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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 1131-1136
Stable Mixed Hematopoietic Chimerism in Dog Leukocyte
Antigen-Identical Littermate Dogs Given Lymph Node Irradiation Before
and Pharmacologic Immunosuppression After Marrow Transplantation
By
Rainer Storb,
Cong Yu,
Todd Barnett,
John L. Wagner,
H. Joachim Deeg,
Richard A. Nash,
Hans-Peter Kiem,
Peter McSweeney,
Kristy Seidel,
George Georges, and
J. Maciej Zaucha
From the Clinical Research Division and Public Health Sciences
Division, Fred Hutchinson Cancer Research Center; Department of
Medicine, University of Washington; and Swedish Medical Center Tumor
Institute, Seattle, WA.
 |
ABSTRACT |
Stable mixed donor/host hematopoietic chimerism can be accomplished
in dog leukocyte antigen (DLA)-identical littermate dogs given
sublethal (200 cGy) total-body irradiation (TBI) before and
immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP) after transplant (Blood 89:3048, 1997). Studies were
based on the hypothesis that drugs that prevent graft-versus-host
disease (GVHD) after transplant also suppress host-versus-graft (HVG) reactions and thereby enhance engraftment. Here, we asked whether pretransplant TBI provided marrow space for the graft to home or caused
host immunosuppression. To address the questions, recipients were given
pretransplant irradiation to cervical, thoracic, and abdominal lymph
nodes (except pelvis), DLA-identical littermate marrow grafts, and
MMF/CSP posttransplant. Six dogs that received 450 cGy irradiation
showed initial engraftment. Two rejected their grafts after 8 and 18 weeks, 1 died with GVHD and engraftment, and 3 are alive as mixed
chimeras after 57 to 97 weeks. Four dogs given 200 cGy irradiation also
showed initial engraftment, but rejected their grafts after 10 to 18 weeks. Mixed chimerism was present in nonirradiated marrow and lymph
node spaces and involved granulocytes, T cells, and monocytes. While
other explanations are possible, results seem consistent with the
hypothesis that pretransplant radiation provides host
immunosuppression, and grafts can create their own marrow space. These
data set the stage for the development of novel transplant regimens
that substitute immunosuppressive for cytotoxic agents.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
CONVENTIONAL ALLOGENEIC hematopoietic
stem-cell transplants involve conditioning of recipients by intense and
toxic chemoradiation, which has the triple purpose of eradicating the underlying disease, creating marrow space for the graft to home, and
destroying the host's immune system in a broad and nonspecific manner
for the graft to be accepted. To prevent graft-versus-host disease
(GVHD), grafts are either depleted of T cells or, more often,
recipients are given postgrafting immunosuppression. We have recently
proposed a new concept for conducting allotransplants, which is founded
on the knowledge that both host-versus-graft (HVG) and GVH reactions
are T-cell-mediated in the major histocompatibility complex
(MHC)-identical setting. Consequently, we sought to optimize postgrafting immunosuppression not only to prevent GVHD, but also to
control HVG reactions. This enabled us to reduce markedly the dose of
pretransplant total-body irradiation (TBI) needed for uniformly
successful engraftment. Specifically, a short course of postgrafting
mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed the TBI dose
to be lowered from the supralethal range of 920 cGy to the sublethal
and nonmyeloablative level of 200 cGy.1 Dogs transplanted
in this manner became stable mixed donor/host hematopoietic chimeras.
The finding raised the questions whether low-dose (200 cGy) TBI in this
model primarily served to create marrow space for the graft to home or
whether its role was to provide host immunosuppression. To address
these questions, the present study substituted lymph node irradiation
for TBI before transplant and sought to determine whether stable mixed
chimerism could be established in unirradiated marrow and lymph node spaces.
| |
MATERIALS AND METHODS |
Litters of harriers, beagles, Walker hounds, pit bull/beagle
crossbreeds, and other mixed breeds were either raised at the Fred
Hutchinson Cancer Research Center (Seattle, WA) or purchased from
commercial kennels in the state of Washington. The dogs weighed from
7.0 to 13.3 (median, 9.6) kg and were 7 to 27 (median, 8) months old.
