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Features of Rituximab‐Induced Killing of B Lymphocytes

Anti-B lymphocyte antibodies (Abs) represent a major advance in the therapy of haematological cancers and a revolutionary breakthrough in the B cell involving systemic diseases. On the basis that the B cell-related molecule CD20 arises early from the bone marrow, and maintains its B-lymphocyte specificity throughout the cell differentiation pathway except plasma cells, this marker is ideally suited as a target for B cell depleting agents. Intriguingly, CD20-knockout mice do not show any phenotype. Rituximab (RTX) was the first chimerical CD20 monoclonal Ab (mAb) to be approved by the Food and Drug Administration for treatment of relapsed or refractory, low-grade or follicular non-Hodgkin’s lymphoma (NHL). Thereafter, the drug has served its purpose in NHLs [1] with response rates around 60%, but not in chronic lymphocytic leukaemia (CLL), with response rates as low as 25% [2]. The work on rheumatoid arthritis (RA) pioneered by Edwards and Cambridge [3] has then spawned a number of trials in autoimmune settings such as RA, systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (SS). RTX has also been successfully administered in individuals awaiting renal transplantation. These attempts have yielded varying results. There were marked differences among histological types of NHLs in the earliest studies [1]. Then, CLL proved to be less responsive to RTX than lymphoma, and B cell depletion was therapeutic in some, but not in all patients with RA [4]. Nonetheless, little is known about mechanisms of resistance. Trivial explanations include lower serum levels of RTX in CLL than in NHL and variations in the membrane expression of CD20 [5] on B lymphocytes of leukaemia (10, 000 molecules per cell), compared with those of lymphoma (100, 000 molecules per cell). Thus, more efficient harnessing of CD20 on B lymphocytes might amplify the effects of RTX. This was achieved by transfecting the gene of transcription factors for cd20 in leukaemic B cells [6]. Human antichimeric Ab response may also occur, but the rate of this seroconversion is low. Parenthetically, in contrast to what used to be claimed, the majority of long-lived plasmablasts is CD20-positive, and as such can be deleted with RTX [7]. Thus, the constancy of serum immunoglobulin and autoAb levels is more questionable than used to be thought. Finally, evidence has emerged that RTX-opsonized cells are sequestered by the mononuclear phagocytic system, and released back into the circulation after the RTX-CD20 complexes have been shaved by phagocytes [8]. The efficacy of RTX may rather be diminished when the pathogenesis of the condition provides B cells with survival signals such as the B cell-activating factor of the tumour necrosis factor family (BAFF). The higher the level before treatment, the shorter the duration of the B cell lymphopenia not only in CLL [9] but also in primary SS [10]. Consistent with these observations, murine B cells are refractory to depletion in autoimmune-prone strains compared with non-autoimmune-prone strains, possibly because of the excess production of BAFF in the former mice [11]. This finding implies that at least some patients resist RTX as a byproduct of their autoimmune condition itself. In addition, various signals from the micro-environment (including integrin-regulated homeostasis) and circulatory dynamics of B cells (B cells have to be accessible) define distinct sensitivities in CD20-directed effects [12]. Understanding the way RTX operates is required to optimize this treatment. Thus, the question arises as to how the mAb applies its anti-tumour potential. Different mechanisms work together during B cell depletion. Upon crosslinking, RTX dictates the partition of clustered CD20 into the lipid rafts (LRs), favours the involvement of a p38 mitogen-activated protein kinase and results in apoptosis of RA B cells [13]. The ability of this mAb to recruit complement on the B cell membrane and trigger the complement-mediated lysis (CML) is also associated with segregation of CD20 into the LRs [14]. Complement-dependent cell-mediated or Ab-dependent cell-mediated cytotoxicities (ADCC) are other mechanisms. Of particular interest, CML and ADCC act simultaneously, and CML-resistant cells are ADCCsensitive and vice versa [15]. Furthermore, RTX-induced B cell depletion decreases the number of activated T cells, and increases the expression of FoxP3 in regulatory T cells in SLE nephritis [16]. Whether or not ADCC is important in the therapeutic effectiveness of RTX is not fully clarified, but remains to be confirmed. This response is linked to FccRIIA and FccRIIIA polymorphisms in lymphoma [17] and SLE [18], but neither in CLL [19] nor in primary SS [9]. Relative to CML, the importance of ADCC may thus vary among patients from disease to disease and across the histological types. The response diverges in follicular lymphoma B cells of different maturation stages. B cell development relies on series of changing surface phenotypes. In this respect, their increased sensitivity to apoptosis compared with centroblasts suggests that centrocytes are negatively selected, although numerous autoreactive memory B cells exit the germinal centres and enter the long-lived memory compartment [20]. Overall and irrespective of the mechanism by which they are achieved, the results are satisfactory. In sum, RTX takes several pathways to kill the cells. Their relative importance depends not only on the disease, but also on the I N V I T E D E D I T O R I A L doi: 10.1111/j.1365-3083.2008.02132.x .