In vitroActivation of B-CLL Cells

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Abstract
Apart from surface Ig receptors, a variety of membrane molecules have now been described to deliver activation and progression signals to human B cells. Among them, CD40 antigen is likely to play a crucial role in the antigen-dependent maturation process. Recent studies performed in the laboratory have established that presentation of anti-CD40 mAbs in a crosslinked fashion by mouse Ltk(-) cells stably expressing human FcyRII/CDw32, allowed normal human B cells to enter into sustained proliferation. In their overwhelming majority, B-CLL cells are positive for CD40 expression. We have therefore examined the capacity of purified B-CLL cells to be stimulated by various cytokines for growth and differentiation, following crosslinking of slgs or CD40 antigen. In most B-CLL specimens studied, IL-2 was the sole factor, among a wide panel of cytokines tested, which reproducibly and significantly induced proliferation of leukemic B cells activated with anti-Ig reagents (SAC or anti-IgM antibodies). Unlike normal B cells, the great majority of anti-Ig activated B-CLL cells failed to proliferate in response to IL-4. In this activation system, IL-4 profoundly suppressed the IL-2 driven proliferation of B-CLL. An opposite pattern of growth-response was obtained following ligation of CD40 since IL-4 elicited proliferation of B-CLL whereas the growth-promoting effect of IL-2 was reduced. Under these culture conditions, IL-4 and IL-2 displayed additive effects on leukemic B cell growth. Surprisingly, IL-4 combined with anti-CD40 mAb allowed activation of certain leukemia specimens otherwise refractory to other stimulatory signals. Most B-CLL samples were induced for IgM synthesis upon SAC stimulation. This Ig response was potentiated by IL-2 and antagonized by IL-4. Anti-CD40 mAb used alone or in combination with cytokines (IL1-IL6, IFNγ, TNFα, TGFβ) failed to induce Ig secretion from B-CLL. No evidence for Ig isotype switching was obtained with the cytokines listed above, whatever the mode of B-CLL activation. Taken together, our results suggest that B-CLL can be released in vitro from their apparent maturation block, by IL-2 and anti-Ig reagents or by IL-4 and immobilized anti-CD40 mAb. Additionally, the data reported here suggest that development of the agonistic and antagonistic activities of IL-4 on B cell growth and differentiation may depend upon the nature of the activation signal provided.