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The Carlos and Marguerite Mason Transplantation Biology Research Center, Departments of Surgery, Emory University School of Medicine, Atlanta, GA 30322
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In recent years, several clinically relevant immunomodulatory or tolerance induction regimens have been reported that incorporate the use of Abs and/or fusion proteins that target the CD28/B7 and CD40/CD154 pathways with or without the concomitant administration of donor cells (splenocytes or bone marrow cells (BMCs)3) (5, 6, 7, 8, 9). Although the immunological mechanisms underlying the effectiveness of these regimens are incompletely understood, recent advances have suggested that the development of tolerance involves the participation of CD4+ regulatory T cells that are activated or exert their function in a CTLA-4-dependent manner. Furthermore, evidence suggests that the continued presence of a vascularized allograft can itself play a critical role in tolerance maintenance (10). Although several of these studies have indicated costimulation blockade (CB)-based regimens can inhibit chronic rejection, the duration of follow-up and the tests of the stability of tolerance in these studies provide insufficient data upon which to draw firm conclusions about long-term outcomes (5, 6, 7).
The induction of mixed hemopoietic chimerism has been a promising strategy for the induction of robust immunological tolerance for many years (11, 12). Although in the past most chimerism induction regimens required the use of gamma irradiation and/or depletion of the peripheral immune system (13, 14, 15, 16, 17), more recently, protocols using either the administration of mega doses of donor bone marrow or the use of minimally myelosuppressive recipient conditioning combined with various forms of CB have increased the likelihood that clinically acceptable tolerance induction regimens based on these principles can be devised (18, 19). The strategy that we have used incorporates the CTLA4-Ig fusion protein to target the CD80/CD86-CD28 pathway and MR1, an anti-CD154 mAb to target the CD40-CD40 ligand (CD40L) interactions, and the administration of donor BMCs after conditioning the recipient with a minimally myelosuppressive dose of the chemotherapeutic conditioning agent, busulfan (Bu). This regimen induces high level, stable mixed hemopoietic chimerism and specific deletional tolerance to fully MHC-mismatched allogeneic skin grafts (20).
Due to the limitations of the skin allograft model, our earlier studies were unable to address the important issue of degree of protection conferred from acute cellular infiltration and chronic rejection. Because of the increasing evidence that tolerance may not equate to freedom from chronic rejection, we used the murine cardiac allograft model to compare the ability of this and other promising tolerance induction regimens to protect vascularized allografts from immunologic injury during tolerance induction and to prevent chronic rejection. The need for such studies is underscored by the report by Russell et al. (4) that was published during the preparation of this work that demonstrated that even the induction of robust tolerance using chimerism induction strategies may not always be sufficient to prevent chronic rejection.
In this study, we compare the effects of several clinically relevant CB-based tolerance induction regimens to promote cardiac allograft survival, to induce donor-specific tolerance, and to prevent acute and chronic allograft rejection. We find that treatment regimens consisting of CB alone (CTLA4-Ig and anti-CD40L), CB and donor BMCs, and CB and donor splenocytes (DST) promote long-term allograft survival, but do not confer robust tolerance nor prevent chronic rejection in the face of a rechallenge with a donor skin graft. In contrast, a regimen consisting of CTLA4-Ig, anti-CD40L, donor BMCs, and a minimally myelosuppressive dose of Bu produced stable donor-specific tolerance, and prevented both early and late cellular infiltration and chronic allograft vasculopathy, despite the rigorous rechallenge of a donor skin graft.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Adult male 6- to 8-wk-old C57BL/6 (B6) (H-2b), BALB/c (H-2d), and C3H/HeJ (H-2k) mice were obtained from The Jackson Laboratory (Bar Harbor, ME). All mice were housed in specific pathogen-free conditions and in accordance with institutional guidelines.
Bone marrow preparation and treatment regimens
Bone marrow was flushed from tibiae, femurs, and humeri. Red cell lysis was performed using a Trizma base ammonium chloride solution. The donor BMCs were resuspended at 2 x 107 cells/250 µl sterile saline and injected i.v. on the day of cardiac transplantation (day 0). Hamster anti-mouse CD40L (MR1; Bioexpress, Lebanon, NH) and CTLA4-Ig (Bristol-Myers Squibb, Princeton, NJ) were administered on days 0, 2, 4, 6, 14, 28, 60, and 90 (500 µg/dose i.p., respectively). The recipients received Bu (20 mg/kg, i.p.) on day 5 and second dose of donor BMCs (i.v.) on day 6 (20). Mice in other groups received CB consisting of anti-mouse CD40L and CTLA4-Ig alone, CB with two doses of donor BMCs (without Bu), or CB with two doses of DST (2 x 107 cells on days 0 and 6).
