EPISPREAD_XP · Cellular And Molecular Mechanisms Of Cross-Presentation In Epitope Spreading Following Immune Responses To Anti-Tumor Vaccines
6РП — Действия „Мария Кюри“
- Период
- 2005-02-01 → 2007-01-31
- Финансиране от ЕС
- 153 072 €
- Участници
- 1
- Схема
- EIF
Линиите свързват координатора с партньорите. За проекти отпреди 2014 г. CORDIS не винаги дава точни координати. Тези точки са на ниво град или държава.
Накратко на български
Механизмите на „разширяване на епитопите“ се изследват чрез ваксиниране на мишки с конкретен антиген, което предизвиква имунен отговор към други, не включени във ваксината части от тумора. Разбирането на този процес може да помогне за създаването на по-ефективни ваксини за терапия срещу рак.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - EPISPREAD_XP (Cellular And Molecular Mechanisms Of Cross-Presentation In Epitope Spreading Following Immune Responses To Anti-Tumor Vaccines)
In the project 'EPISPREAD_XP' Dr A.K. Nussbaum and Prof. S. Amigorena attempted to elucidate mechanisms related to the 'epitope spreading' phenomenon. The term refers to the observation of secondary immune responses after the treatment of cancer patients with tumour-specific vaccines. Epitope spreading leads to the induction of additional immune responses against the tumour which have been observed to be beneficial for the patient. It is therefore conceivable that understanding epitope spreading could lead to more efficient vaccine-based cancer therapies. Our goal was to model epitope spreading in mice and use this model to ask questions on the related cellular and molecular mechanisms. Our mouse (C57BL/6) model was based on the mouse melanoma tumour B16, expressing several known endogenous and exogenous (model) tumour antigens. Our vaccine protocol was a mixture of prophylactic and therapeutic vaccines. The vaccines consisted of short peptides representing tumour antigen epitopes of killer T lymphocytes (CD8+ T cells) and short immunestimulatory deoxyribonucleic acid (DNA) sequences (ODN CpG), which functioned as adjuvants. The project proved very challenging, mostly because of the very nature of the epitope spreading immune response. It was very weak, thus often at the limit of detection. However, we did succeed in establishing the model. When mice bearing B16 melanoma tumours were vaccinated with the tumour antigen trp2, strong CD8+ T cell responses against the vaccine were measured. However, we also observed a CD8+ T response to a model tumour antigen which was not present in the vaccine, as a result of epitope spreading. This new experimental tool was ready for exploitation to elucidate underlying cellular and molecular mechanisms. Knowledge on such mechanisms would it easier to improve therapeutic cancer vaccines. Our mouse model for epitope spreading was the first of its kind. All employed epitopes were known, thus allowing for much focused monitoring of all the CD8+ T cell responses involved. This fact was expected to prove very helpful in case of elucidating how the epitope spreading response was initially triggered.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Significance: Combating major diseases, such as cancer, is an important objective in the area of Life Sciences in the 6th Framework Programme. The challenging goal of vaccination in cancer-bearing patients is to induce long-lasting antigen-specific immunit y to protect the host against tumor establishment. Although in several cases tumor rejection in mice as well as in humans has been reported, the results of current tumor immunotherapy protocols are still disappointing. Background: We propose to study epito pe spreading (ES), a process whereby epitopes distinct from an inducing epitope (e.g. a vaccine) become targets of an evolving immune response. Only recently, ES was found to play a role in anti-tumor immune responses and in tumor regression following anti -tumor vaccinations. It is thus conceivable that ES can be exploited to make anti-tumor vaccines more efficient. However, the cellular and molecular mechanisms of ES are largely unknown.Dendritic cells (DC), pulsed with tumor peptides, have been used as an ti-tumor vaccines. DC induce some immune responses by cross-presentation, which seems to depend on the fusion of phagosomes with the endoplasmic reticulum and on the association of immunoproteasomes with phagosomes.Methods: We will establish a mouse model for ES following anti-tumor vaccinations by peptide-pulsed DC. We will use this model to study (a) the role and mechanisms of cross-presentation in ES, (b) ES in wild-type versus immunoproteasome-KO mice and (c) specific requirements for the processing and the nature of the tumor antigen. Our in vivo experiments will be complemented by in vitro studies to assess the cell biology of ES by microscopic techniques.Prediction: Our proposed experiments will elucidate cellular and molecular mechanisms of ES and th us increase our understanding of vaccination-induced anti-tumor immune responses. Our results are expected to have high relevance for clinical trials of anti-tumor vaccinations.
Оригинален текст от CORDIS (на английски).
Участници
- INSTITUT CURIE, SECTION RECHERCHE · PARISКоординаторНиво градФранция
Връзки
Данни: CORDIS, © Европейски съюз