Th135 - IL-10 Producing Tolerogenic Dendritic Cells Modulate B Cell Responses in Vitro and in Vivo

Konstantina Morali – IRCCS Ospedale San Raffaele, San Raffaele Telethon Institute for Gene Therapy; Juulke Steuten – Department of Immunopathology – Sanquin Research, Amsterdam, Netherlands; Fabio Russo – IRCCS Ospedale San Raffaele, San Raffaele Telethon Institute for Gene Therapy; Francesca Romana Santoni de Sio – IRCCS Ospedale San Raffaele, San Raffaele Telethon Institute for Gene Therapy; Anja Ten Brink – Department of Immunopathology, – Sanquin Research, Amsterdam, Netherlands; Marieke Van Ham – Department of Immunopathology – Sanquin Research, Amsterdam, Netherlands

Abstract Text: Tolerogenic dendritic (tolDC) cell-based therapies offer the possibility of restoring immune regulation by targeting only the detrimental immune responses against disease-associated antigen (Ag)s. IL-10-modulated DC generated from monocytes by IL-10 gene transfer (DCIL-10) have been proven to modulate T cell responses, to promote the differentiation of regulatory T cells, and to prevent autoimmune diabetes in pre-clinical models. Since IL-10 regulates B cell responses by modulating antibody (Ab) production and excessive B cell activation, and DC are involved in providing second signals to B cells for their full activation, we dissected the impact of DCIL-10 on B cell responses in vitro and in vivo. We demonstrate that DCIL-10 promoted allogeneic human naïve and memory B cell activation and proliferation and induced isotype switching by promoting IgG4 secretion in memory B cells. DCIL-10-mediated modulation of naïve B cells is cell-to-cell contact dependent, while of memory B cells is IL-10 dependent. In a newly developed in humanized mouse model treatment with allogeneic DCIL-10 prevented IgG Ab secretion. Finally, treatment with Ag-pulsed DCIL-10 directly promoted B cell maturation and induction of Ag-specific IgG release, and indirectly prevented the expansion of Ag-specific B cells, overall reducing the secretion of Ag-specific IgG in vivo. Collectively these data demonstrate for the first time that IL-10-producing DC directly and indirectly modulate Ag-specific B cell responses. The ability of IL-10-engineered DC to regulate, in addition to T, B cell responses, opens new perspectives for defining an innovative cell-based approach to promote Ag-specific tolerance in the context of autoimmune diseases.