Walter Schmidt

AFFiRiS AG, Wien, Vienna, Austria

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Publications (16)36.13 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in Leucine-rich repeat kinase 2 (LRRK2) are frequently involved in both familial and sporadic forms of Parkinson’s disease (PD). Until now, no functional murine LRRK2 transgenic model is publicly available that fully recapitulates the clinical symptoms of PD. We recently developed a novel mouse model of Parkinson’s disease over-expressing human wild-type LRRK2 under the control of the neuron specific Thy1.2 promoter. In order to determine whether neuron-specific over-expression of human wild-type LRRK2 would lead to phenotypic alterations in this novel mouse model for PD, we started to implement a battery of classical behavioural tests. Mice were subjected to behavioural testing at 4, 8, 12 and 16 months of age. After completing a modified SHIRPA screen for general health and reflexes, animals were tested for cognitive, functional and motoric alterations assessing anosmia, nesting behaviour, memory deficits, and deficits in grip strength, endurance and motor-coordination. We found that expression of human LRRK2 under the control of the neuron specific Thy1.2 promoter results in viable offspring, which develops age dependent, progressive phenotypical alterations at around 8 months of age. Results depicting these deficits will be discussed. Based on the initial findings presented, this novel transgenic model over-expressing LRRK2 could be instrumental to further elucidate the biologic and pathologic role of Leucine repeat rich kinase-2 (LRRK2) in the nervous system and could thus be a suitable tool for studying the effects of therapeutic drugs for PD in animals.
    10th International Conference AD/PD, Barcelona, March 2011; 03/2011
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2011; 7(4).
  • Markus Mandler, Walter Schmidt, Frank Mattner
    Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2011; 7(4).
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    ABSTRACT: Neurodegenerative diseases are still an area of unmet medical need. This is in contrast to our increasing knowledge on their pathology (e.g., Alzheimer's- (AD), Parkinson's (PD) disease). They are driven by the cerebral accumulation and aggregation of specific proteins (e.g., β-amyloid and hyperphosphorylated tau in the case of AD) in defined brain regions and, as a consequence, death of neurons. Accordingly, removal of given protein aggregates is expected to modify the course of the respective neurodegenerative disease. This has been convincingly demonstrated in animal models of human diseases. However, not every technology that can be used and proves successful in animal models can be translated to the human situation. As highlighted by recent progress in the field of AD research, specific immunotherapy is a viable option in this regard. Given the fact that the aggregates are composed of self-proteins, immunotherapeutic approaches have to consider the issue of potential autoimmunity. This is especially true in case of vaccines. An innovative solution to this problem is offered by the so called AFFITOME® technology, which relies on the use of "doubles" of native molecules, functionally mimotopes or AFFITOPES® if identified by AFFiRiS, as the antigenic vaccine component.
    Human vaccines 11/2010; 6(11):948-52. · 3.14 Impact Factor
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2010; 6(4).
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2009; 5(4).
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2009; 5(4).
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    ABSTRACT: Subcutaneous injection of GM-CSF-expressing cancer cells into experimental animals results in protective cancer immunity. To delineate the mode of action of such vaccines, we used trinitrophenyl, the antigenic moiety of the contact allergen trinitrochlorobenzene, as surrogate Ag. Trinitrophenyl-derivatized bone marrow-derived dendritic cells were found to elicit a contact hypersensitivity response in syngeneic, but not in allogeneic recipients, compatible with their expected mode of direct Ag presentation. When expressing GM-CSF, haptenized M3 melanoma cells were also able to induce a contact hypersensitivity response but, in contrast to bone marrow-derived dendritic cells, not only in syngeneic but also in allogeneic recipients. This argues for a critical role of host APC. To identify their nature, we introduced the beta-galactosidase (betagal) gene into M3-GM cells. Their administration activated betagal-specific, L(d)-restricted CTL in syngeneic BALB/c mice. Evaluation of lymph nodes draining M3-GM-betagal injection sites revealed the presence of cells presenting the respective L(d)-binding betagal peptide epitope. Based on their capacity to activate betagal-specific CTL, they were identified as being CD11c(+) dendritic cells. These experiments provide a rational basis for the use of GM-CSF-based melanoma cell vaccines in an allogeneic setting.
    The Journal of Immunology 12/2003; 171(10):5180-7. · 5.52 Impact Factor