They were observed for disease for at least 60 days before study. All
were immunized for leptospirosis, papillomavirus, distemper, hepatitis,
and parvovirus. Research was conducted according to the principles
outlined in the Guide for Laboratory Animal Facilities and Care
prepared by the National Academy of Sciences, National Research
Council. The research protocols were approved by the Institutional
Animal Care and Use Committee of the Fred Hutchinson Cancer Research
Center. The kennels are certified by the American Association for
Accreditation of Laboratory Animal Care.
DLA-matched littermate donor/recipient pairs were chosen on the basis
of identity by highly polymorphic MHC class I and class II
microsatellite markers.2 In addition, specific DLA DRB1 allelic identity was determined by direct sequencing.3
For lymph node irradiation, a high-energy linear accelerator (Varian
CLINAC 6, Palo Alto, CA) was used. The irradiation was delivered with a 6 million electron volt beam using equally weighted anterior and posterior ports to treat the central portion of the dogs.
The field extended from the upper pelvis to the base of the skull. The
pelvis itself, the lower extremities, the head, and the upper
extremities, as well as most of the ribs, were blocked by lead shields.
The limitation of the technique was that marrow in the vertebrae and
sternum was irradiated, while, in turn, pelvic, splenic, splanchnic,
medullary, and peripheral lymphoid tissues remained unirradiated.
Irradiation doses studied were 450 and 200 cGy, respectively, and were
delivered at 200 cGy/min in a single setting. Two dogs were given 450 cGy lymph node irradiation and no marrow grafts to assess the effect of
irradiation on peripheral blood cell counts.
Marrow for transplantation was aspirated from the donors under general
anesthesia through long needles inserted into humeri and
femora.4 After appropriate screening, marrow was infused intravenously (IV) within 4 hours of lymphoid irradiation at doses of
2.1 to 4.8 (median, 4.0) × 108 nucleated cells/kg.
The day of marrow infusion was designated as day 0. All dogs were given
standard postgrafting care.5 This included twice-daily oral
nonabsorbable antibiotics, polymyxin sulfate and neomycin sulfate,
which were begun on day -1 and given until day 14 after transplant,
and prophylactic systemic ceftazadime, injected twice daily from day 0 until day 14. None of the transplanted dogs required RBC or platelet
transfusion support. The dogs' clinical status was assessed twice
daily. WBC counts, platelet counts, hematocrits, and differentials were
performed daily through day 21 and twice weekly thereafter.
All marrow recipients were given MMF 10 mg/kg twice daily
subcutaneously (SC), on days 0 to 27, and CSP 10 mg/kg twice daily orally on days  1 to 35 after transplant, 7.5 mg/kg twice daily on days 36 to 50, 5 mg/kg twice daily on days 51 to 75, and 3 mg/kg
twice daily on days 76 to 100.1 Hematopoietic engraftment was assessed by sustained recoveries of granulocyte and platelet counts
after the postirradiation nadir and by documentation of donor
(CA)n repeat polymorphisms in cells from peripheral blood, popliteal lymph nodes, and marrow. Graft rejection was defined as
complete disappearance of cells with donor (CA)n repeat
polymorphisms. The (CA)n dinucleotide repeats were assessed
using a polymerase chain reaction (PCR)-based assay.6 The
assay has the sensitivity to reliably detect donor or host cells down
to a level of 2.5% of the total cell population. Mixed hematopoietic
chimerism was quantified by estimating the proportion of donor-specific
DNA among host DNA using the storage phosphorimaging technique and defined as between 2.5% and 97.5% donor cells after
transplant.7 The marrow aspiration (humeral head) and lymph
node (popliteal area) biopsy sites used after transplant were outside
of the irradiation field. Marrow aspirates and lymph node biopsies were
performed under general anesthesia.
Cell separations were performed using monoclonal antibodies and a
fluorescence-activated cell sorter (Vantage FACSSORT; Becton Dickinson,
San Jose, CA). Granulocytes were first separated from mononuclear cells
by a Ficoll cut (specific gravity, 1.074) and then further purified
using the monoclonal antibody DM5, which recognizes a canine myeloid
antigen.8 CD4 and CD8+ T cells were purified
using monoclonal antibodies CA9.JD3 (anti-CD4) and CA13.1E4
(anti-CD8).9
When studies were completed, dogs were euthanized and underwent
complete autopsies, which included histopathologic examinations.
| |
RESULTS |
Lymph node irradiation controls.
