In their recently reported study (), Mélet and colleagues found that rituximab, a monoclonal antibody that specifically targets the B cell marker CD20, also induces up to 37% depletion of CD4+ T cells (naive and memory cells) and CD8+ T cells from the peripheral blood of patients with rheumatoid arthritis (RA). Further, they report that the extent of CD4+ T cell depletion is more predictive of response to therapy than is the extent of B cell depletion. They conclude that rituximab induces substantial depletion of T cells and that monitoring of T cell depletion in response to rituximab treatment may be particularly useful in the clinical setting. Their findings may explain in part the efficacy of rituximab—a B cell–depleting drug—by demonstrating that it is directly and indirectly responsible for the depletion of large numbers of nonreactive and reactive T cells, with the overall effect of aiding in reducing the pathology of predominantly T cell–mediated diseases such as RA and multiple sclerosis.
However, Mélet et al argue that the large-scale depletion of CD4+ T cells they observed after rituximab treatment must be due to indirect effects of rituximab. Specifically, they suggest that the loss of T cell–promoting cytokines and chemokines normally released by the rituximab-treated depleted B cells could partially explain the reduction of T cells found in the peripheral blood of RA patients. Further, they acknowledge the presence of a small percentage of T cells that express CD20, but reason that due to its small frequency this population is likely insignificant with regard to the observed T cell depletion in their study.
Conversely, we would contend that this population of CD20+ T cells is an important target of rituximab. A number of independent studies, including our own, have consistently demonstrated a population of up to 5% of peripheral blood CD3+ T cells in RA patients that express low levels of surface CD20 ([2-4]). Whereas this proportion of T cells is far smaller than the proportion of T cell reduction (37%) found in peripheral blood, this CD20+ T cell population may represent a population that drives autoreactive T cells. From animal models of RA as well as from clinical data, it has become clear that T helper cells that produce the cytokine interleukin-17 (IL-17) are the main drivers of disease (). We have shown that Th17 cells are up to 45-fold more abundant in the peripheral blood of RA patients compared to healthy subjects and that a significant portion of these IL-17–secreting T cells (∼25%) express the CD20 antigen on their cell surface, whereas IL-17–secreting CD20+ T cells were rarely detected in healthy volunteers (). Wilk and coworkers () previously demonstrated that these CD20+ T cells isolated from RA patients expressed messenger RNA for CD20 and are thus a distinct T cell subset. Importantly, those investigators showed that this T cell population was directly depleted by rituximab treatment in vivo.
Consequently, depletion of CD20+ Th17 cells directly by antibody-dependent cellular cytotoxicity occurs in rituximab-treated patients and may directly account for rituximab-mediated elimination of potentially autoreactive T cells. Depletion of this set of autoreactive T cells likely results in a decrease in T cell–activating cytokines and chemokines, an effect that by itself, or together with the indirect effects of B cell depletion on cytokine/chemokine levels proposed by Mélet and coworkers, may account for the therapeutic efficacy of rituximab in a T cell–driven disease. Further studies that dissect possible direct versus indirect effects of anti-CD20 therapy on T cells may help to guide the design of a novel generation of T cell–targeted therapeutic agents that selectively deplete such pathogenic T cell populations in patients with RA.