4 results
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2. α-Synuclein vaccination modulates regulatory T cell activation and microglia in the absence of brain pathology.
- Author
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Christiansen, Josefine R., Olesen, Mads N., Otzen, Daniel E., Romero-Ramos, Marina, and Sanchez-Guajardo, Vanesa
- Subjects
DOPAMINE receptors ,IMMUNIZATION ,SYNUCLEINS ,IMMUNOTHERAPY ,T cells ,ANIMAL experimentation ,CELLS ,COMPARATIVE studies ,ENZYME-linked immunosorbent assay ,FLOW cytometry ,IMMUNOHISTOCHEMISTRY ,IMMUNOLOGY technique ,RESEARCH methodology ,MEDICAL cooperation ,MICE ,NERVE tissue proteins ,RECOMBINANT proteins ,RESEARCH ,WESTERN immunoblotting ,EVALUATION research ,PARKINSONIAN disorders ,PREVENTION - Abstract
Background: Passive and active immunization with α-synuclein has been shown to be neuroprotective in animal models of Parkinson's disease. We have previously shown that vaccination with α-synuclein, long before α-synuclein-induced brain pathology, prevents striatal degeneration by inducing regulatory T cell infiltration in parenchyma and antibody deposition on α-synuclein overexpressing neurons. However, the effect of peripheral α-synuclein on the immune system is unknown, as are the mechanistic changes induced in the CD4 T cell population during successful neuroprotective animal studies. We have studied the changes induced by vaccination with α-synuclein in the CD4 T cell pool and its impact on brain microglia to understand the immune mechanisms behind successful vaccination strategies in Parkinson's disease animal models.Methods: Mice were immunized with WT or nitrated α-synuclein at a dose equivalent to the one used in our previous successful vaccination strategy and at a higher dose to determine potential dose-dependent effects. Animals were re-vaccinated 4 weeks after and sacrificed 5 days later. These studies were conducted in naive animals in the absence of human α-synuclein expression.Results: The CD4 T cell response was modulated by α-synuclein in a dose-dependent manner, in particular the regulatory T cell population. Low-dose α-synuclein induced expansion of naive (Foxp3 + CCR6-CD127lo/neg) and dopamine receptor type D3+ regulatory T cells, as well as an increase in Stat5 protein levels. On the other hand, high dose promoted activation of regulatory T cells (Foxp3CCR6 + CD127lo/neg), which were dopamine receptor D2+D3-, and induced up-regulation of Stat5 and production of anti-α-synuclein antibodies. These effects were specific to the variant of α-synuclein used as the pathology-associated nitrated form induced distinct effects at both doses. The changes observed in the periphery after vaccination with low-dose α-synuclein correlated with an increase in CD154+, CD103+, and CD54+ microglia and the reduction of CD200R+ microglia. This resulted in the induction of a polarized tolerogenic microglia population that was CD200R-CD54CD103CD172a+ (82 % of total microglia).Conclusions: We have shown for the first time the mechanisms behind α-synuclein vaccination and, importantly, how we can modulate microglia's phenotype by regulating the CD4 T cell pool, thus shedding invaluable light on the design of neuroimmunoregulatory therapies for Parkinson's disease. [ABSTRACT FROM AUTHOR]- Published
- 2016
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3. Specific recognition and inhibition of Ewing tumour growth by antigen-specific allo-restricted cytotoxic T cells.
- Author
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Thiel, U., Pirson, S., Müller-Spahn, C., Conrad, H., Busch, D. H., Bernhard, H., Burdach, S., Richter, G. H. S., and Müller-Spahn, C
- Subjects
EWING'S sarcoma ,TUMOR antigens ,T cells ,CELL transplantation ,TUMOR markers ,IMMUNOTHERAPY ,BIOCHEMISTRY ,RESEARCH ,IMMUNIZATION ,CELL culture ,OSTEOSARCOMA ,ANIMAL experimentation ,RESEARCH methodology ,ISOANTIGENS ,CELL physiology ,MEDICAL cooperation ,EVALUATION research ,BONE tumors ,PHENOMENOLOGY ,COMPARATIVE studies ,IMMUNITY ,DNA-binding proteins ,CELLS ,CELL lines ,MICE - Abstract
Background: The development of a successful immunotherapy is hampered by an ineffective T-cell repertoire against tumour antigens and the inability of the patient's immune system to overcome tolerance-inducing mechanisms. Here, we test the specific recognition and lytical potential of allo-restricted CD8(+) T cells against Ewing tumour (ET) associated antigens Enhancer of Zeste, Drosophila Homolog 2 (EZH2), and Chondromodulin-I (CHM1) identified through previous microarray analysis.Methods: Following repetitive CHM1(319) (VIMPCSWWV) and EZH2(666) (YMCSFLFNL) peptide-driven stimulations with HLA-A 0201(+) dendritic cells (DC), allo-restricted HLA-A 0201(-) CD8(+) T cells were stained with HLA-A 0201/peptide multimers, sorted and expanded by limiting dilution.Results: Expanded T cells specifically recognised peptide-pulsed target cells or antigen-transfected cells in the context of HLA-A 0201 and killed HLA-A 0201(+) ET lines expressing the antigen while HLA-A 0201(-) ET lines were not affected. Furthermore, adoptively transferred T cells caused significant ET growth delay in Rag2(-/-)γ(C)(-/-) mice. Within this context, we identified the CHM1(319) peptide as a new candidate target antigen for ET immunotherapy.Conclusion: These results clearly identify the ET-derived antigens, EZH2(666) and CHM1(319), as suitable targets for protective allo-restricted human CD8(+) T-cell responses against non-immunogenic ET and may benefit new therapeutic strategies in ET patients treated with allogeneic stem cell transplantation. [ABSTRACT FROM AUTHOR]- Published
- 2011
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4. Shaping and reshaping CD8+ T-cell memory.
- Author
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Harty, John T. and Badovinac, Vladimir P.
- Subjects
T cells ,CELLS ,IMMUNE response ,IMMUNIZATION ,VACCINATION ,ANTIGENS - Abstract
The ability to develop and sustain populations of memory T cells after infection or immunization is a hallmark of the adaptive immune response and a basis for protective vaccination against infectious disease. Technical advances that allow direct ex vivo identification and characterization of antigen-specific CD8
+ T cells at various stages of the response to infection or vaccination in mouse models have fuelled efforts to characterize the factors that control memory CD8+ T-cell generation. Here, we dissect the input signals that shape the characteristics of the memory CD8+ T-cell response and discuss how manipulation of these signals has the potential to reshape CD8+ T-cell memory and improve the efficacy of vaccination. [ABSTRACT FROM AUTHOR]- Published
- 2008
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