Two dogs were given 450 cGy lymph node irradiation, but neither marrow
grafts nor MMF/CSP. Figure 1 shows their
granulocyte, lymphocyte, and platelet changes over a period of 35 days
following irradiation. Both dogs showed declines in platelet counts to
less than 100,000/µL beginning on days 10 and 11. Thereafter,
platelet counts slowly returned to the normal range. Similarly,
moderate declines in granulocyte counts were noted with nadirs of 2,500 and 3,200 cells/µL, respectively, seen on day 8. Thereafter, counts slowly returned to the normal range. Lymphocyte counts declined dramatically, and nadirs were reached between days 8 and 10 with subsequent slow recovery. Hematocrits remained within the normal range
(not shown).
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| Fig 1.
Median peripheral blood platelet, granulocyte, and
lymphocyte changes in dogs given 450 cGy total-lymphoid irradiation
(TLI) and no marrow grafts (n = 2), 450 cGy TLI, marrow grafts, and
postgrafting MMF/CSP (n = 6), or 200 cGy TBI, marrow grafts, and
postgrafting MMF/CSP (n = 12).
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DLA-identical marrow grafts.
Table 1 summarizes the results of
allogeneic marrow transplants. All 6 recipients given 450 cGy lymph
node irradiation showed initial evidence of allogeneic engraftment,
which was manifested as mixed donor/host chimerism. Two of the 6 lost
their grafts at 8 and 18 weeks after transplantation, respectively, and
survived with complete autologous recovery. One of the 4 remaining dogs died with acute GVHD at slightly more than 6 weeks after transplant. This dog's hematopoietic system was almost entirely replaced by donor
cells. Three dogs have remained stable mixed chimeras between 57 and 97 weeks after transplant.
Figure 2 illustrates peripheral blood
changes and microsatellite marker studies in dog E400 with sustained
graft. As was seen in control dogs, the degree of myelosuppression from
the lymph node irradiation in the transplanted dog was mild. The
recipient's granulocyte count reached a nadir of 3,400 cells/µL by
day 9 after transplant, and the platelet count a nadir of 101,000 cells/µL by day 14. Counts returned rapidly to pretransplant levels.
In contrast, lymphocyte counts declined to a nadir of 200 cells/µL on
day 9; pretransplant levels have as yet not been reached by day 270. The microsatellite marker studies illustrate mixed chimerism not only
among nucleated peripheral blood cells, but also among popliteal lymph
node and marrow cells obtained from sites outside of the irradiation
field. Mixed chimerism was present already in the first marrow sample,
which was taken at 4 weeks after transplant. As part of a separate
study,10 dog E400 was given an IV infusion of 6.1 × 107 alloreactive CD3+ T cells/kg from the
marrow donor 72 weeks after the original transplant (Fig 2). Within 6 weeks of infusion, microsatellite markers of host origin disappeared
from DNA of nucleated peripheral blood, marrow, and lymph node cells.
Only cells of donor origin have been found during the subsequent period
of observation, which now extends to 25 weeks. This conversion from
mixed to all donor chimerism occurred in the absence of clinically
evident GVHD.
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| Fig 2.
(A) Peripheral blood granulocyte, platelet, and
lymphocyte changes in dog E400 conditioned with 450 cGy TLI and given a
marrow graft from a DLA-identical littermate on day 0, followed by
postgrafting MMF/CSP for 4 and 14.3 weeks, respectively. (B) Results of
testing for microsatellite markers of donor and recipient cells before
transplantation (lanes 1 and 2) and recipient cells after marrow
transplantation (lanes 3 to 13). G, granulocytes; BM, bone marrow; MNC,
mononuclear cells; LN, lymph node; DLI, donor lymphocyte infusion.
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The microsatellite marker studies on 3 of the remaining dogs
conditioned by 450 cGy lymph node irradiation are shown in Fig 3. Initial allogeneic engraftment and
subsequent rejection were seen in dog E535. Dogs E527 and E399 remained
stable mixed chimeras. The initial donor contribution in E399 was
estimated to be 5% to 10%. Within 6 weeks of infusion of donor
lymphocytes at week 57 after transplant,10 the donor
contribution increased to  90%.
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| Fig 3.
Microsatellite marker studies of donor and recipient
cells before transplantation and recipient cells after marrow
transplantation in 3 dogs given 450 cGy TLI, marrow grafts from
DLA-identical littermates on day 0, and postgrafting MMF/CSP for 4 and
14.3 weeks, respectively. CD4, CD4+ T cells; CD8,
CD8+ T cells.
