Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4472-4478
Recombinant CD40L Treatment Protects Allogeneic Murine Bone Marrow
Transplant Recipients From Death Caused by Herpes Simplex Virus-1
Infection
By
Janice L. Beland,
Heiko Adler,
Nadia C. Del-Pan,
Wende Kozlow,
Janice Sung,
William Fanslow, and
Ilonna J. Rimm
From the Department of Pediatric Oncology, Dana-Farber Cancer
Institute and Children's Hospital, Harvard Medical School, Boston, MA;
and Immunex, Seattle WA.
 |
ABSTRACT |
Posttransplant infection associated with host immune deficiency is
the major cause of nonrelapse mortality of human bone marrow transplant
recipients. In a new murine model of posttransplant infection,
allogeneic bone marrow transplant recipients were infected with herpes
simplex virus-1 (HSV-1) via intraperitoneal inoculation 12 weeks after
transplantation. Allogeneic transplant recipients with
graft-versus-host disease (GVHD) had significantly increased mortality
from HSV-1 encephalitis, with deficiencies of both specific anti-HSV-1
antibody and total serum IgG2a. GVHD mice displayed a Th2 cytokine
profile (increased interleukin-4 [IL-4] and decreased interferon-
)
and decreased lipopolysaccharide (LPS) responses, suggesting that both
T-cell and B-cell defects contributed to the impaired production of
antibody. Because passive transfer of hyperimmune serum protected mice
from HSV-1 infection, we hypothesized that CD40 ligand (CD40L), which
induces B-cell maturation, would protect mice from HSV-1 infection.
CD40L-treated GVHD mice showed elevated IgG2a levels and increased
survival compared with vehicle-treated transplant recipients.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
INFECTION ASSOCIATED with posttransplant
immunodeficiency is the major cause of nonrelapse death in bone marrow
transplant recipients.1,2 Posttransplant patients have
frequent bacterial, viral, and fungal infections, indicating that
infection is the result of host immunodeficiency rather than the
virulent nature of a single pathogen. Defects in both B-cell and T-cell
function contribute to human posttransplant
immunodeficiency.3,4 Murine posttransplant immunodeficiency
is associated with multiple functional defects, including impairments
in T cells, B cells, adhesion molecules, and signaling
molecules.5-9
Previous studies of viral infection with concurrent murine allogeneic
bone marrow transplantation showed that infection and GVHD synergized
to exacerbate the infection and increase graft-versus-host disease
(GVHD).10-12 Earlier work has focused on viral infection that occurred concurrently with transplantation, before engraftment. However, many severe clinical infections occur after engraftment, and
murine models have not yet been developed to address the issue of late
infection.
We designed a murine model consisting of allogeneic bone marrow
transplantation followed by herpes simplex virus-1 (HSV-1) infection to
investigate the mechanisms of posttransplant immunodeficiency and to
test potential cytokine therapies. HSV-1, which produces a rapid,
measurable immune response, was chosen as a model pathogen to represent
the herpes viruses which often infect bone marrow transplant
patients.1 The goal of this work was to evaluate the effect
of the posttransplant immunodeficient state on the response to a
single, representative pathogen and to test potential cytokine
therapies that may decrease morbidity and mortality due to viral
infection.
Because CD40L treatment accelerated B-cell maturation in a syngeneic
murine bone marrow transplant system,13 we have
investigated the use of this cytokine as a therapy for posttransplant
immunodeficiency. The binding of CD40L to CD40 stimulates B-cell
proliferation, differentiation, and antibody secretion. Other effects
of CD40L binding include B7-2 upregulation and the rescue of B cells
from apoptosis.14,15
| |
MATERIALS AND METHODS |
Mice.
Female CBA/J and B10.BR mice, purchased from the Jackson Laboratory
(Bar Harbor, ME), were transplanted at 11 to 13 weeks of age. The CBA/J
and B10.BR mouse strains, which are both H-2k, differ at
multiple minor histocompatibility loci. Transplantation of bone marrow
from B10.BR mice to CBA/J mice simulated bone marrow transplantation
with matched unrelated donors. Female Igh-6 (B-cell-deficient mice)16 were purchased from Jackson Laboratory and used at
12 weeks of age.
Bone marrow transplantation.