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    ABSTRACT: The s.c injection of tumor Ag-derived, MHC class I-binding peptides together with cationic poly-amino acids (e.g., poly-L-arginine; pR) has been shown to protect animals against a challenge with tumor cells expressing the respective peptide(s). Given our only restricted knowledge about immunogenic tumor-associated peptides, we sought to determine whether this pR-based vaccination protocol would also induce protective cancer immunity if large proteins were used instead of peptide epitopes. We found that the intracutaneous administration of the model Ag beta-galactosidase (beta-gal) together with pR (referred to as pR-based protein vaccine; pR-PV) was significantly more potent in protecting mice against the growth of beta-gal-expressing RENCA cells than the protein alone. Coadministration of pR enhanced both the beta-gal-induced specific humoral and CD8 response. The protective effect required CD8(+), but neither CD4(+) T lymphocytes nor beta-gal-specific Abs. beta-Gal priming of protective CD8(+) T lymphocytes was found to be CD4(+) T cell-independent, to take place within the draining lymph nodes, and to be accomplished by day 5 after vaccination. Ablation of the injection sites as early as 1.5 h after pR-PV administration still led to protection in a large proportion of the animals, indicating that certain protein Ags administered intradermally in the context of polycations are quickly transported to the draining nodes, where they induce molecular and cellular events resulting in the helper-independent priming and expansion of Tc1 cells. However, optimal protection required the prolonged presence of the injection site, suggesting that pR-PV injection facilitates the formation of a cutaneous depot of Ag-charged cells capable of migration and T cell activation.
    The Journal of Immunology 12/2002; 169(9):5217-26. · 5.52 Impact Factor
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    ABSTRACT: This study describes an entirely synthetic vaccine composed of antigenic peptides (T cell epitopes), oligodeoxynucleotides containing CpG-motifs (CpG-ODN) and poly-L-arginine (pR). CpG-ODN are known to be potent inducers of predominantly type 1-like immune responses, while polycationic amino acids, like pR, facilitate the uptake of antigens into antigen presenting cells (APCs). We demonstrate that the application of peptides and pR/CpG-ODN results in strongly enhanced peptide-specific immune responses as compared to the application of peptides with either of the immunomodulators alone. High numbers of antigen-specific T cells can be observed even after only one injection of the vaccine for a remarkably long period of time (at least 372 days). Furthermore, the potentially harmful systemic release of pro-inflammatory cytokines induced upon injection of CpG-ODN is inhibited. Thus, the combined application of CpG-ODN and pR may represent a novel vaccine strategy in humans.
    Vaccine 11/2002; 20(29-30):3498-508. · 3.49 Impact Factor
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    ABSTRACT: For the design of potent subunit vaccines, it is of paramount importance to identify all antigens immunologically recognized by a patient population infected with a pathogen. We have developed a rapid and efficient procedure to identify such commonly recognized antigens, and here we provide a comprehensive in vivo antigenic profile of Staphylococcus aureus, an important human pathogen. S. aureus peptides were displayed on the surface of Escherichia coli via fusion to one of two outer membrane proteins (LamB and FhuA) and probed with sera selected for high Ab titer and opsonic activity. A total of 60 antigenic proteins were identified, most of which are located or predicted to be located on the surface of the bacterium or secreted. The identification of these antigens and their reactivity with individual sera from patients and healthy individuals greatly facilitate the selection of promising vaccine candidates for further evaluation. This approach, which makes use of whole genome sequence information, has the potential to greatly accelerate and facilitate the formulation of novel vaccines and is applicable to any pathogen that induces Abs in humans and/or experimental animals.
    Proceedings of the National Academy of Sciences 06/2002; 99(10):6573-8. · 9.81 Impact Factor
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    ABSTRACT: Vaccines that induce high numbers of sustained T cell responses are urgently needed for the treatment of numerous diseases including cancer. Antigen-presenting cells (APCs), the most important of which are dendritic cells, orchestrate antigen-dependent T cell responses in that they present antigens to T cells in an appropriate environment. Here we present evidence that after vaccination with a simple mixture of the cationic poly-amino acid poly-L-arginine and tumor antigen-derived peptide antigens, large numbers of antigen-specific T cells are induced and APCs mediate the generation of T lymphocytes. We observe that after s.c. injection, MHC class II(+) cells infiltrate injection sites and are loaded with large amounts of antigen in vivo under the influence of poly-L-arginine. Consequently, numerous antigen-charged APCs can be detected in draining lymph nodes of vaccinated animals. Antigen-specific T cell responses induced are systemic and were readily detected more than 4 months after the last vaccination, the latest time point we measured. By contrast, even after repeat injections, we were consistently unable to detect antibody responses against poly-L-arginine, allowing this compound to be used for numerous booster injections. Clinical trials in cancer patients using poly-L-arginine as immunostimulant will be carried out in the near future.