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Table 2 shows a more detailed study of
microsatellite marker results in 1 of the transplanted dogs (E527)
using flow cytometry and phosphorimage analysis. The analysis,
performed 38 weeks after transplant, showed that mixed chimerism
included all cell lineages studied. Peripheral blood granulocytes
showed a donor contribution of 45%, mononuclear cells 35%,
CD4+ cells 65%, and CD8+ cells 55%.
Furthermore, 25% of lymph node cells and 45% of marrow cells were
composed of donor cells.
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Table 2.
Microsatellite Marker Results in Dog E527 38 Weeks
After 450 cGy Lymphoid Irradiation and Marrow Transplant
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|
Figure 1 shows the median peripheral blood cell counts from all 6 dogs
studied. Except for lower lymphocyte counts, blood cell changes were
comparable to those in lymph node radiation controls. The lower
lymphocyte values were likely due to MMF. The median platelet nadir was
at 70,000 cells/µL and the granulocyte nadir at 3,000 cells/µL.
Only the dog with GVHD (E481) experienced a platelet nadir less than
10,000 cells/µL, presumably the result of the elimination of host
hematopoiesis by GVHD. By comparison, historical control dogs given 200 cGy TBI1,11 experienced more profound declines and more
delayed recoveries of granulocyte and platelet counts, while their
lymphocyte counts were comparable to those in lymph node radiation
controls (Fig 1).
At a dose of 200 cGy lymph node irradiation, all 4 dogs so treated
showed initial allogeneic engraftment. The 4 rejected their allografts
after 10 to 18 weeks as judged by the disappearance of donor
microsatellite marker bands in DNA of cells from marrow and peripheral
blood. The maximum contributions of donor cells in the 4 dogs ranged
from 5% to 10%. Their peripheral blood counts experienced only
moderate changes after transplant, with a median platelet nadir of
108,000/µL (day 13), granulocyte nadir of 4,100/µL (day 12), and
lymphocyte nadir of 900/µL (day 3). Counts recovered promptly.
| |
DISCUSSION |
Previous studies showed that stable mixed donor/host hematopoietic
chimerism was reliably established in a canine model of DLA-identical
marrow transplantation when recipients were conditioned by sublethal
and nonmyeloablative TBI (200 cGy) and given a short course of MMF/CSP
after transplant to control residual HVG and also GVH
reactions.1,11 This raised the questions whether TBI was
required to provide host immunosuppression or create marrow space for
the allograft to home. Within the limitations of the experimental
design, current findings of long-term mixed chimerism in dogs
conditioned with 450 cGy lymph node irradiation are consistent with the
concept that an important role of pretransplant irradiation was to
effect host immunosuppression and that marrow space could be created by
the grafts themselves, most likely through subclinical GVH reactions.
Direct evidence for the GVH effect came from the stable presence of
donor cells in marrow and lymph node spaces that were located outside
of the irradiation field. Results support the hypothesis that
allografts can be achieved by substituting effective host
immunosuppression for cytotoxic pretransplant therapy including TBI.
Effective pretransplant immunosuppression combined with posttransplant
immunosuppression (MMF/CSP), which is aimed at controlling both host
and donor immune cell activities would result in mutual graft/host
tolerance that would be manifested as stable mixed donor/host chimerism.
The external-beam lymph node irradiation used here lacked specificity
and excluded a substantial proportion of the dogs' lymphoid tissues,
eg, those in marrow, bowel, spleen, pelvis, and peripheral lymph nodes.
This probably explains why 2 of the dogs given 450 cGy radiation and
all dogs given 200 cGy ultimately rejected their allografts.
A number of preclinical studies in inbred strains of mice have also
explored the development of less intensive conditioning programs for
establishing allogeneic hematopoietic engraftment.12-22 Most studies have included host T-cell depletion by in vivo
administration of antibodies that were combined with TBI at high but,
at least in mice, sublethal doses and dose rates. TBI was often
delivered along with pretransplant thymic irradiation and postgrafting
CSP or even high-dose posttransplant cyclophosphamide. Most studies that have involved allogeneic transplants did not address the questions
of marrow space versus immunosuppression since all included TBI.