Bone marrow was flushed from the femurs and tibiae of donor mice and
washed one time with supplemented RPMI (RPMI1640
[Mediatech, Herndon, VA] with penicillin-streptomycin
[100 IU/mL], L-glutamine [2 mmol/L], 2-ME [55 µmol/L], HEPES
[10 mmol/L], and 10% heat-inactivated fetal bovine serum [Sigma, St
Louis, MO]). Bone marrow cells were resuspended in Leibovitz's L-15
medium (Life Technologies, Inc, Grand Island, NY). Recipient mice were
irradiated with 1,100 cGy split dose irradiation and then injected
intravenously with donor bone marrow cells (5 × 106
cells). T-cell-depleted bone marrow transplant recipients were reconstituted with bone marrow that had been treated with two rounds of
lysis with anti-Thy 1.2 and Complement (Accurate Chemicals & Scientific
Corp, Westbury, NY). In one group, T cells (4 × 105
nylon wool passed spleen cells, 75% CD3+ cells) were added
to the bone marrow to produce recipient mice, which developed minimal
GVHD.8 All procedures were performed in accordance with
protocols approved by the Animal Care Committee of the Dana-Farber
Cancer Institute.
Viral infection with HSV-1 (KOS 1.1).
The mice were infected with HSV-117 at 5 × 107 plaque forming units (pfu)/mouse via intraperitoneal
injection 12 weeks after bone marrow transplantation. As in other
studies of murine HSV-1 infection,18,19 examination of the
central nervous system (CNS) tissues of dying GVHD mice showed the
presence of HSV-1 antigen and inflammation (data not shown), suggesting
HSV-1 encephalitis as the cause of death. Most deaths from HSV-1
infection occurred within 10 days of viral inoculation. Immunological
studies below were performed on surviving mice.
CD40L treatment.
Trimeric murine recombinant CD40L20 was generously provided
by Immunex (Seattle, WA). Mice were treated with 6 µg CD40L or
vehicle (10% glycerol in saline) by intraperitoneal injection three
times per week, starting the day before HSV-1 injection.
Cell culture preparation and proliferation assays.
Two weeks after HSV-1 inoculation, mice were killed by CO2
asphyxiation and immunological studies were performed. Isolated splenocytes were washed and resuspended in supplemented RPMI. Viable
cells were determined by Trypan blue exclusion.
Proliferation of recipient splenocytes to ultraviolet inactivated virus
(4 × 105 pfu) or extract (a virus-free lysate of
control Vero cells) was measured after 4 days incubation at 37°C
and 5% CO2. Lipopolysaccharide (LPS; 10 µg/mL;
Sigma)-stimulated proliferation was measured after 2 days. Recipient
splenocytes were incubated in supplemented RPMI with LPS, inactivated
virus, or extract in triplicate wells of 96-well microtiter plates with
4 × 105 cells/well. Cells were pulsed with 1 µCi
3H-thymidine/well for the final 5 hours of incubation and
harvested. Incorporated 3H-thymidine was determined.
Flow cytometry.
Splenocytes were stained for flow cytometry. Fc receptor binding was
blocked with phosphate-buffered saline (PBS) containing 10% rat whole
serum (Zymed Laboratories, San Francisco, CA). As described,17 the following monoclonal antibodies,
conjugated with either fluorescein isothiocyanate, phycoerythrin, or
biotin (used with Streptavidin-Red670 [Life Technologies, Inc]) were used for staining: anti-B220, anti-CD4, anti-CD8, anti-CD3.
Specific anti-HSV-1 antibody and total serum IgG1 and IgG2a
measurement.
HSV-1-specific IgG1 and IgG2a antibodies in serum were determined by
enzyme-linked immunosorbent assay (ELISA).21 Total serum IgG1 and IgG2a levels were determined using Radial
Immunodiffusion (RID) Kits for mouse IgG1 and IgG2a (The Binding Site,
Birmingham, UK). The tests were performed following the instructions of
the manufacturer.
Cytokine detection.
