Soluble CD40 ligand induces selective proliferation of lymphoma cells in primary mantle cell lymphoma cell cultures

Interaction between CD40 and the CD40 ligand (CD40L) is critical for the su rvival and proliferation of B cells during immunopoiesis, However, the role of CD40L in the pathogenesis of malignant lymphomas is ambiguous. Primary mantle cell lymphoma (MCL) cells were cultured in the presence of recombina nt human CD40L trimer (huCD40LT), and a significant time- and dose-dependen t induction of DNA synthesis was observed in thymidine incorporation assays (n = 7, P < .04). The maximal rate of DNA synthesis was reached at huCD40L T doses of 100 ng/mL and above after 4 days of culture, but a significant i ncrease of DNA synthesis was detected already at doses of 1 ng/mL (P = .03) . HuCD40LT never inhibited the basal level of DNA synthesis. These findings established 400 ng/mL of huCD40LT far 4 days as standard conditions in the system. Under these conditions, huCD40LT significantly increased the propo rtion of cells in the S/G(2)/M phases of the cell cycle in 4 of 7 studied c ases, while the fraction of apoptotic cells remained unchanged (n = 7), HuC D40LT also induced expression of CD80/B7-1, CD86/B7-2, and CD96/Fas and up- regulated the expression of HLA-DR (n = 6), With the use of bromodeoxyuridi ne incorporation in triple-color flow cytometric analysis, it was found tha t huCD40LT induced cell-cycle progression in light chain-restricted cells o nly, of which a median of 14% (range, 0.5% to 29%; n = 4) returned to G(0/1 ) phase DNA content after bromodeoxyuridine incorporation, demonstrating co mpletion of at least one cell cycle in the presence of huCD40LT. Thus, prim ary clonal MCL cells are activated and can proliferate in the presence of h uCD40LT as a single agent. (Blood. 2000; 96:2219-2225) (C) 2000 by The Amer ican Society of Hematology.