Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3163-3164
CONTROVERSIES IN HEMATOLOGY
Rebuttal to Tarte, Chang, and Klein
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ARTICLE |
TARTE ET AL REFER to three studies, two letters to the
editor and one recent publication from their group, that have failed to
show HHV-8 in multiple myeloma (MM) bone marrow stroma cells
(BMSCs).1-3 Importantly, the types of BMSCs produced by long-term marrow culture are highly heterogeneous, and the cell populations that were evaluated for the presence of HHV-8 were not
fully characterized in these studies. In addition, no positive controls
(Kaposi's sarcoma [KS] patients) were included in the analysis;
thus, the sensitivity of the polymerase chain reaction (PCR) assay
could not be assessed.1-3 Anderson's group4
has recently confirmed the presence of HHV-8 in MM BMSCs with a similar immunophenotype to our own.5 Although the Tisdale group was able to amplify ORF26 but not ORF72 products in most MM BM
samples,6 we and Anderson's group have easily amplified
product in these patients using primers from both of these ORFs in
addition to other HHV-8 ORFs. The inability to find HHV-8 in BM
aspirates from myeloma patients is consistent with our own
experience.5 In contrast, we and others have detected HHV-8
in the BM biopsies from most MM patients.7,8 We have used
primer pairs from many HHV-8 ORFs and have found consistent detection
in fresh BM biopsies from MM patients but not in normal subjects or in
patients with other malignancies. Importantly, the conditions necessary to amplify product are optimized for each of our primer pairs before
use. In addition, the integrity of the sample DNA is assured by
serially diluting it until only one copy of it is present and then
performing PCR amplification with actin primers. The lack of viral
interleukin-6 (vIL-6) expression in the BM biopsies3 is
consistent with our recent report showing the infrequent expression of
this viral homologue in fresh BM biopsies from these
patients.9
Tarte et al also showed lack of HHV-8 in 30 BM aspirates from MM
patients collected after a second high-dose therapy
procedure.10 This is consistent with our previous results
on BM aspirates posttransplant.5 Unfortunately, studies
using fresh BM biopsies have not been reported by this group, except in
a single case in which the clinical status of the patient is not
recorded.3 In addition, the lack of HHV-8 in BM aspirates
obtained from the 4 patients who relapsed after high-dose therapy is
consistent with our ability to detect HHV-8 in aspirates from less than
10% of similarly treated patients.
It is intriguing that MM patients have weak11 or no
detectable antibodies12,13 against HHV-8. This finding may
reflect the relative general immunodeficiency that is the hallmark of MM or a specific immune defect that does not allow generation of
antibodies against HHV-8. A more interesting possibility is that the
type of HHV-8 present in MM patients is different than that present in
KS and body cavity lymphoma (BCL) patients. In support of this, we have
identified in MM patients consistent changes in the HHV-8 sequence
present in regions of the virus that are largely responsible for the
immune response.9 These differences may help explain the
inability to identify antibodies that were developed using KS tissues.
Recently, specific viral strains of another gammaherpesvirus,
Epstein-Barr, have been associated with the development of lymphoid
malignancies.14 Similarly, HHV-8 derived from KS tissues
show distinct genetic differences from BCL-derived viruses, and these
different viral isolates show different biological
effects.15 Moreover, recent data from KS patients show that
certain subtypes of HHV-8 may even predict more aggressive clinical
characteristics of the tumor.16
The investigators suggest that the HHV-8-infected BMSCs in myeloma
patients are not actually dendritic cells (DCs), because they have not
been demonstrated to provide antigen-presenting cell function. Quite to
the contrary, Anderson's group has shown that these virally infected
DCs are, in fact, functional.17 There is also marked
heterogeneity in the type of DCs generated in these different culture
systems.18 To assume that the DCs analyzed for viral
presence by other groups were identical to those shown to contain virus
in our and Anderson's long-term marrow cultures is a leap of faith.
The studies from Tarte et al19 and Yi et al20
characterized their DCs as CD1a and CD4-expressing cells, in contrast
to the HHV-8-containing DCs in our and Anderson's studies that lacked
expression of both of these markers.4,5 In addition, the
DCs in Yi et al's study also lacked CD83, which was found on the
HHV-8-containing DCs. Consistent with Tarte et al19 and
others21 and the absence of CD34 on the BMSCs infected with
HHV-8 from our and Anderson's groups,4,5 we also have rarely found HHV-8 in CD34-enriched autograft material.22
We certainly believe that it may be possible to generate functional DCs
from CD34-selected and other autograft material for clinical use based
on our results and these other studies as well as the recent report
from Raje et al.17
Thus, our studies support the presence of HHV-8 in the vast majority of
bone marrow and peripheral blood samples from MM patients. It also
suggests that the viral strain may be unique in these patients and may
help explain the weak or lack of a serological response in these
individuals. It remains to be determined the part that this virus
plays in the development of this B-cell malignancy, but its uniqueness
among these patients suggests that it has an important role in
the disease pathogenesis.
| |
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