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http://hdl.handle.net/2445/200587
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DC Field | Value | Language |
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dc.contributor.advisor | Santamaria i Vilanova, Pere, 1960- | - |
dc.contributor.advisor | Serra Devecchi, Pau | - |
dc.contributor.author | Solé Sánchez, Patricia | - |
dc.contributor.other | Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut | - |
dc.date.accessioned | 2023-07-12T08:18:44Z | - |
dc.date.available | 2023-07-12T08:18:44Z | - |
dc.date.issued | 2020-12-09 | - |
dc.identifier.uri | http://hdl.handle.net/2445/200587 | - |
dc.description.abstract | [eng] Regulatory cells are essential to immune homeostasis. Both autoimmune diseases and the progression of cancer are related to alterations in the development and/or function of the regulatory compartment. In addition to the well-known FoxP3+ T regulatory (Treg) cells, other FoxP3- IL-10-producing subsets have been described. These are generally referred to as T-regulatory type 1 cells (Tr1) although they appear to comprise a phenotypically heterogeneous subset. Cells negative for CD25 and expressing LAP, LAG-3 or CCR5 and PD-1, cells IL-7R negative or regulatory cells induced by vitamin D3 or CD46- stimulation are some examples of cell types that may correspond to cells of a single lineage but were identified as distinct based on incomplete market sets. Although CD49b and LAG-3 co-expression have been associated with IL-10 expression in both murine and human Tr1-like cells, some of the above Tr1- like subsets were Lag-3low , and both markers lack the specificity and sensitivity required to address this conundrum. Other surface markers have been associated with the Tr1 phenotype, including ICOS, CTLA-4, PD-1, TIM-3 or Tigit, as well as transcription factors like T-bet, AhR and/or Nfil3, among others. The lack of Tr1 subset-specific markers for cell isolation and downstream phenotypic, functional, transcriptional and epigenetic studies, has hindered the study of this T cell subset, specifically whether all these IL-10-producing T-reg cells that do not belong to the classical FoxP3+ /CD25+ subset actually belong to one or a collection of phenotypically and transcriptionally different subsets of cells. In fact, a number of studies employing a variety of therapeutic approaches for the treatment of autoimmunity have claimed the Treg-ness/Tr1-ness of the pharmacodynamic response, often solely on the basis of increased IL-10 expression in bulk splenic CD4+ T-cells. Thus, it is unclear if the various phenotypes ascribed to IL-10-producing FoxP3-negative CD4+ T-cells correspond to non-Tr1 cell types, to different stages of Tr1 cell differentiation along a continuum, or to a bona-fide subset of terminally-differentiated Tr1 cells with distinct phenotypic and/or functional properties and either stable or plastic gene expression programs. Unfortunately, the transcriptional and epigenetic correlates that help define true Tr1-likeness remain undefined. Treatment with nanoparticles (NPs) coated with mono-specific disease-relevant peptide-major histocompatibility complex class II (pMHCII) molecules suppresses inflammation in several organ- specific autoimmune disease models without impairing systemic immunity. We have provided evidence of therapeutic efficacy in animal models with established type 1 diabetes (T1D), experimental autoimmune encephalomyelitis (EAE), experimental arthritis, and more recently, spontaneous primary biliary cholangitis (PBC), primary sclerosis cholangitis (PSC) and autoimmune hepatitis (AIH). pMHCII-NP therapy functions by reprogramming cognate antigen-experienced CD4+ T cells into FoxP3- IL-10-producing Tr1-like cells and inducing their expansion. This results from the sustained assembly of large TCR microclusters upon pMHCII-TCR interaction, leading to rapid, robust and prolonged TCR signaling that induces expression of IL-10, IL-21, LAG-3, ICOS and PD-1, as well as T-bet and c-Maf transcription factors. This happens in an antigen-presenting cell (APC)- and IL-27-independent manner. | ca |
dc.format.extent | 237 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | ca |
dc.publisher | Universitat de Barcelona | - |
dc.rights | (c) Solé Sánchez, Patricia, 2023 | - |
dc.source | Tesis Doctorals - Facultat - Medicina i Ciències de la Salut | - |
dc.subject.classification | Immunitat cel·lular | - |
dc.subject.classification | Nanopartícules | - |
dc.subject.classification | Cèl·lules T | - |
dc.subject.classification | Epigenètica | - |
dc.subject.classification | Nanomedicina | - |
dc.subject.other | Cellular immunity | - |
dc.subject.other | Nanoparticles | - |
dc.subject.other | T cells | - |
dc.subject.other | Epigenetics | - |
dc.subject.other | Nanomedicine | - |
dc.title | Transcriptional and epigenetic re-programming of autoantigen-specific CD4+ T-cells by pMHC class II-based nanomedicines | ca |
dc.type | info:eu-repo/semantics/doctoralThesis | ca |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca |
dc.identifier.tdx | http://hdl.handle.net/10803/688641 | - |
Appears in Collections: | Tesis Doctorals - Facultat - Medicina i Ciències de la Salut |
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File | Description | Size | Format | |
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PSS_PhD_THESIS.pdf | 45.02 MB | Adobe PDF | View/Open |
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