Characterization of the in vivo immunomodulatory properties of CD5 and CD6
Our goal in this doctoral thesis was to study the immunomodulatory effects of CD5 and CD6, two proteins expressed on the lymphocytes membrane. These two proteins belong to the Scavenger Receptors Cystein- Rich superfamily, characterized by the presence of one or more cysteine rich domains. The inter...
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| Formato: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Recursos: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/593499 |
| Acesso em linha: | http://hdl.handle.net/10803/593499 |
| Access Level: | acceso abierto |
| Palavra-chave: | Immunoteràpia Inmunoterapia Immunotheraphy Resposta immunitària Respuesta inmune Immune response Antígens tumorals Antígenos tumorales Tumor antigens Ratolins transgènics Ratones transgénicos Transgenic mice Proteïnes de membrana Proteínas de membranas Membrane proteins Ciències de la Salut 577 |
| Resumo: | Our goal in this doctoral thesis was to study the immunomodulatory effects of CD5 and CD6, two proteins expressed on the lymphocytes membrane. These two proteins belong to the Scavenger Receptors Cystein- Rich superfamily, characterized by the presence of one or more cysteine rich domains. The interaction between CD6 and ALCAM, its principal ligand, is well established but recently more ligands of CD6 have been described. On the other hand, to date there is no consensus about the CD5 ligand/s, although several candidates have been proposed. Previous work carried out with CD5 and CD6-deficient mice revealed the role as negative modulators of the T/B cell receptor signaling. It was observed how its blockade/absence led to a hyper-activation post T cell activation by increment of cell proliferation and calcium mobilization. We decided to generate a transgenic mouse that would expresses high levels of the extracellular region of human CD5 constitutively, in order to block the interactions mediated by membrane-bound CD5 with its ligand/s. This “functional knockout" would resemble what would happen in a clinical application, by injecting the soluble recombinant protein to humans. These mice presented indeed soluble human CD5 in serum, which resulted in immunophenotypical changes that were reproduced in wild-type mice after repeated administration of exogenous rshCD5 protein. The transgenic mice did not reveal any gross alterations in major lymphocyte subpopulations. However, a decrease in T and B cell subsets with regulatory function, as well as an increment in NKT cells were observed. They also presented more severe disease outcome to two different induced experimental autoimmune disease models and a better anti- tumor response against murine melanoma cells (B16-F0) and a genetically modified line of thymoma tumor cells (EG7-OVA). We have observed that this effect is due to the increase in number and activity of the effector cells of the immune system as well as the lowering of the regulatory T cells in the tumor draining lymph nodes. On the other hand, wild-type mice challenged with melanoma showed an improved anti-tumor response as well as changes in the tumor draining lymph node after therapeutic administration of the protein. In addition, in this model, a decrease in IL-6 expression levels was observed, and the loss of efficacy obtained with CD5 administration by depleting NK cells. We also generated another murine model expressing elevated levels of human soluble CD6 in a constitutive way, with the objective of blocking the heterophillic and homophillic interactions of CD6 and its ligands. These mice had a decrease in the spleen and lymph nodes total cell number. Their B cells have reduced proliferative capacity and the regulatory T cell less suppressive activity aside to a reduction of their number. We observed an increment of the anti-tumor response to different tumor cell lines, but their autoimmune response was not exacerbated, as it was expected. These results were reproduced when recombinant soluble human CD6 was injected repeatedly into wild-type mice. The results obtained demonstrate that counteracting the function of membrane-bound CD5/CD6 with sCD5/CD6 may enhance current immunotherapies for cancer, as well as be used in other possible applications such as in acute or chronic infections (CD5 recognizes fungal and viral components, and CD6 bacterial components) and vaccines. |
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