Heart grafting
Fully vascularized heterotopic hearts from BALB/c donors were transplanted into the abdomen of B6 recipients using microsurgical technique on day 0, as previously described (21). Graft survival was followed by palpation at least three times per week. Rejection was defined by complete cessation of palpable contraction confirmed by direct visualization. Histological examination was also performed to confirm the condition of the grafts.
Skin grafting
Full thickness skin grafts (
1 cm2) were
transplanted on the dorsal thorax of recipient mice and secured with a
Band-Aid for 7 days. Rejection was defined as the complete loss of
viable epidermal graft tissue.
Flow cytometric analysis
We performed multicolor flow cyotmetry. Donor and recipient
cells were distinguished by staining with
anti-H-2Kd and
anti-H-2Kb, respectively. To analyze the
degree and distribution of hemopoietic chimerism in multiple
compartments and in multiple organs in the recipient, lineage-specific
markers such as anti-B220 (for B cells), anti-CD4, anti-Gr1
(for granulocytes), anti-CD11b (for monocytes/macrophages),
and CD11c (for dendritic cells) (22, 23) were used.
Peripheral blood was analyzed by staining with fluorochrome-conjugated
Abs (anti-CD11b, anti-GR1, anti-B220, anti-CD8,
anti-H-2Kd,
anti-H-2Kb, anti-V
11,
anti-V5.1/5.2, anti-V8.1/8.2 (BD PharMingen, San Diego,
CA), anti-CD4 (Caltag Laboratories, Burlingame, CA), or Ig isotype
controls (BD PharMingen)), followed by RBC lysis and washing with a
whole blood lysis kit (R&D Systems, Minneapolis, MN). Single cell
suspensions of spleen, abdominal lymph nodes, thymus, or bone marrow
were also analyzed by staining with fluorochrome-conjugated Abs
(anti-B220, anti-CD4, anti-CD8,
anti-H-2Kd,
anti-H-2Kb, anti-V11,
anti-V5.1/5.2, anti-V8.1/8.2, or Ig isotype controls)
after RBC lysis with a Trizma base ammonium chloride solution.
Dendritic cell-enriched populations were prepared as transiently adherent cells from spleen, lymph nodes, thymus, or bone marrow, as previously described (24), and stained with fluorochrome-conjugated Abs (anti-CD11c, anti-H-2Kd, anti-I-Ad (BD PharMingen), or Ig isotype controls). Stained cells were analyzed using CellQuest software on a FACSCalibur flow cytometer (BD Biosciences, Mountain View, CA).
Graft histology
Fresh tissues were fixed in 4% paraformaldehyde until processed and embedded in paraffin (Fisher Scientific, Pittsburgh, PA). Five-micron-thick tissue sections were cut on a microtome and stained with H&E or Masson’s trichrome, according to standard procedures. To evaluate the degree of chronic rejection, the number of vessels, including coronary arteries and i.m. arterioles affected with obliterative vasculopathy, and the total number of vessels in each section of the histological specimen were counted. Histological specimens were reviewed by a single histologist (H. Xu) blinded to the treatment modality.
Statistical analysis
Graft survival between groups was analyzed by Mann-Whitney U test using Stat View 5.0 software (Abacus Concepts, Berkeley, CA). Statistical significance of other data was analyzed by unpaired Student’s t test using Stat View 5.0.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Effects on cardiac allograft survival: all CB-based regimens greatly prolong survival of mouse primary cardiac allografts
As seen in Fig. 1
, untreated B6
recipients or recipients treated with isotype control Abs rejected
BALB/c heart grafts rapidly (median survival time (MST) = 8 days,
n = 10 and 5, respectively). BALB/c hearts were also
acutely rejected by B6 recipients receiving only donor BMCs (MST =
9 days, n = 6), by those receiving donor BMCs and Bu
(MST = 10 days, n = 5), and by those treated with
Bu only (MST = 10 days, n = 4) (data not shown).
In contrast, groups treated with CB (i.e., recipients with CB alone
(n = 6); with CB and BMCs (no Bu) (n =
5); with CB and DST (n = 4); or with CB, BMCs, and Bu
(n = 5)) showed long-term survival of BALB/c heart
grafts (MST >180 days in all these groups) (Fig. 1). There was no
statistically significant difference in BALB/c heart survival among
these groups.
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Next, to determine whether recipients were rendered tolerant,
recipients in the various treatment groups with long-term surviving
BALB/c heart grafts were rechallenged with secondary skin grafts from
BALB/c (donor-specific) and C3H (third party) donors 200 days after
primary heart transplantation. Recipients that had received CB, BMCs,
and Bu uniformly accepted second BALB/c skin grafts (MST >100 days).
