Year: 2009
Type: dissertation
Abstract: The aim of this PhD work was the characterization of the principles of suppression and identification of the cellular mechanisms underlying the oligomer (PLP 139-151 16-mer) induced protection of EAE. The tolerogenic capacity of repeat antigens to control the development of EAE was carried out by using the SJL/J mouse EAE model. It was shown that the protection induced by oligomer T cell epitope PLP 139-151 was dependent of antigen specificity. Importantly, it is also demonstrated that PLP 139-151 16-mer was effective in the treatment of established EAE as its administration after appearance of the first clinical symptoms reversed ongoing EAE. Another important observation was that PLP 139-151 16-mer treatment markedly reduced leukocyte infiltration in the brain and spinal cord. Interestingly, suppression was actively transferred by cells from oligomer treated mice and this finding was consistent after transfer with total lymph node cells, CD4+CD25+ and B cells. Cytokine analysis of cells during the oligomer treatment showed increased production of IL-10 and suggested that suppression is not due to the failure of PLP-specific T cells to respond against the autoantigen, but resulted from the occurrence of suppressive cytokines after antigen specific stimulation. The importance of suppressive cytokines was demonstrated by the inhibition of the protective effect mediated by the epitope-oligomer after in vivo blocking of either IL-10 or TGF-b cytokines. Active suppression provoked by oligomerized peptides was partially mediated by CD4+CD25+ cells, which could be associated with the occurrence of immunosuppressive cytokines. The second part of the present thesis describes the use of parasite-derived repetitive sequences containing self epitopes as a reliable mean to induce tolerance. The fusion constructs that consist of a recombinant protein containing repetitive sequences from the Plasmodium falciparum S-Antigen linked to myelin T cell epitopes, were evaluated in the autoimmune EAE model for the ability of inducing tolerance. The efficacy of the treatment was evident when the antigen was given in form of a vaccination or as therapeutic intervention. The physical link between the T cell epitope and the repeat structure showed to be essential for the effectiveness of the treatment. This protective effect was also found to be antigen-specific and mediated by a process of active tolerance that includes the action of suppressive cytokines like IL-10, probably by the induction of suppressor T cells specific for the epitope linked to the repeat region. In summary, this work strongly supports an immunosuppressive role of repeat antigens to control the development of EAE with potential applications to rational vaccine design and treatment of autoimmune diseases.
Author: Puentes Corredor, Fabiola
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2105031117