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|contributor.advisor||Roncarolo, Maria Grazia||-|
|description.abstract||Thalassemia Major can be cured with allogeneic hematopoietic stem-cell transplantation (HSCT). Persistent mixed chimerism (PMC) develops in around 10% of transplanted thalassemic patients, but the biological mechanisms underlying this phenomenon are poorly understood. IL-10 is an immunomodulant cytokine that plays a central role in controlling inflammation, down-regulating immune responses, and inducing immunological tolerance. Detection of high levels of IL-10, produced by PBMCs of patients with PMC, in comparison to those of patients with complete donor chimerism (CC) or normal donors (ND), prompted us to characterize the T cell repertoire in a thalassemic patient with long-term tolerance following HSCT. From the peripheral blood of the PMC patient, T cell clones of both host and donor origin could be isolated. Together with effector T cell clones, reactive against host or donor alloantigens, we identified regulatory T cell clones, with a cytokine secretion profile typical of type 1 regulatory T cells (Tr1), at high frequencies. Tr1 cell clones, both donor and host derived, were able to inhibit the function of effector T cells of either donor or host origin in vitro, suggesting a contribution by these regulatory T cells to the maintenance of PMC in vivo.
In parallel, we demonstrated that IL-10 could inhibit primary allogeneic proliferation of total PBMCs and could induce antigen-specific T-cell hyporesponsiveness. The use of tolerogenic dendritic cells (DC) differentiated in the presence of IL-10 (DC-10), as compared to monocytes+IL-10, allowed a more consistent anergy induction, even in the context of HLA-matched donors. Importantly, both monocytes+IL-10-anergized and DC-10-anergized T cells preserved their ability to respond to nominal and third party antigens.
All together these results provide first, new insights regarding the mechanisms of peripheral tolerance in transplanted thalassemic patients, and secondly, offer a strong rationale for the development of a clinical protocol for the use of ex-vivo monocytes+ IL-10/DC-10-anergized T cells of donor origin as cellular therapy to promote immune-reconstitution and prevent graft-versus-host disease after HSCT.||en|
|subject||stem cell transplantation||en|
|subject.classification||MED/04 Patologia generale||en|
|title||IL-10 mediated immunological tolerance: preclinical and clinical studies||en|
|degree.name||Immunologia e biotecnologie applicate||en|
|degree.discipline||Facoltà di medicina e chirurgia||en|
|degree.grantor||Università degli studi di Roma Tor Vergata||en|
|Appears in Collections:||Tesi di dottorato in medicina|
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