    Cancer Research 04/2002; 62(5):1477-80. · 8.65 Impact Factor
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    ABSTRACT: Summary With the advent of gene therapy there has been a revival of immunotherapy of cancer. Preclinical studies with the so called tumor vaccines - syngeneic, irradiated tumor cells secreting cytokines - are at present entering clinical trials and hold much promise for efficacious treatment, maybe even cures, of cancer. However, autologous whole cell vaccines which are cytokine gene-modified are expensive and difficult to standardize. In addition, autologous tumor cell cultures, and hence tumor vaccines, cannot be prepared for all patients. For these reasons we have investigated alternative schemes for vaccination against cancer. We have developed vaccines on the basis of tumor antigen- derived peptides using a method, we called "transloading", to transfer peptides efficiently into cells. Such vaccines are chemically well defined and inexpensive to produce. We show in a preclinical mouse model system for mastocytoma, and to a somewhat lesser extent for melanoma, that peptide vaccines give excellent protection against tumor take, provided tumor antigen peptides are injected subcutaneously in conjunction with polycations like polyarginine. Immunohistological investigations on thin sections show that three days after injection, the vaccine bolus is heavily infiltrated by antigen presenting cells which take up peptides. We posit that such antigen presenting cells then migrate into draining lymph nodes where they activate naive T cells to become anti-tumor cytotoxic lymphocytes (CTL). The consequences of strong dependency of peptide sequence on the HLA-type of patients and possible remedies are discussed. One avenue to be tested in mouse models is the injection of mixtures of peptides covering a multiplicity of MHC-specific peptides. Another is the production of recombinant proteins as vaccines whose application is considerably less dependent on HLA-types of patients to be treated. In addition, such proteins would be expected to contain both class I and class II restricted peptides. Alternatively, artificial proteins incorporating many CTL epitopes of known tumor antigens, including members of the MAGE family, thus yielding a SUPERMAGE vaccine with utility for several human HLA- types could be designed. The prophylactic application of peptide/polyepitope vaccines can be envisaged.
    01/1998;
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    ABSTRACT: Transfection of a variety of tumor lines with the IL-2 gene strongly reduces their tumorigenic potential when applied to either euthymic or athymic animals. To elucidate the mechanisms underlying this phenomenon, we inoculated IL-2-transfected M-3D melanoma (M-3D-IL-2) cells into DBA/2 mice immunosuppressed by g-irradiation. Animals thus treated developed pigmented tumors, suggesting that IL-2 transfection of melanoma cells, instead of altering their neoplastic growth properties, renders them capable of evoking a tumoricidal host response. To define the critical effector cell, we injected M-3D-IL-2 and, for control purposes, nontransfected M-3D cells into DBA/2 recipients and analyzed the injection site. We found that 1) IL-2-expressing M-3D cells induce a much stronger inflammatory reaction than wild-type cells, 2) in both instances the infiltrate consists mainly of macrophages (40 - 60%) and granulocytes (30 - 40%), and 3) only the infiltrate of M-3D-IL-2 cell deposits contains a minor fraction of NK cells (;1-2%). When we reconstituted sublethally irradiated animals with various leukocyte subsets, we found that un- fractionated as well as macrophage-depleted peritoneal lavage cells but not NK cell-depleted peritoneal lavage cells were able to suppress the growth of IL-2-expressing M-3D cells. In vivo leukocyte depletion experiments showed that the NK cell-depleting asialo-GM1 antiserum, but not anti-macrophage and/or anti-granulocyte reagents, restored the tumorigenicity of M-3D-IL-2 cells. Our results indicate that the inflammatory tissue response evoked by IL-2-transfected cancer cells includes the attraction and/or activation of NK cells and that, in the experimental system used, these cells are critically needed for successfully controlling cancer growth in vivo. The Journal of Immunology, 1999, 162: 6650 - 6657.
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Publication Stats

216 Citations
36.13 Total Impact Points

Institutions

  • 2010
    • AFFiRiS AG
      Wien, Vienna, Austria
  • 2002–2003
    • Intercell
      Wien, Vienna, Austria
    • Campus Vienna Biocenter (CVBC)
      Wien, Vienna, Austria