Splenocytes from immunized recipients were cultured with inactivated
virus and supernatants collected. Interferon- (IFN-) and
interleukin-5 (IL-5) levels were determined by ELISA. All measurements
were performed using recombinant cytokine standards and "pairs"
of capture and peroxidase-conjugated secondary antibodies, all
purchased from PharMingen (San Diego, CA) and used according to the
protocol supplied by PharMingen. The plates were developed using avidin-peroxidase and 2,2
-Azino-bis
(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) substrate (Sigma) and
read at 405 nm using an ELISA reader. The lower detection limit of the
assay was 100 pg/mL for IFN-. To measure IL-4, culture supernatants
were tested in collaboration with Dr Abul Abbas using the
cytokine-dependent cell line CT4S in the presence of IL-2 blocking
antibodies.22
Passive transfer experiments.
Hyperimmune HSV-1 antiserum was generated in normal B10.BR mice by
three intraperitoneal injections of HSV-1 (5 × 107
pfu/mouse) given at 2-week intervals. Serum was heat inactivated for 30 minutes at 56°C, and each mouse received 200 µL via tail vein
injection.
Cytotoxic T lymphocyte (CTL) assay.
Two weeks after viral infection, mice were killed and splenocyte cell
suspensions (6 × 107 mononuclear cells) were prepared
in 900 µL of unsupplemented RPMI. Cells were exposed to HSV-1
(ultraviolet irradiation-inactivated preparation equivalent to
multiplicity of infection [MOI] of 1.5) in a total volume of 1.8 mL
for 1 hour at 37°C. Supplemented RPMI 1640 (10 mL) was added and
cultures were incubated for 4 days. Target L929 cells (American Type
Culture Collection, Rockville, MD) were labeled overnight with 100 µCi 51Cr per 5 × 106 cells. On the day
of assay, targets were incubated for 1 hour with HSV-1 (MOI = 10),
washed and added at 1 × 104 cell/well to 96-well
plates with effector cells at ratios of 100:1 to 3.12:1. Plates were
incubated for 4 hours at 37°C and 5% CO2, centrifuged,
and percent-specific lysis calculated.
| |
RESULTS |
GVHD mice have decreased survival from HSV-1.
Irradiated CBA mice were reconstituted with T-cell-depleted bone
marrow, or T-cell-supplemented bone marrow to generate an allogeneic
control group (control) and a group with partial recovery from acute
GVHD (GVHD). At 12 weeks posttransplantation, the GVHD group had a 20%
weight loss due to GVHD as compared with the control group
(Fig 1). In addition, the LD50
of control mice was more than twofold higher than that of GVHD mice
(Table 1). Normal B10.BR and CBA/J mice had
LD50 values greater than both transplant groups.
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| Fig 1.
GVHD transplant recipients have decreased weight gain.
Posttransplant weights of the control and GVHD groups are shown. Data
points represent means ± SEM of 8 to 20 mice per group. This
experiment is representative of three similar experiments.
|
|
HSV-1 immune responses of GVHD mice.
Twelve weeks after bone marrow transplantation, mice were infected with
HSV-1 at a dose (5 × 107 pfu/mouse) chosen to ensure
that sufficient numbers of GVHD mice survived for the analysis of the
immune response. Two weeks after infection, HSV-1-specific T-cell
proliferative (Fig 2A) and cytotoxic responses (Fig 2B) were equivalent in GVHD and control mice. Cells from
GVHD mice produced decreased IFN- and increased IL-4 in response to
HSV-1 (Fig 2C and D), consistent with a Th2 shift.
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| Fig 2.
T cells from GVHD mice generate normal proliferative and
normal CTL response to HSV-1. GVHD mice display a Th2 cytokine response
to HSV-1. (A) Nylon wool-separated T cells from GVHD mice respond well
to HSV-1. 3H-Thymidine incorporation by recipient
splenocytes in response to inactivated virus or media alone was
measured. Groups consisted of two or three mice, and the mean and SEM
are shown. This experiment is representative of three similar
experiments. (B) HSV-1 CTL assays showed that GVHD and control mice
generated similar CTL responses after HSV-1 infection. Lysis of
mock-infected L929 targets was less than 20%. The data shown were from
one of three similar experiments. (C) Splenocytes were cultured in
vitro with ultraviolet irradiation-inactivated HSV-1 or with an extract
from uninfected Vero cells, and IFN- production was measured from
supernatants. The mean and standard error of three replicate wells are
shown; data are representative of three similar experiments with three
mice per group in each experiment. The quantity of IFN- produced by
the extract control was below the limit of detection of the assay.
