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| Author(s): |
Fernanda Gonçalves Martello
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2010-03-11 |
| Examining board members: |
Veronica Porto Carreiro de Vasconcellos Coelho;
Ana Maria Caetano de Faria;
Maria Notomi Sato
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| Advisor: | Veronica Porto Carreiro de Vasconcellos Coelho |
| Abstract | |
Heat shock proteins (HSPs) have dual immunologic functional activity inducing both proinflammatory and regulatory responses. These properties place HSPs and their peptides as molecules displaying great potential as immunomodulatory agents. In this study, our goal was to identify potential immunoregulatory Hsp60 peptides, analyzing their capacity to modify the expression of immunoregulatory (REG) or proinflammatory (INFLAMMA) genes in PBMC of healthy individuals. The REG/INFLAMMA gene panel analysis showed that most peptides displaying an immunoregulatory profile belong to the Hsp60 N-terminal region. We selected 3 peptides that showed the highest REG/INFLAMMA ratio (N2, N6 and N7) for functional studies. Cytokine analysis showed good correspondence between messenger RNA and protein production induced by the peptides, and N7 peptide induced high IL-10/IFN- ratio. The selected peptides also interacted directly with purified T lymphocytes, indicating an APC-independent activity for Hsp60 peptides. Despite differences between the effect on PBMC and on purified lymphocytes, Hsp60 peptides induced predominantly REG type of gene expression modifications, with the induction of Foxp3 and GATA-3. The selected peptides, N2, N6 and N7, were capable of inhibiting allogeneic proliferation (highest inhibition: N7 peptide 60,53%) and the proliferation induced by anti-CD3 antibody (highest inhibition: N7 peptide 31,01%). We concluded that our REG/INFLAMMA gene expression panel was appropriate to indentify regulatory Hsp60 peptides. Among their possible suppressive mechanisms, we can point out the action of the regulatory cytokines IL-10 and TGF-, the inhibition of proinflammatory transcription factors T-bet and RORt and the generation of regulatory T cells. The next step, ongoing in our lab, is to test these peptides in experimental models of allotransplantation and autoimmune diseases, aiming at future therapeutic applications in the clinic. (AU) | |