Bone marrow or stem cell transplantation

Oral

Use of a Bispecific anti-cd86 X monomeric-il-10 Adaptirtm Molecule to Induce Alloantigen-specific tr1 Cells

Friday, June 16
6:15 PM - 7:30 PM

IL-10 is a potent immunosuppressive cytokine that promotes the differentiation of tolerogenic dendritic cells (DC-10) and the induction of alloantigen-specific T regulatory type 1 (Tr1) cells in vitro. Use of IL-10 in vivo is limited by its effects on multiple cell types that are not solely inhibitory. ES210 is a bi-specific ADAPTIR molecule from Aptevo Therapeutics composed of an anti-CD86 fused with monomeric IL-10 that specifically induces IL-10R signaling in CD86+ antigen-presenting cells. We tested whether ES210 could replace soluble-IL-10 during induction of tolerogenic DCs and alloantigen-specific Tr1 cells in vitro


DC-10 and alloantigen-specific Tr1 cells (T-allo10) were differentiated in the presence of IL-10 as previously reported, or in the presence of ES210 (DC-ES210 and T-alloES210, respectively; n=12). DC-ES210 cytokine production was assessed by ELISA. Presence of LAG3+CD49b+ Tr1 cells was investigated in T-allo10/T-alloES210, together with alloantigen-specific proliferation, cytokine production and suppression of CD4+ proliferation.


ES210 induced differentiation of tolerogenic DC that produced high levels of IL-10. DC-ES210 induced similar percentages of LAG3+CD49b+ Tr1 cells compared to DC-10. T-ES210 cell cultures presented alloantigen-specific anergy, high IL-10/IFN-γ production ratio and high suppressive properties comparable to those of T-allo10. Alloantigen-specific anergy of T-allo10 and T-alloES210 was maintained upon exposure to inflammatory cytokines.


In conclusion, ES210 induces differentiation of tolerogenic DC and functional alloantigen-specific Tr1 cells in vitro. As ES210 blocks T-cell expansion in a murine graft-versus-host model, our findings suggest this could be mediated by Tr1 cells. ES210 holds promise as a therapeutic agent in vivo in the context of immune-mediated diseases.

Laurence Pellerin

Postdoctoral fellow
Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University

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    Pauline Chen

    Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University

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      Gabriela Hoyos

      Aptevo Therapeutics

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        Rosa Bacchetta

        Associate Professor
        Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University

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          Maria-Grazia Roncarolo

          Professor
          Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University

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            Use of a Bispecific anti-cd86 X monomeric-il-10 Adaptirtm Molecule to Induce Alloantigen-specific tr1 Cells



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