Significant differences were detected between the extract and virus
data (P  .05, Student's t-test). (D) Splenocytes
were cultured in vitro with ultraviolet irradiation-inactivated HSV-1
or with an extract from uninfected Vero cells, and IL-4 production was
measured from supernatants. Data from a single experiment is shown.
Significant differences were detected between the extract and virus
data (P .05, t-test). Results from two additional
experiments measuring IL-5 were similar to the IL-4 experiment (data
not shown).
|
|
GVHD mice had impaired B-cell function, as measured by decreased
proliferative response to LPS when compared with control mice
(Fig 3A). Two weeks after
HSV-1 infection, Control mice generated a fivefold increase in total
serum IgG2a (Fig 3B), a particularly important immunoglobulin subclass
for immunity to viral infection.23,24 In contrast, GVHD
mice failed to generate any increase in total serum IgG2a in response
to HSV-1 (Fig 3B). In response to HSV-1 inoculation, control transplant
recipients generated substantial levels of specific anti-HSV-1 IgG2a.
However, the anti-HSV-1 IgG2a level of GVHD mice was only 25% of the
control (Fig 3C). Total serum IgG1 and specific anti-HSV-1 IgG1 levels
of GVHD mice were similar to control mice (data not shown). Because Th2
cytokines were critical for the production of IgG1,25 the
decreased IgG2a production of GVHD mice was consistent with the finding
that the cells from GVHD mice were polarized to a Th2 phenotype, as
described in chronic GVHD.26,27
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| Fig 3.
GVHD splenocytes proliferated poorly in
response to LPS, and GVHD mice failed to generate increased total serum
IgG2a and specific anti-HSV-1 IgG2a after viral inoculation. (A)
Spleen-cell proliferative response to LPS or medium alone was measured.
Representative B-cell numbers show that control and GVHD mice had
similar B-cell numbers. The experiment shown is representative of four
similar experiments. (B) Total serum immunoglobulin levels were
measured by radial immunodiffusion before and 2 weeks following HSV-1
infection. Preinfection and postinfection serum results are shown. Each
mouse group consists of three mice, and the mean and SEM are shown.
This experiment is representative of three similar experiments.
Significant differences (P < .05, t-test) are
detected between total serum IgG2a levels in control group and the GVHD
group after HSV-1 infection. (C) Serum levels of specific anti-HSV-1
IgG2a were determined by ELISA. The data shown are the mean and SEM of
five similar experiments that included 15 mice. The IgG2a level of the
GVHD group is significantly decreased compared with the IgG2a level of
control mice (P < .05, t-test).
|
|
Passive transfer of HSV-1 immune serum protected GVHD mice from HSV-1
mortality.
Because B cells and antibody protected against HSV-1-induced
mortality,18,28,28a we tested the hypothesis that antibody
production was critical for successful immune response to HSV-1
infection. GVHD mice were given intravenous injection of either
hyperimmune HSV-1 antiserum or saline on the day after inoculation with
2 × 108 pfu HSV-1. Hyperimmune HSV-1 antiserum
increased the survival of HSV-1 infected GVHD mice
(Fig 4).
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| Fig 4.
Passive transfer of HSV-1 immune serum protected GVHD
mice from HSV-1 mortality. GVHD mice were injected with hyperimmune
HSV-1 serum or saline on the day following HSV-1 inoculation (2 × 108 pfu). Survival was monitored daily. Survival of the two
groups was significantly different (Wilcoxon rank sum test, P
= .03).
|
|
CD40L therapy prolonged survival and increased total serum IgG2a.
To stimulate B-cell differentiation, 12-week-posttransplant recipients
were treated with CD40L (6 µg) three times per week for 2 weeks until
they were killed. Vehicle-treated mice received a similar treatment
with 10% glycerol. HSV-1 inoculation followed the first CD40L
injection (schema shown on x-axis of Fig
5C).
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| Fig 5.
CD40L treatment stimulated IgG2a production and improved
survival of GVHD mice following HSV-1 infection but did not affect
survival of B-cell-deficient mice. CD40L was given intraperitoneally
(6 µg/mouse, three times a week) to control and GVHD mice.
Vehicle-treated control and GVHD mice received glycerol diluted with
saline. (A) Mice were inoculated with HSV-1 2 weeks before sacrifice.
