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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1487-1495
RAPID COMMUNICATION
Bone Marrow and Peripheral Blood Dendritic Cells From Patients With
Multiple Myeloma Are Phenotypically and Functionally Normal Despite the
Detection of Kaposi's Sarcoma Herpesvirus Gene Sequences
Noopur Raje,
Jianlin Gong,
Dharminder Chauhan,
Gerrard Teoh,
David Avigan,
Zekui Wu,
Dongshu Chen,
Steven P. Treon,
Iain J. Webb,
Donald W. Kufe, and
Kenneth C. Anderson
From the Department of Adult Oncology, Dana-Farber Cancer Institute,
and the Department of Medicine, Harvard Medical School, Boston, MA; and
the Department of Hematology, Singapore General Hospital, Singapore.
Multiple myeloma (MM) cells express idiotypic proteins and other
tumor-associated antigens which make them ideal targets for novel
immunotherapeutic approaches. However, recent reports show the presence
of Kaposi's sarcoma herpesvirus (KSHV) gene sequences in bone marrow
dendritic cells (BMDCs) in MM, raising concerns regarding their
antigen-presenting cell (APC) function. In the present study, we sought
to identify the ideal source of DCs from MM patients for use in
vaccination approaches. We compared the relative frequency, phenotype,
and function of BMDCs or peripheral blood dendritic cells (PBDCs) from
MM patients versus normal donors. DCs were derived by culture of
mononuclear cells in the presence of granulocyte-macrophage
colony-stimulating factor and interleukin-4. The yield as well as the
pattern and intensity of Ag (HLA-DR, CD40, CD54, CD80, and CD86)
expression were equivalent on DCs from BM or PB of MM patients versus
normal donors. Comparison of PBDCs versus BMDCs showed higher surface
expression of HLA-DR (P = .01), CD86
(P = .0003), and CD14 (P = .04) on PBDCs. APC function, assessed using an allogeneic mixed lymphocyte reaction (MLR),
demonstrated equivalent T-cell proliferation triggered by MM versus
normal DCs. Moreover, no differences in APC function were noted in
BMDCs compared with PBDCs. Polymerase chain reaction (PCR) analysis of
genomic DNA from both MM patient and normal donor DCs for the 233-bp
KSHV gene sequence (KS330233) was negative, but nested PCR
to yield a final product of 186 bp internal to KS330233 was
positive in 16 of 18 (88.8%) MM BMDCs, 3 of 8 (37.5%) normal BMDCs, 1 of 5 (20%) MM PBDCs, and 2 of 6 (33.3%) normal donor PBDCs.
Sequencing of 4 MM patient PCR products showed 96% to 98% homology to
the published KSHV gene sequence, with patient specific mutations
ruling out PCR artifacts or contamination. In addition, KHSV-specific
viral cyclin D (open reading frame [ORF] 72) was amplified in 2 of 5 MM BMDCs, with sequencing of the ORF 72 amplicon revealing 91% and
92% homology to the KSHV viral cyclin D sequence. These sequences
again demonstrated patient specific mutations, ruling out
contamination. Therefore, our studies show that PB appears to be the
preferred source of DCs for use in vaccination strategies due to the
ready accessibility and phenotypic profile of PBDCs, as well as the
comparable APC function and lower detection rate of KSHV gene sequences
compared with BMDCs. Whether active KSHV infection is present and
important in the pathophysiology of MM remains unclear; however, our
study shows that MMDCs remain functional despite the detection of KSHV
gene sequences.
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