Rituximab disciplines T cells, spares platelets

Just when we're comfortable thinking that Rituximab's efficacy in idiopathic thrombocytopenic purpura (ITP) is due directly to B-cell depletion, along comes a paper that challenges the notion. It appears that B-cell depletion really affects abnormal T-cell subsets and only these changes correlate with increased platelet counts; this may change the game of how we view therapeutic design in ITP.

Rituximab (Rituxan), a monoclonal anti-CD20 antibody, is an efficacious therapy in patients with non-Hodgkin lymphoma. There has also been a great deal of interest in its beneficial effects in patients with several autoimmune disorders, including idiopathic thrombocytopenic purpura (ITP). A systematic review of several noncontrolled trials has shown that the use of this monoclonal antibody produces platelet responses in approximately 62% of patients with chronic ITP.¹  The mechanism of action of rituximab in ITP is assumed to be due to selective depletion of CD20⁺ B cells, which affects autoantibody development.²  Although the pathogenesis of ITP is autoantibody-mediated, IgG autoantibodies are driven by T-cell–dependent mechanisms and many reports have described several consistent T-cell abnormalities in ITP.³  The efficacy of a B-cell–depleting therapy, despite the presence of autoreactive T cells, led Stasi and colleagues in this issue to demonstrate that the therapeutic efficacy of rituximab is actually due to normalizing abnormal autoreactive T-cell responses in patients with ITP.

The authors studied 30 adult patients with chronic ITP that were treated with the standard rituximab dose of 375 mg/m² weekly for 4 weeks, and employed a variety of sophisticated techniques to analyze several T-cell parameters prior to treatment and at 3, 6, and 12 months after treatment. The results were correlated with the patients' responder status. What they found was not only convincing, but quite astonishing. The pretreatment T-cell abnormalities, including elevated Th1/Th2 (and Tc1/Tc2) cytokine ratios, elevated CD4⁺ T-cell–associated Bcl-2/Bax mRNA levels, and oligoclonal T-cell expansion, were completely reversed by 3 months after treatment. This was observed only in those patients who responded to rituximab therapy; these normalization changes persisted for as long as 6 to 12 months after therapy. These results suggest the intriguing hypothesis that only when T-cell subsets can be modulated is rituximab therapy effective. The reasons for these results are not clear, but may relate to how B-cell populations can be important in maintaining T-cell activation patterns by interactions such as CD40/CD40L ligation. The results are also consistent with the recently reported efficacy of rituximab in patients with refractory chronic graft-versus-host disease, which is known to be a T-cell–mediated disorder.⁴  Significantly decreasing the total mass of CD20⁺ B cells by rituximab therapy in ITP may cause a collapse of autoreactive T-cell stimulation and normalization of the T-cell repertoire even as the B cells begin to return months after the therapy. Clearly, more research is warranted to further understand this most interesting phenomenon. This important work truly lends credence to the notion that attacking T cells in ITP, even if via the slaughter of B cells, is perhaps the real way to design successful therapies for this disorder.