Serum was obtained by orbital bleed on day 14 immediately before
killing. Total serum IgG2a was measured by radial immunodiffusion:
( ) pre-HSV-1 infection, ( ) post-HSV-1 glycerol-treated, ( )
post-HSV-1 CD40L-treated. Significant differences (P < .05, t-test) were found between the glycerol and CD40L-treated GVHD
groups. (B) Serum levels of HSV-1-specific and IgG2a were determined
by ELISA 2 weeks post-HSV-1 infection: () post-HSV-1
glycerol-treated, () post-HSV-1 CD40L-treated. The increase in
HSV-1-specific IgG2a in GVHD mice does not reach statistical
significance. The data shown are the mean and SEM of six similar
experiments that included 50 mice. (C) Mice were monitored daily for
survival after infection with HSV-1. The GVHD-CD40L and GVHD-glycerol
group are significantly different (P < .05, log-rank test).
Each group included 15 mice. (D) Two groups of Igh-6
(B-cell-deficient) mice were inoculated with HSV-1 (1 × 108 pfu, 4.5LD50) and treated with: () CD40L
or () glycerol. Both groups of mice have similar survival. The CD40L
and glycerol groups each included three mice.
|
|
Total serum immunoglobulin and specific anti-HSV-1 antibody of GVHD
mice were measured before and after treatment with CD40L or glycerol.
Total serum IgG2a increased 1.5-fold in GVHD mice receiving CD40L
compared with GVHD mice receiving glycerol (Fig 5A). CD40L treatment
also produced a detectable but not statistically significant increase
in specific anti-HSV-1 IgG2a antibody (Fig 5B). CD40L-treated GVHD
mice had improved survival compared with glycerol-treated GVHD mice
(Fig 5C). These data suggest that CD40L therapy, which generates
increased antibody production, protected HSV-1-infected GVHD mice from
death.
To determine if CD40L effects on B cells were of primary importance, we
tested if CD40L treatment could protect Igh-6 (B-cell-deficient mice)16 from HSV-1 infectious death. Two groups of
B-cell-deficient mice were inoculated with CD40L or glycerol (6 µg
intraperitoneally 3×/wk). Both groups had similar mortality and
all mice were dead by 9 days (Fig 5D). These data suggested that
CD40L-mediated stimulation of B cells (rather than macrophages or CTL)
was critical for HSV-1 infectious resistance.
| |
DISCUSSION |
To establish an animal model of posttransplant infection related
morbidity and mortality, we inoculated murine allogeneic bone marrow
transplant recipients with HSV-1 after engraftment. Allogeneic
transplant recipients with GVHD had increased mortality from HSV-1 and
generated decreased total serum IgG2a and decreased specific
anti-HSV-1 antibody in response to HSV-1 infection. Passive transfer
of immunoglobulin protected GVHD mice and B-cell-deficient mice from
HSV-1 encephalitis, suggesting that B cells and immunoglobulin were of
primary importance in protection from HSV-1
encephalitis.28a
Because CD40L promoted B-cell maturation in a syngeneic bone marrow
transplant model,13 we tested the ability of CD40L to improve survival of allogeneic transplant recipients after HSV-1 infection. When given concurrently with HSV-1, CD40L therapy increased the level of total serum IgG2a and improved the survival of allogeneic mice with GVHD.
The concurrence of GVHD and viral infection exacerbated the pathology
of both diseases. Using the Parent into F1 (P 
F1) model of
graft-versus-host reaction (GVHR), Shanley and colleagues found that
mice with concurrent murine cytomegalovirus (MCMV) infection and GVHR
developed a severe interstitial pneumonitis that was not detected in
mice with either MCMV or GVHD alone.12 Cray and
Levy,29 using the P F1 model, detected increased anti-host CTL activity in MCMV-infected animals. Antihost CTL activity
was a measure of increased GVHD during infection. In both of these
studies viral infection and GVHR were induced simultaneously. Increased
host immunodeficiency was reported by Via30 in a P F1
mouse model in which GVHD was induced following MCMV infection. GVHD
and MCMV infection reduced subsequent development of T-cytotoxic responses to trinitrophenyl-modified syngeneic cells.
