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IL-10 mediated immunological tolerance: preclinical and clinical studies

Author: Serafini Giorgia
Serafini G
Publication venue
Publication date: 24/08/2009
Field of study

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

ART

Early stress and dissociation: Psychopathological pathways

Author: Amore M.
Serafini G.
Publication venue
Publication date: 01/01/2020
Field of study

Objectives In the last two centuries, researchers tried to investigate the complex effects of early life stress on developing brain as well as the mechanisms underlying dissociation that may be frequently linked to traumatic experiences. Clinically, dissociation may be found in many psychiatric disorders and may be defined as the disruption of important human functions such as memory, identity, consciousness, thinking, emotions, body representation, motor control as well as behavior. The aim of the present review was to selectively review data about the link between traumatic experiences, dissociation and psychopathological patways. Methods A detailed search regarding the association between traumatic experiences, dissociation, and psychopathological patways has been carried out. Results Based on the most relevant included studies (n = 16), a chronic hypothalamic pityuitary adrenal (HPA) axis dysregulation (that may include both hyperactivity and hypoactivity) has been found in subjects with childhood traumatic experiences. The dysregulated stress system in subjects who have suffered from early traumatic conditions is able to promote important neuroendocrine and immune impairments together with inducing inflammatory-related conditions. Exposure to early-life traumatic experiences may be also linked to relevant psychopathological and neurocognitive consequences with multiple psychopathological conditions that may be developed in individuals with a positive history of traumatic experiences. Importantly, early adversities are closely related to enhanced chronicity, suicidal behavior, and poorer treatment response. Conclusions Although dissociation may be diagnosed both in acute and chronic conditions, many clinicians are, unfortunately, not able to correctly detect these conditions. The main implications related to the link between trauma, dissociation, and most relevant psychopathological conditions are discussed

Archivio istituzionale della ricerca - Università di Genova