CD40 AND THE EFFECT OF ANTI-CD40-BINDING ON HUMAN MULTIPLE-MYELOMA CLONOGENICITY

CD40 is a 48 kDa glycosylated phospoprotein that is a member ol the tu mor necrosis factor receptor (TNF-R) superfamily. CD40 was originally identified in B lymphocytes, and is found on monocytes, dendritic cell s, some carcinoma cell lines, and the thymic epithelium. CD40 is expre ssed on normal pre-B through mature B stages of differentiation. For n ormal B cells, the cross-linking of CD40 induces cell cycle progressio n, long-term proliferation in vitro, IgE secretion, increased adhesion molecule (LFA-I) expression, and low level IL-6 secretion. The natura l ligand of CD40 (CD40L, gp39, or T-BAM, for T-B cell activating molec ule) was recently identified as an inducible molecule expressed transi tionally on activated T cells. Although originally believed to be abse nt in normal and malignant plasma cells, CD40 has been demonstrated on the majority of myeloma cell lines and myeloma cells from plasma cell dyscrasia (PCD) patient specimens tested. CD40 activation modulated m yeloma cell proliferation and clonogenicity in vitro, suggesting that the CD40 pathway is active in myeloma cell growth. For the IL-6 depend ent cell line ANBL-6, CD40 activation was associated with autocrine IL -6 production. However, the IL-6 pathway does not appear to play a pre dominant role in CD40 activation of non-IL-6-dependent MM cell lines a nd patient primary bone marrow cultures. The possible pathophysiologic role of the CD40 receptor in human multiple myeloma is discussed.