Papers by Achim Schneeberger
Alzheimer's & Dementia, 2015
Journal of Immunology, Nov 15, 2003
Subcutaneous injection of GM-CSF-expressing cancer cells into experimental animals results in pro... more 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 -galactosidase (gal) gene into M3-GM cells. Their administration activated gal-specific, L d-restricted CTL in syngeneic BALB/c mice. Evaluation of lymph nodes draining M3-GM-gal injection sites revealed the presence of cells presenting the respective L d-binding gal peptide epitope. Based on their capacity to activate gal-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.
J Dtsch Dermatol Ges, 2006
H G Zeitschrift Fur Hautkrankheiten, 2000
Up to now conventional therapy strategies could influence the course of metastatic melanoma posit... more Up to now conventional therapy strategies could influence the course of metastatic melanoma positively only in single cases. Medicine has the duty, but also the chance, to develop and to test new therapeutical regimen. They may result from growing knowledge of molecular basics of melanoma and other neoplastic diseases. Moreover current knowledge of the cellular and molecular mechanisms involved in the induction/modulation of immunological answers and progress of the characterization of melanoma antigen enable the development of successful vaccination strategies. It is the aim of this article to introduce some of the gene- and immunotherapeutical ideas which are already under clinical investigation.
Jnha the Journal of Nutrition Health and Aging, Mar 1, 2009
Based on the notion that cerebral accumulation of certain Abeta species is central to AD pathogen... more Based on the notion that cerebral accumulation of certain Abeta species is central to AD pathogenesis and endowed with the knowledge that emerged during clinical testing of the first human Alzheimer vaccine, AN1792, we designed a new generation of Alzheimer vaccines. Rather than relying on full-length Abeta itself or fragments thereof, AFFITOPE vaccines use short peptides, mimicking parts of the native Abeta sequence, as their antigenic component. The technology created to identify these peptides, termed AFFITOPE-technology, at the same time provides the basis for the multi-component safety concept realized in AFFITOPE vaccines. First, as they are nonself, AFFITOPES don't need to break tolerance typically established against self proteins. This allows us to use aluminium hydroxide, the agent first approved as immunological adjuvant for human use and, thus, exhibiting an excellent safety profile. Second, AFFITOPES employed in Alzheimer vaccines are only 6 amino acids in length, which precludes the activation of Abeta-specific autoreactive T cells. Third, and above all, the AFFITOPE technology allows for controlling the specificity of the vaccine-induced antibody response focusing it exclusively on Abeta and preventing crossreactivity with APP. In a program based on two AFFITOPES allowing neoepitope targeting of Abeta (free N-terminus), this approach was taken all the way from concept to clinical application. Early clinical data support the safety concept inherent to AFFITOPE Alzheimer vaccines. Further clinical testing will focus on the identification of the optimal vaccine dose and immunization schedule. Together, result of these trials will provide a solid basis for clinical POC studies.
Acta Neuropathologica, 2014
Pyroglutamylated amyloid-β (pE(3)-Aβ) has been suggested to play a major role in Alzheimer&am... more Pyroglutamylated amyloid-β (pE(3)-Aβ) has been suggested to play a major role in Alzheimer's disease (AD) pathogenesis as amyloid-β (Aβ) oligomers containing pE(3)-Aβ might initiate tau-dependent cytotoxicity. We aimed to further elucidate the associations among pE(3)-Aβ, full-length Aβ and hyperphosphorylated tau (HP-τ) in human brain tissue. We examined 41 post mortem brains of both AD (n = 18) and controls. Sections from frontal and entorhinal cortices were stained with pE(3)-Aβ, HP-τ and full-length Aβ antibodies. The respective loads were assessed using image analysis and western blot analysis was performed in a subset of cases. All loads were significantly higher in AD, but when using Aβ loads as independent variables only frontal pE(3)-Aβ load predicted AD. In frontal and entorhinal cortices pE(3)-Aβ load independently predicted HP-τ load while non-pE(3)-Aβ failed to do so. All loads correlated with the severity of AD neuropathology. However, partial correlation analysis revealed respective correlations in the frontal cortex only for pE(3)-Aβ load only while in the entorhinal cortex respective correlations were seen for both HP-τ and non-pE(3)-Aβ loads. Mini Mental State Examination scores were independently predicted by entorhinal HP-τ load and by frontal pE(3)-Aβ load. Here, we report an association between pE(3)-Aβ and HP-τ in human brain tissue and an influence of frontal pE(3)-Aβ on both the severity of AD neuropathology and clinical dementia. Our findings further support the notion that pE(3)-Aβ may represent an important link between Aβ and HP-τ, and investigations into its role as diagnostic and therapeutic target in AD are warranted.
Neurobiology of Aging, 2012
Journal of Investigative Dermatology, 2000
Journal of Investigative Dermatology, 2004
DNA vaccines can induce impressive specific cellular immune response (IR) when taking advantage o... more DNA vaccines can induce impressive specific cellular immune response (IR) when taking advantage of their recognition as pathogen-associated molecular patterns (PAMP) through Toll-like receptors (TLR) expressed on/in cells of the innate immune system. Among the many types of PAMP, immunostimulatory DNA, so-called CpG motifs, was shown to interact specifically with TLR9, which is expressed in plasmacytoid dendritic cells (pDC), a key regulatory cell for the activation of innate and adaptive IR. We now report that CpG motifs, when introduced into the backbone, are a useful adjuvant for plasmid-based DNA (pDNA) vaccines to induce melanoma antigen-specific protective T cell responses in the Cloudman M3/DBA/2 model. The CpG-enriched pDNA vaccine induced protection against subsequent challenge with melanoma cells at significantly higher levels than its parental unmodified vector. Preferential induction of an antigen-specific, protective T cell response could be demonstrated by (i) induction of antigen-dependent tumor cell protection, (ii) complete loss of protection by in vivo CD4 þ /CD8 þ T cellbut not NK cell-depletion, and (iii) the detection of antigen-specific T cell responses but not of relevant NK cell activity in vitro. These results demonstrate that employing PAMP in pDNA vaccines improves the induction of protective, antigen-specific, T cell-mediated IR.
