Autoantibodies are the hallmark of many autoimmune diseases, including rheumatoid arthritis (RA) (20
). One of the most promising strategies to control pathogenic autoantibodies is B cell depletion using a CD20-specific antibody (4
). However, long-term B cell depletion is difficult to maintain and repopulation of the B cell repertoire is often accompanied by the return of arthritis symptoms (8
). Clearly, new strategies to inhibit the activation of autoreactive B cells upon repopulation would help increase its therapeutic effectiveness. Recently, we identified the IDO pathway as a major contributor to autoantibody production in a mouse model of RA (10
). Inhibition of IDO with 1MT attenuated arthritis progression by reducing autoantibody levels, suggesting an important role for IDO in driving autoreactive B cell responses. Using Immunoglobulin transgenic mice, we show here that IDO activity is essential for the differentiation of autoreactive B cells into antibody secreting cells, but is not necessary for the initial stages of B cell activation. Furthermore, the addition of 1MT to B cell depletion therapy prevented the re-emergence of autoantibody secreting cells and arthritis symptoms following reconstitution of the B cell repertoire. Our data suggest that IDO inhibitors could be used in conjunction with B cell depletion as an effective co-therapeutic strategy in the treatment of RA.
Our data demonstrate that IDO plays a role in driving the differentiation of B cells into ASCs in vivo
. However, blocking IDO activity with 1MT does not inhibit antibody production from purified B cells in vitro
), suggesting that 1MT may affect B cell differentiation indirectly by affecting the microenvironment in which the B cells are being activated. In support of this, levels of IL-4, IL-6, IL-10, and IL-13, cytokines necessary for B cell antibody production, were all decreased in 1MT-treated mice. 1MT inhibited ASC formation at the late/post germinal center stage, but does not appear to affect long-lived plasma cells, as Ig titers and numbers of ASCs were not diminished in mice treated with 1MT after the onset of arthritis. This stage-specific effect could be advantageous in that 1MT treatment would only affect the generation of newly formed ASCs and not inhibit memory responses to pathogens to which we have acquired immunity through vaccination or prior exposure.
A positive role for IDO in driving B cell-mediated autoimmune responses is in contrast to the traditional view of IDO having a suppressive function in T cell-mediated immunity (21
). These findings may have implications for the development of the IDO inhibitor 1MT as a clinical agent. 1MT is currently in early stage clinical testing as an anti-cancer therapeutic (25
). Based on IDO’s presumed inhibitory action on T cells, one concern has been that the use of 1MT might induce severe autoimmune-based toxicities. The use of 1MT did exacerbate symptoms in some induced models of autoimmunity (26
). However, there is no evidence of spontaneous autoimmunity resulting from 1MT treatment in non-autoimmune mouse models (29
) and our findings in the K/BxN RA model actually show reduced autoantibody levels and evidence of improvement in inflammatory autoimmune symptoms with 1MT treatment (10
). Therefore, together with our findings demonstrating IDO’s role in driving autoantibody production, this suggests that the potential application of IDO inhibitors may be more far reaching than is currently appreciated.
One potential new use of IDO inhibitors that our data point to is in a co-therapuetic strategy to increase the effectiveness of B cell depletion therapy. In K/BxN mice and other mouse models of RA, treatment with anti-CD20 leads to a rapid depletion of B cells from the circulating B cell repertoire (7
). However, as the anti-CD20 antibody is cleared from the circulation, the B cell repertoire repopulates and disease symptoms return (19
). This is also seen in human RA patients where the reemergence of the B cell repertoire is often accompanied by the return of arthritis symptoms (8
). A second treatment cycle with Rituximab will sometimes, but not always, reduce the flare in arthritis symptoms (31
). Even when multiple treatment cycles are possible, maintaining patients on B cell depletion therapy may not be desirable long-term. Although not as significant a problem as with other biologic therapies such as TNF blocking agents, patients on B cell depletion therapy do exhibit a higher risk of infections (31
). Furthermore, as B cells provide critical immune functions outside of their ability to produce antibody, including cytokine secretion and antigen presentation, depletion of the entire B cell repertoire will adversely impact the immune system as a whole. In support of this, B cell depletion in mouse models has been shown to inhibit T cell function (6
In summary, our data suggest that adding IDO inhibitors to B cell depletion therapy is an effective way to inhibit the reemergence of autoantibody secreting cells while allowing the repopulation of the B cell repertoire. Therefore, combination therapy with anti-CD20 and 1MT has the potential to benefit RA patients by both eliminating pathogenic B cells that are already present and preventing new ones from being generated.