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Blood, 15 November 2001, Vol. 98, No. 10, pp. 2992-2998
IMMUNOBIOLOGY
Dendritic cells from patients with myeloma are numerically normal
but functionally defective as they fail to up-regulate CD80
(B7-1) expression after huCD40LT stimulation because of inhibition
by transforming growth factor- 1 and
interleukin-10
Ross D. Brown,
Belinda Pope,
Allan Murray,
Warren Esdale,
Daniel M. Sze,
John Gibson,
P. Joy Ho,
Derek Hart, and
Doug Joshua
From the Institute of Haematology, Royal Prince Alfred
Hospital, Sydney, New South Wales, and the Mater Medical Research
Institute, Brisbane, Queensland, Australia.
Limited response to idiotype vaccination in patients with myeloma
suggests that there is a need to develop better immunotherapy strategies. It has been determined that the number of high-potency CMRF44+CD14 CD19
dendritic cells (DCs) in the blood of patients with myeloma (range, 0.03%-0.8% of mononuclear cells [MNCs]; n = 26) was not
significantly different from that in controls (range, 0.05%-0.8% of
MNCs; n = 13). Expression of the costimulatory molecules CD80 and
CD86 on DCs from these patients (mean, 29%±17% of MNCs and
85%±10% of MNCs, respectively) was also normal
(mean, 29%±17% and 86%±16% of MNCs, respectively). Up-regulation
of CD80 expression in response to stimulation by human (hu)CD40LT + interleukin (IL)-2 was significantly reduced on the DCs of patients
with myeloma during stable disease (n = 9) and was absent during
progressive stages (n = 7) of disease. Similar effects were seen on B
cells but not on monocytes of the same group of patients. CD86
expression on DCs was high before (86%) and after (89%) stimulation.
Inhibition of CD80 up-regulation was neutralized by either
anti-transforming growth factor (TGF)- 1 or
anti-IL-10. Up-regulation of CD80 on DCs of controls was inhibited by
rTGF-1 in a dose-dependent manner. Serum
TGF-1 and IL-10 levels were normal in most patients
studied. Cytoplasmic TGF-1 was increased in plasma cells
during progressive disease. Thus patients with myeloma have normal
numbers of DCs, but CD80 expression may fail to be up-regulated in the
presence of huCD40LT because of tumor-derived TGF-1 or
IL-10. Autologous high-potency DCs may have to be tested for CD80
up-regulation and biologically modified ex vivo before idiotype priming
for immunotherapy.
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