In the single study involving irradiated recipients, Shanley, Korngold,
and Forman31 examined cytomegalovirus (CMV) viral clearance
in an irradiated allogeneic transplant model (B10.BR CBA/J
recipient). In this study, mice were infected with MCMV immediately or
14 days after transplantation. In both cases, the combined presence of
GVHD and virus lead to increased viral titers in the lungs and salivary
glands.
Our results confirm and extend the notion that GVHD increases
susceptibility to mortality from viral infection. The novel aspect of
our study was the fact that we examined a viral infection initiated
after full engraftment had occurred. In addition, previous studies of
viral infection and murine bone marrow transplantation were performed
in a P F1 model of GVHD that did not involve irradiation.5,12,29,30 Because patients generally receive total body irradiation, resulting in the generation of cytokines that
may affect the immune response, an irradiated system of murine transplantation is a more appropriate model of human posttransplant infection. We showed that the recovery period after GVHD is associated with persistent immunodeficiency and increased morbidity and mortality due to viral infection.
In this murine GVHD model, mice develop weight loss due to GVHD in the
early posttransplant period. The animals then recover and, at 12 weeks,
appear well but underweight. This is an appropriate model of recipients
of unrelated bone marrow transplants. These patients frequently develop
mild GVHD in the immediate posttransplant period and then recover to an
apparently healthy state associated with subtle immunocompromise within
a few months after transplant.
Defects in B-cell function following bone marrow transplantation have
also been previously documented. Kagan, Chaplin, and Saxon7
reported that patients showed defective B-cell activation, proliferation, and differentiation during the first 10 months following
bone marrow transplantation. Storek32 observed that human bone marrow transplant survivors continue to have low IgG production at 1 year posttransplant, perhaps due to the lack of isotype-switched B cells. From studies of murine systemic
graft-versus-host reactions induced by injecting Parent lymphocytes
into F1 recipients, Xenocostas reported that systemic GVHD produces a
decrease in pre-B cells and early B-cell numbers in the bone
marrow.5 In the P F1 system, B-cell antibody responses
are suppressed by GVHD, even after B lymphocyte numbers have recovered
to normal numbers.33 GVHD due to mismatches in
histocompatibility antigens resulted in a delay in the appearance and a
reduction in the numbers of pre-B cells.9 We showed that
minor histocompatibility mismatch induced GVHD affected B-cell function
12 weeks after transplantation and that this decreased function
resulted in decreased immune response to HSV-1 infection.
CD40L treatment increased resistance to HSV-1 infection, probably as a
result of an increase in total serum IgG2a. Alternative mechanisms may
have contributed to CD40L-induced protection from HSV-1 mortality.
CD40L may have caused B7-2 upregulation, which increased both CTL
generation and/or macrophage IL-12 production. Either augmented
HSV-1 CTL activity or IL-12 action could have produced HSV-1
protection. Data showing that CD40L failed to protect B-cell-deficient
mice from HSV-1 infection (Fig 5D) make these explanations less likely.
Although anti-CD40L antibody treatment early after transplantation
limited the development of GVHD,34,35 we did not observe any increase in GVHD in CD40L-treated mice; this may be due to the
timing of our CD40L treatments. At 12 weeks after transplantation, the
initial critical expansion of mature donor T cells had already occurred. Therefore, late CD40L treatment may avoid stimulation of
mature donor T-cell expansion, while allowing the enhancement of newly
developed immune responses.
In our new model of posttransplant immunodeficiency, HSV-1 infection of
murine transplant recipients with GVHD resulted in decreased antibody
production and increased mortality. CD40L therapy increased total serum
IgG2a production and improved survival after HSV-1 infection,
suggesting that B-cell maturation stimuli may improve posttransplant
immunodeficiency.
| |
ACKNOWLEDGMENT |
The authors thank Dr Steven Burakoff for helpful conversations and Dr
Paul Martin for critical reading of the manuscript.
| |
FOOTNOTES |
Submitted November 11, 1997;
accepted August 4, 1998.
Supported by the Mallinckrodt Foundation, a Claudia Adams Barr
Investigator Award, and NIH PO1-CA39542 (I.J.R.) and a DFG grant
(H.A.).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Ilonna J. Rimm, MD, PhD, Genetics
Institute, 87 Cambridge Park Dr, Cambridge MA 02140.
| |
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Abstract
Introduction