Immunomodulatory Dendritic Cells Inhibit Th1 Responses and Arthritis via Different Mechanisms

Abstract

Dendritic cells (DCs) are professional APCs which have the unique ability to present both foreign and self-Ags to T cells and steer the outcome of immune responses. Because of these characteristics, DCs are attractive vehicles for the delivery of therapeutic vaccines. Fully matured DCs are relatively well-defined and even used in clinical trials in cancer. DCs also have the potential to influence the outcome of autoimmunity by modulating the underlying autoimmune response. To gain a better appreciation of the abilities and mechanisms by which immunomodulatory DCs influence the outcome of T cell responses, we studied several immunomodulatory DCs (TNF-, IL-10-, or dexamethasone-stimulated bone marrow-derived DCs) side by side for their ability to modulate T cell responses and autoimmune diseases. Our data show that these differentially modulated DCs display a different composition of molecules involved in T cell activation. Although, all DC subsets analyzed were able to inhibit the induction of collagen-induced arthritis, the modulation of the underlying immune response was different. Vaccination with TNF- or IL-10-modulated DCs altered the Th1/Th2 balance as evidenced by the induction of IL-5- and IL-10-secreting T cells and the concomitant reduction of the IgG2a-IgG1 ratio against the immunizing Ag. In contrast, DCs modulated with dexamethasone did not affect the ratio of IL-5-producing vs IFN-γ-producing T cells and tended to affect the Ab response in a nonspecific manner. These data indicate that distinct mechanisms can be used by distinct DC subsets to change the outcome of autoimmunity.

Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

“…Previous studies focused on the ability of tolerogenic DCs to inhibit Th1 cell responses (15,(17)(18)(19)30). In contrast, we observed an improvement in arthritis without an effect on Th1 cell responses.…”

“…Several studies have shown that prophylactic treatment with tolerogenic DCs (e.g., IL-4-transduced DCs and TNF-treated DCs) is associated with a reduced type II collagen-specific IgG2a:IgG1 ratio, indicative of a switch from a Th1 cell-driven toward a Th2 cell-driven type II collagen-specific immune response (17,18). In contrast, we did not observe such a change in the type II collagen-specific antibody isotype ratio after tolerogenic DC treatment.…”

“…For instance, DCs transduced with FasL or IL-4 have been used to prevent CIA and to inhibit arthritis symptoms in mice with established disease (15)(16)(17). Tolerogenic DCs modified by drugs (dexamethasone; Bay 11-7082) or cytokines (tumor necrosis factor [TNF]) have been used successfully to prevent the onset of CIA (18)(19)(20)(21)(22) or to suppress established arthritis in a different model, the antigeninduced arthritis model (23).…”

“…Type II collagen-specific antibodies in the sera of mice with CIA are often used to examine the class of the type II collagen-specific immune response (17)(18)(19)30). Type II collagen-specific IgG2a antibodies are associated with a Th1 cell-driven immune response, whereas type II collagen-specific IgG1 antibodies are associated with a Th2 cell-driven response (18).…”

“…Type II collagen-specific IgG2a antibodies are associated with a Th1 cell-driven immune response, whereas type II collagen-specific IgG1 antibodies are associated with a Th2 cell-driven response (18). Sera from tolerogenic DC-and HBSS-treated mice were collected 14 days after the first tolerogenic DC injection.…”