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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 2186-2188
CORRESPONDENCE
Kaposi's Sarcoma-Associated Herpesvirus Is Not Detected With
Immunosuppression in Multiple Myeloma
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LETTER |
To the Editor:
Kaposi's sarcoma-associated herpesvirus (KSHV) is involved in the
pathogenesis of all forms of Kaposi's sarcoma (KS).1 In
acquired immunodeficiency syndrome (AIDS)-associated KS, KSHV detection
in peripheral blood mononuclear cells increases with immunosuppression.2 Posttransplant KS are generally due to KSHV reactivation,3 and complete KS remission is often
achieved after reduction or cessation of immunosuppressive
therapy.4 Serologic studies have shown that 80% to 90% of
KS patients have detectable antibodies against KSHV.5 These
data clearly demonstrate that KSHV is under immunological control in KS
patients.
Recently, KSHV was detected in long-term cultures of bone marrow
stromal cells (BMSC) with a phenotype of dendritic cells (DC)6 and in bone marrow (BM) core biopsies from patients
with multiple myeloma (MM).7,8 The physiopathological
relevance of KSHV in this interleukin-6 (IL-6)-related disease could
be that it encodes for a viral IL-6 (vIL-6) able to stimulate the growth of human MM cell lines.9 However, these results
contradict what is known about KSHV infection and MM. Epidemiological
studies show that KSHV and non-AIDS KS are found at higher incidence in Italy5 and that this is clearly not the case for
MM.10 In addition, five groups reported a lack of
antibodies against KSHV antigens in MM patients despite a normal
humoral response to other herpesvirus.11-15 Finally, we and
others were recently unable to found KSHV in DC samples obtained from
apheresis cells of MM patients,16,17 and Masood et
al14 failed to detect KSHV DNA in long-term BMSC cultures
from MM patients. This discrepancy led us to explore the possibility
that an extremely low level of KSHV infection in MM patients, leading
to variable detection, may be reactivated during severe
immunosuppression.
Ten patients with MM were treated with a double high-dose chemotherapy
(HDC; 140 mg/m2 melphalan plus 8 Gy total body irradiation)
supported by autograft with purified CD34+ cells
(reinjection of 4.02 ± 1.03 × 106
CD34+/kg; range, 2.88 to 5.73 × 106/kg).
CD34+ progenitors were purified by the clinical-grade
method from Cellpro (Bothell, WA), leading to a 35.6-fold enrichment in
hematopoietic progenitors from a mean value of 2.4% ± 1.08%
CD34+ cells (range, 0.99% to 3.47%) before purification
to 85.4% ± 7.1% CD34+ cells (range, 72.4% to 92.8%)
after purification. The resulting graft was 1,407-fold depleted of T
cells (reinjection of 0.11 ± 0.08 × 106
CD3+ cells/kg; range, 0.05 to
0.25 × 106/kg). Four of 10 patients relapsed within 1 year. The peripheral blood CD4+ T-cell count was monitored
at 3, 6, and 12 months after the second purified autograft. Eight of 10 patients had less than 200 CD4+ cells/µL for at least 3 months, with a mean duration of 7 months for the 6 evaluable over 1 year (Table 1). Many infectious events arose during this first year after second HDC (median of 3 episodes per
patient). In particular, 7 of 10 patients suffered from herpesvirus reactivation (Table 1). Because KS has rarely been associated with
hematopoietic stem cell transplantation, no kinetic study was
available; thus, repeated polymerase chain reaction (PCR) amplification
was performed to detect KSHV in BM samples harvested before and 90, 180, and 360 days after the second HDC. KSHV DNA was monitored in 1 µg of genomic DNA (ie, 150,000 cells), in a blinded fashion and in
two different laboratories, using a PCR assay against the
KS330233 KSHV sequence.1 This sensitive method allowed the detection of KSHV DNA in less than 1 pg of genomic DNA from
the KSHV-infected BCBL-1 cell line that corresponds to approximately 5 KSHV genome copies.16,18 KSHV DNA was not detected in any
of the 35 BM samples tested (Fig 1). The
lack of KSHV detection was not due to the presence of Taq polymerase
inhibitors, in particular heparin, because the sensitivity of KSHV PCR
was the same when assayed with either DNA harvested from heparinized BM
mononuclear cells or DNA from cells collected without heparin (Fig 1).
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| Fig 1.
Lack of KSHV reactivation during treatment-induced
immunosuppression in MM patients. (A) DNA samples extracted from BM
before and 90, 180, and 360 days after second HDC were amplified by PCR
using the KSHV 330233 primers. Each PCR was performed on 1 µg of genomic DNA and the amplification products were transferred to
a nylon membrane and hybridized with a 32P end-labeled
internal probe. The positive control (lane C) was the PCR product from
the KSHV-infected BCBL-1 cell line. (B) Lanes 1 through 5 contain
10-fold dilutions of BCBL-1 DNA from 1 ng (lane 1) to 0.1 pg (lane 5).
BCBL-1 DNA was diluted in the DNA extracted from heparinized BM
mononuclear cells from patient no. 1 90 days after the second HDC, so
that all PCR were run on 1 µg of total DNA. These data are
representative of 10 experiments performed with the heparinized DNA
samples extracted from the 10 patients 90 days after second HDC.
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Three explanations may account for the discrepancy between the negative
PCR with BM aspirates, the negative serological results, the lack of
KSHV reactivation in immunosuppressed MM patients, and the positive PCR
with stromal cultures and BM biopsies. (1) MM patients could be
infected with a variant of KSHV that can escape the immune system or
that encodes for antigens not recognized by the available immunological
assays. This could explain the failure to detect anti-KSHV antibodies.
(2) KSHV could be under a strict T-cell-mediated immune control in MM
patients, leading to a very difficult detection by sensitive PCR. In
this case, because infected cells remain undetectable in whole BM
samples after double HDC and graft of purified CD34+ cells,
one could hypothesize that this treatment has not destroyed anti-KSHV-specific CD4+ and CD8+ T cells,
contrary to other anti-herpesvirus T cells. (3) KSHV could be not
involved in MM patients, and its detection could be linked to
false-positive PCR, as pointed out recently by Moore.19
These contradictions need to be elucidated, but our present results
emphasize that, if KSHV or a variant of KSHV is really involved in MM,
it is not a major factor in relapse occuring in immunosuppressed
patients after autologous graft and raises the question of its causal
role in MM.
Karin Tarte
IGMM
CNRS
Montpellier,
France
Sonja J. Olsen
Division of
Epidemiology
Columbia University
New York,
NY
Jean-François Rossi
Eric Legouffe
Service
d'Hematologie et d'Oncologie Medicale
CHU Lapeyronie
Montpellier,
France
Zhao-Yang Lu
Michel Jourdan
U475,
INSERM
Montpellier, France
Yuan Chang
Department of
Pathology
Columbia University
New York, NY
Bernard Klein
Unite de Therapie Cellulaire
CHU Saint
Eloi
Montpellier, France
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