However, in earlier studies, Slavin et al23,24 reported on
allogeneic marrow engraftment in mice using 1,600 cGy total lymphoid
irradiation. In another study, Leong et al25 used
dimethylbusulfan "as a selective `space'-creating myelosuppressive
agent and CD4 plus CD8 monoclonal antibodies as sole immunosuppressive
agents" to condition inbred mice for hematopoietic grafts. They
concluded that both creation of marrow space and host immunosuppression were needed for successful grafts. Their argument was based on the
assumption that dimethylbusulfan was strictly myelosuppressive. However, their conclusions may have to be tempered somewhat by the
earlier demonstration in a random-bred canine allograft model that
high-dose dimethylbusulfan was not only myelosuppressive, but also
immunosuppressive.26 Specifically, half of the dogs treated
with a single dose of 10 mg dimethylmyleran/kg experienced sufficient
immunosuppression for stable allogeneic hematopoietic engraftment, and
the engraftment rate could be further increased to 90% with additional
small doses of antithymocyte serum. The dimethylmyleran
doses used in the most successful murine studies ranged from 8 to 20 mg/kg.25
There is recent evidence from studies in syngeneic or congenic mice
that infusion of very large numbers of marrow cells (8 × 109 cells/kg) without conditioning of recipients can lead
to engraftment of transplanted cells.27 In contrast with
the observations in mice by Stewart et al and the current findings in
dogs conditioned by lymphoid radiation, were reports on successfully
transplanted, nonconditioned humans and dogs with severe combined
immunodeficiency disease (SCID) in which either direct chromosome
analysis of marrow cells or PCR-based testing for the genotype of the
 -chain gene in blood monocytes showed exclusively recipient
cells,28,29 while T cells were either all or partially of
donor type. An exception was a patient who developed myelosuppression
and aplasia in the course of GVHD and then changed to all donor type
hematopoiesis after a second transplant.30,31 The current
canine results of mixed marrow chimerism and the subsequent conversion
to all donor chimerism by lymphocyte infusion10 can also be
explained by creation of marrow space through (subclinical) GVHD.
Based on the canine data with lymphoid irradiation, we have treated 2 patients with congenital T-cell deficiencies other than SCID by marrow
grafts without conditioning but with MMF/CSP for 4 and 5 weeks,
respectively, after transplant.32 This was done under the
assumption that the inherited T-cell deficiencies were functionally
equivalent to those induced in current dogs by lymphoid irradiation.
Both patients have stably engrafted. The first patient, a 30-year-old
man, is now more than 6 months after transplant. In addition to donor
T- and B-cell engraftment, 95% of his granulocytes and 50% of his
marrow cells are of donor origin. These results give indirect support
to the notion that allografts that involve all cell lineages may be
achievable solely with the help of immunosuppression, an approach that
would avoid the toxicities associated with current high-dose transplant
regimens and, thereby, be safe enough to be performed in the ambulatory
care setting.
| |
ACKNOWLEDGMENT |
We are grateful to Dr George Sale from the Fred Hutchinson Cancer
Research Center Pathology group for review of histopathology and to
Lori Ausburn, Eric Bell, Alix Smith, and the technicians of the Canine
Shared Resource and of the hematology and pathology laboratories for
their technical assistance. Dr Barbara Johnston provided veterinary
supervision. Bonnie Larson and Harriet Childs provided manuscript
preparation and illustration. We would like to thank Dr Tom Matthew at
Roche Bioscience (Palo Alto, CA) for providing MMF.
| |
FOOTNOTES |
Submitted October 23, 1998; accepted April 9, 1999.
Supported in part by Grants No. CA15704, HL36444, HL03701, and DK42716
from the National Institutes of Health (NIH), Department of Health and
Human Services, Bethesda, MD; by a grant from the Gabriella Rich
Leukemia Foundation (P.M.); by NIH Grants No. DK09718 (G.G.) and
RR12558 (J.L.W.); and by a prize from the Josef Steiner Krebsstiftung,
Bern, Switzerland, and the Laura Landro Salomon Endowment Fund (R.S.).
H.P.K. is a Markey Molecular Medicine Investigator.
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 correspondence to Rainer Storb, MD, Fred Hutchinson Cancer
Research Center, 1100 Fairview Ave N, D1-100, PO Box 19024, Seattle, WA
98109-1024.
| |
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