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Anti-CD40 antibody binding modulates human multiple myeloma clonogenicity
in vitro
AW Tong, BQ Zhang, G Mues, M Solano, T Hanson and MJ Stone
Cancer Immunology Research Laboratory, Charles A. Sammons Cancer Center,
Baylor University Medical Center, Dallas, TX 75246.
Ligand binding of the B-cell lineage antigen CD40 enhances growth and
interleukin-6 (IL-6) secretion in human B cells (the CD40/IL-6 loop). IL-6
has an autocrine and paracrine role in human multiple myeloma (MM) cell
growth. With the use of the CD40 monoclonal antibody (MoAb) G28-5, we
examined CD40 expression and the effect of CD40 binding on MM clonogenic
colony (MCC) formation to characterize the IL-6/CD40 loop activity in MM.
CD40 was expressed on plasmacytoid cells in 21 of 28 plasma cell dyscrasia
(PCD) bone marrow (BM) biopsies tested (10 of 14 MM, 2 of 2 Waldenstrom's
macroglobulinemia [WM], 2 of 2 plasma cell leukemia [PCL], 6 of 8
monoclonal gammopathy of undetermined significance [MGUS], and 1 of 2
primary amyloidosis [AL]). G28-5 binding increased MCCs by 35% to 150% in
11 of 17 CD40+ PCD BM cultures, but did not affect MCC formation in CD40-
specimens or normal BM colony forming units (CFU-GEMM, CFU-GM, BFU-E).
Responsive cultures originated from BM of patients with MM (2 of 5 cases
tested), WM (2 of 2), PCL (2 of 2), and MGUS (5 of 6). CD40-responsiveness
was not significantly inhibited by the presence of an anti-IL-6 MoAb (2 of
2 MGUS cultures tested), and did not correlate with the capacity to respond
to IL-6 stimulation (n = 17, P > .05) or a detectable level of
endogenous IL-6 (n = 15, P > .05). Additional studies were performed
with PCD cell lines to characterize the interrelationship of CD40
activation and IL-6 production. Fifty percent to greater than 95% of cells
from the RPMI 8226 and ARH77 lines expressed CD40, whereas 6% of U266 cells
were CD40+. For RPMI 8226, ARH-77, and U266 cells, the increased MCC
formation after anti-CD40 stimulation was not affected by the presence of
an anti-IL-6 neutralizing MoAb and was not accompanied by detectable IL-6
secretion. There was no apparent increase in IL-6 mRNA transcription
following G28-5 treatment of U266 or RPMI 8226 cells. Our observations
indicate that CD40 is expressed in a subset of human myeloma cells present
in various PCDs. Cell-line studies suggest that the CD40+ myeloma cell may
regulate MM clonogenic colony formation without activating the IL-6
pathway.
Volume 84,
Issue 9,
pp. 3026-3033,
11/01/1994
Copyright © 1994 by The American Society of Hematology
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