Background/Purpose: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of innate immune cells with immunosuppressive properties. We previously identified MDSCs in the synovial fluid (SF) of mice with proteoglycan-induced arthritis (PGIA), a T cell-dependent model of rheumatoid arthritis (RA). Although SF MDSCs potently inhibited antigen-specific T cell proliferation in vitro, they were not available in quantities necessary for testing their in vivo suppressive activity in PGIA. Using bone marrow (BM)-derived MDSCs, expanded in culture in the presence of growth factors, we sought to determine whether these cells could exert suppression on antigen-specific responses and arthritis severity upon their transfer to syngeneic mice with PGIA. An important additional goal of this study was to identify MDSCs in the SF of human patients with RA.

Methods: As reported previously, MDSCs with strong suppressor activity were successfully expanded from murine BM in vitro in the presence of GM-CSF, G-CSF, and IL-6. We used the adoptive transfer model of PGIA, in which spleen cells from arthritic wild type donors were injected with antigen (PG) into syngeneic SCID recipients. After the clinical signs of arthritis began to develop, the SCID mice were divided into groups with similar average disease scores. The control groups received a second injection of arthritic spleen cells and PG, while the experimental groups received the same plus MDSCs. Disease severity was monitored by visual scoring. Three weeks later, spleen cells from the SCID recipients were tested for antigen (PG)-specific proliferation, and sera were assayed for anti-PG antibody titers. Human SF and blood were obtained from consenting RA patients undergoing therapeutic joint aspiration. The phenotype of SF cells was determined by flow cytometry with antibodies to human MDSC-specific markers. The ability of RA SF MDSCs to suppress T cell proliferation was tested by culturing autologous blood mononuclear cells in the presence or absence of SF cells. T cell proliferation was induced via anti-CD3/CD28 antibodies or with Mitomycin C-treated allogeneic lymphocytes.

Results: Arthritis severity in SCID mice injected with BM MDSCs were significantly lower (mean score 3.5) than in control mice injected with spleen cells only (mean score 8.25) (n=10 mice/treatment). PG-specific T-cell responses and serum IgG1 type antibodies were also significantly reduced in the BM MDSC recipient groups. Regarding the human system, both granulocytic and monocytic MDSC-like cells were identified in SF samples (n=9) from RA patients. RA SF MDSCs suppressed the proliferation of autologous blood T cells ex vivo, although the inhibitory effects were not as strong as those in the murine system. Depletion of T cells from the RA SF cell population further improved the MDSC-mediated suppression of blood T cell proliferation.

Conclusion: Murine BM-derived MDSCs effectively suppress arthritis upon injection into SCID mice developing adoptively transferred PGIA. Cells with MDSC-like phenotype and immunosuppressive activity are also present in the SF of RA patients. Our results suggest that MDSCs could represent a novel therapeutic tool in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/suppression-of-immune-responses-and-joint-inflammation-by-myeloid-derived-suppressor-cells-in-a-t-cell-dependent-mouse-model-of-rheumatoid-arthritis/