Journal of Investigative Dermatology, 2003
The Journal of Immunology, 2002
The s.c injection of tumor Ag-derived, MHC class I-binding peptides together with cationic poly-a... more 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 β-galactosidase (β-gal) together with pR (referred to as pR-based protein vaccine; pR-PV) was significantly more potent in protecting mice against the growth of β-gal-expressing RENCA cells than the protein alone. Coadministration of pR enhanced both the β-gal-induced specific humoral and CD8 response. The protective effect required CD8+, but neither CD4+ T lymphocytes nor β-gal-specific Abs. β-Gal priming of protective CD8+ T lymphocy...
Journal of Dermatological Science, 1998
Journal of Dermatological Science, 1998
Bacterial DNA ha8 recently been dwxwered to directly stimulate the mammalian innate immune system... more Bacterial DNA ha8 recently been dwxwered to directly stimulate the mammalian innate immune system This effect 18 mediated by angle stranded ODN, conraining unmethylated CpG dinucleotides. Here we studied the influence of ODN on proliferation and differentiation of CD4+ T cells (Th) durmg activation by APC and antigen. Th from Balb/c mice were mimed for 3 davs in v&o with antizen and APC either in the presence or absence of 6DN 1668. To some conditions IL-4 or antr-IL-4 mAb llBl1 was added. Thereafter, cells were cultured with IL-2 for 7 days, then washed and counted and identtcal cell numbers were restimulated for &?okine productron. Primmg in the absence of ODN led to a ThO phenotype, addition of IL-4 enhanced ThZ and additiw of mAb 11B 11 Thl development. Priming m the presence of ODN 1668 promoted IFN-y production during restnnulation at least tenfold and completely suppressed IL-4 secretion. In addmon to thus strong Thl differentiation, the ODN enhanced Th cell expansion sevenfold. ODN 1668 did not influence expressron of costimulatory molecules such 88 B7.11B7.2. Surprisingly, addition of ODN dunng T cell priming together with IL-4 at&shed the capaaty to produce IFNy, enhanced IL4 secretion and induced an even stronger Th expansion. Whde promotion of IFN-y expression cwld be explained by APC derived IL-l'& the enhanced T cell expansion and the silencmg of IFi%y production in T cells primed together with IL4 strongly suggest lhat certain ODN provide novel, IL12 independent ccstimulatory s1gn8ls that allow to generate potent anhgen specific regulatory T cells.
JDDG, 2006
IgA pemphigus is a rare pustular autoimmune disease with exclusive IgA anti-keratinocyte cell sur... more IgA pemphigus is a rare pustular autoimmune disease with exclusive IgA anti-keratinocyte cell surface antibody reactivity. Two subtypes have been discerned: in the subcorneal pustular dermatosis type, desmocollin 1 has been identified as a targeted autoantigen, while in few cases of the intraepidermal neutrophilic type, IgA anti-desmoglein 1 or IgA anti-desmoglein 3 reactivity has been demonstrated. A 48-year-old white male presented with generalized large confluent pustules. Skin pathology was assessed by histology and direct immunofluorescence analysis. IgG/IgA autoantibodies against desmoglein 1/3 and desmocollin 1 were measured by ELISA and indirect immunofluorescence using desmocollin 1 cDNA-transfected COS7 cells, respectively. Histopathology revealed subcorneal pustules and direct immunofluorescence microscopy exclusively showed in vivo bound IgA with an intercellular pattern in the epidermis. Desmocollin 1 was identified as a target of IgA autoantibodies by indirect immunofluorescence microscopy utilizing desmocollin 1 cDNA-transfected COS7 cells. In addition, IgA anti-desmoglein 1 reactivity was demonstrated by ELISA. Neither IgA anti-desmoglein 3 nor IgG anti-desmoglein 1/3 autoantibodies were present. Both desmocollin 1 and desmoglein 1 were autoantigens in this patient with IgA pemphigus and a distinct clinical presentation. To our knowledge, this is the first IgA pemphigus case with dual autoantibody reactivity.
Human Vaccines, 2010
Neurodegenerative diseases are still an area of unmet medical need. This is in contrast to our in... more 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.
Clinical and Experimental Dermatology, 2000
Thus far, the use of classical anti-cancer treatment modalities had only rarely a beneficial impa... more Thus far, the use of classical anti-cancer treatment modalities had only rarely a beneficial impact on the prognosis of patients with metastatic melanoma. We as physicians have therefore the obligation as well as the chance to develop and test new therapeutic strategies. Our growing knowledge about the genetic basis of melanoma provides one platform to fulfil this task. Another one comes from our increasing understanding of the molecular and cellular mechanisms involved in the induction/modulation of immune responses, as well as the progress made in the field of identification of melanoma antigens, and allows for the development of a new generation of vaccines. The aim of this article is to discuss several of these new concepts towards the use of immune and gene therapy of melanoma.
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Papers by Achim Schneeberger