amino acids (L5, L9, and T10) induced the strongest T cell proliferation and produced high levels of cytokines, especially IL-2 and IFN-g. In addition, the immunodominance of peptide P1 was confirmed by the significant reduction in the allograft survival time in comparison to the non-immunized control animals. Since the TCR Vß repertoire of rejected graft-infiltrating cells in rejected allografts was similar to the profile observed after in vitro restimulation of P1-primed T cells, we concluded that peptide P1 is able to activate the alloreactive T cell population. Our results demonstrate the particular role of the dominant peptide P1 (residues 1-19) in the allograft rejection in WF to LEW rat strain combination. In the second set of experiments, we investigated the fine specificity of the dominant peptide P1-activated T cells using peptide analogues from P1. The "recipient-adapted" analogues were designed by changing the allogeneic RT1.Au amino acids (L5, L9, T10) one-by-one with the correspondent syngeneic RT1.Al amino acids (M5, D9, I10) in the sequence of peptide P1. The six peptide analogues (A1.1-A1.6) consisting of either one or two allogeneic amino acids were able to induce a specific T cell proliferative response and cytokine production. Analogue A1.5 with only one allogeneic amino acid (L5) was of particular interest because it induced a low T cell proliferation and high cytokine levels, especially IL-4 and IL-10. In addition, immunization with A1.5 did not influence the allograft survival time in comparison to the non-immunized LEW recipients. A1.5 was the only analogue able to down-regulate the proliferation of P1-primed T cells. Our results reveal that A1.5 is an MHC competitor as confirmed by the in vitro MHC competition assay and the inhibition of the negative effect of P1 on the allograft survival time when recipients were immunized with a mixture of P1 and A1.5. These findings suggest that it is possible to design peptide analogues, such as A1.5, which do not stimulate the dominant peptide P1-specific T cell population and even more, are able to block its presentation in the MHC molecule. In all, the results indicate that the specific suppression of indirect allorecognition can be achieved by using peptide analogues of the dominant allopeptide.},
  language  = {en}
}