SHORT ANALYTICAL REVIEWRituximab-induced B cell depletion in autoimmune diseases: Potential effects on T cells
Introduction
Following its highly successful and currently standard use in the treatment of malignant lymphomas, rituximab, an anti-human CD20 chimeric monoclonal antibody, has recently been introduced in the treatment of systemic autoimmune diseases. It has been approved for use in patients with rheumatoid arthritis (RA) and is currently being evaluated in a variety of other autoimmune diseases ranging from systemic lupus erythematosus (SLE) to the ANCA-associated vasculitides and multiple sclerosis with highly promising initial results in some instances.
Even though the initial rationale was perhaps to disrupt or at least reduce the production of autoantibodies (autoAb) that are thought to mediate some aspects of tissue damage encountered in the setting of autoimmune systemic disorders, it has become evident that the therapeutic effects of B cell depletion are disproportionately larger than the effects such treatment has on circulating autoAb titers [1], [2], [3].
Physiologically, B cells are not simply antibody and autoAb producers. They are also highly capable antigen-presenting cells (APC) and cytokine-producing cells. B cell depleting therapies should be expected to alter all aspects of B cell participation in the immune response, the T and B cell cross-talk in particular; therefore, these therapeutic strategies might be viewed more broadly on the basis of such immune-response modification. This is exemplified by the fact that rheumatoid factor (RF) status does not affect significantly the clinical response of rituximab-treated patients with RA. Administration of rituximab in RF positive patients in the first pivotal study led to profound RF decreases associated with reductions in disease activity [4]. Therefore, falling levels of RF may have a role in the responses of RF (+) patients with RA. However, subsequent studies showed that RF(−) patients with RA present equal responses to rituximab treatment [5], [6]. Whether the therapeutic effect on seronegative RA is partly due to unmeasured autoantibodies or other mechanisms remains to be clarified. In this review we present a summary of emerging data obtained from therapeutic studies in patients with autoimmune diseases suggesting that administration of rituximab may be also viewed, at least indirectly, as an anti-T cell treatment approach.
Section snippets
Lessons from animal models of systemic autoimmunity
Elegant studies conducted in the 90′s clearly demonstrated that B cells contribute more than just autoAb in the autoimmune response of lupus-prone models. B cells in T cell-deficient animals are able to produce immunoglobulin and cause autoimmunity [7] and pre-B cells from NZB X NZW F1 mice are able to sustain a high IgG autoAb production profile and to cause systemic autoimmunity when transferred to immunodeficient SCID mice questioning thus the “dominant” role of T cells in autoimmunity [8].
B cell depletion studies of RA in chimeric models
One such study has been performed so far. The investigators transplanted synovial tissue obtained from biopsies performed in patients with RA into SCID mice and subsequently infused the mice with anti-CD20 mAb [15]. Following B cell depletion the transplanted synovial fragments were analyzed. Rituximab infusions efficiently depleted transplanted tissues from B cells but also produced a significant reduction in the numbers of infiltrating T cells. Additionally, the levels of pathogenically
Alterations in T cell activation status in B cell depleted patients with SLE
Following the regulatory approval of rituximab in the treatment of patients with RA several studies have been published evaluating B cell depletion strategies in other systemic autoimmune diseases. The potential effects of such therapies on the T cell compartment and its function have been reported in only a handful of them, the majority from studies of B cell depletion in patients with the archetypal autoimmune disease SLE. Even though the APC function of lupus B cells has not been formally
Induction of regulatory T cells after rituximab in patients with SLE
Recent studies have provided evidence of numerical reductions of T cells with regulatory properties (Tregs) in patients with SLE, particularly at active disease stages. Miyara et al. showed that the extent of Treg (CD4+CD25bright) depletion correlates with the clinical severity of lupus flare, while Tregs derived from these patients are hypersensitive to Fas/FasL-dependent apoptosis suggesting that decreased Tregs in patients with active lupus result from elimination in vivo via inappropriate
Data from studies in patients with other autoimmune diseases
Limited data regarding the potential impact of B cell depletion therapies on T cells have emerged from the study of other autoimmune diseases. Results from a Phase II trial of rituximab as an add-on therapy in patients with relapsing-remitting multiple sclerosis (RRMS) have been recently reported [33]. The authors evaluated numbers of B and T cells in the cerebrospinal fluid (CSF) of patients with RRMS at 1 week before and at 24 weeks following B cell depletion treatment. As they mention, an
Progressive multifocal leucoencephalopathy following B cell depletion: A role for T cells?
Progressive multifocal leucoencephalopathy (PML) is a potentially fatal disorder resulting by ineffective immunosurveillance of JC virus, the causative agent of PML [35]. While 80% of the population are JC virus seropositive, simple infection does not result in CNS disease. Reactivated, pathogenic JC virus is believed to transit to CNS through B cells or as a cell-free virus [35], [36], [37]. PML typically occurs as a complication in patients with chronic illness with secondary
Conclusion and future directions
The therapeutic use of the anti-CD20 mAb rituximab in patients with autoimmune diseases has provided the unique opportunity to examine in transient human ‘knock out models’ the role of B cells in the pathogenesis and clinical expression of these diseases. In different diseases in which rituximab treatment has been used, clinical improvement does not al ways correlate with decreases in autoantibody titer apart from the RF (+) patients with RA. The data accumulated so far provide support to the
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