In contrast, recipients treated with CB and BMCs, CB and DST, or CB
alone showed evidence of donor-specific hyporesponsiveness, but
eventually rejected second BALB/c skin grafts (MST = 53, 33, and
30 days; n = 4, 4, and 5, respectively) (Fig. 2). Recipients from all groups promptly
rejected C3H (third party) skin grafts (MSTs = 14 days) (data not
shown).
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The most commonly used endpoint for the assessment of murine
heterotopic cardiac allograft survival is the cessation of a palpable
heartbeat. To gain better insight into the degree to which the various
regimens protected the allografts from immunologic injury (acute and
chronic rejection), we performed detailed histological examinations of
these BALB/c heart grafts using H&E and Masson’s trichrome staining at
14, 28, 60, 90, and 300 (i.e., 100 days after secondary skin grafts)
days after heart transplantation or at the time of allograft
failure. Allografts harvested at time points up to 90 days
posttransplant (while treatment with CB is ongoing) were free of
myocardial injury in all groups receiving CB (CB alone (Fig. 3D); CB and BMCs (Fig. 3E); CB and DST (Fig. 3F); or CB, BMCs, and Bu
(Fig. 3C)). However, allografts treated with CB alone or CB
and DST had rare sparse interstitial infiltrates, whereas allografts
treated with CB, BMCs, and Bu were indistinguishable from syngeneic
grafts (Fig. 3B). Grafts harvested on day 14, 28, or 60 in
these recipients (either treated with CB alone; CB and BMCs; CB and
DST; or CB, BMCs, and Bu) had similar histology to those harvested on
day 90 (data not shown). These data suggest that prolonged treatment
with anti-CD40L and CTLA4-Ig can protect vascularized murine
cardiac allografts during the induction phase of these regimens.
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D), with CB and BMCs (Fig. 4E), or with CB and DST (Fig. 4F) showed typical
changes characteristic of severe chronic rejection, including severe
interstitial fibrosis, diffuse infiltration of mononuclear cells, and
obliterative vasculopathy with diffuse intimal thickening in coronary
arteries in the grafts. The number of coronary arteries and i.m.
arterioles affected with obliterative vasculopathy in these three
groups ranged from 64 to 87% of vessels observed (Table I). This occurred despite the continued
survival of the grafts as assessed by palpation. Examples of normal
cardiac histology (Fig. 4A) and BALB/c cardiac allograft
undergoing acute rejection in an untreated B6 recipient 10 days after
transplantation (Fig. 4B) are shown for comparison.
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C). In the recipients of CB,
BMCs, and Bu, cardiac allografts were morphological normal and remained
free of interstitial or vascular pathology, similar to that of naive
BALB/c heart (Fig. 4A). No vessels with obliterative
vasculopathy were observed in specimens (10 coronary cross
sections/specimen) from recipients treated with CB, BMCs, and Bu
(TableI). Very similar results were observed in all groups when
recipients were treated with CB on days 0, 2, 4, 6, 14, and 28. We have
not tested shorter treatment regimens. Effects on recipient immune system: analysis of the distribution and kinetics of hemopoietic chimerism
Next, we compared the degree and distribution of hemopoietic
chimerism in the recipients of each regimen. As expected, only
treatment with CB, BMCs, and a nonmyeloablative dose of Bu could induce
multilineage hemopoietic chimerism in peripheral blood of recipients
after day 14 (Fig. 5, A–C).
Similar levels of donor chimerism were observed among
B220+, CD4+ cells, and
CD11c+ dendritic cells in spleen (Fig. 5D), abdominal lymph node (Fig. 5E), bone marrow
(Fig. 5F), and thymus (Fig. 5G). Recipients with
no treatment, donor BMCs alone, donor BMCs and Bu, or CB alone
had no detectable hemopoietic chimerism in any organs (data not shown).
Recipients treated with CB and donor BMCs (no Bu), or with CB and two
doses of DST showed minimal donor chimerism on day 14 and virtually
undetectable levels of donor cells thereafter, suggesting that those
donor cells were not engrafted populations, but only passenger
leukocytes (Fig. 5, A and B).
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11 and
V5 T cells only occurred with hemopoietic chimerism
As a measure of the ability of these regimens to reshape the
recipients’ peripheral T cell repertoire, we tracked the fate of the
mouse mammary tumor virus superantigen-reactive T cells as a surrogate
marker for antidonor reactive T cells (16, 18, 20). Donor
BALB/c mice express mouse mammary tumor virus-8 and 9 in association
with MHC class II I-E molecules and delete V11- and V5-bearing
CD4+ T cells, whereas recipient B6 mice do not
express I-E and use V11 on 4–5% of CD4+ T
cells and V5.1/2 on 2–3% of CD4+ T cells
(25, 26). As anticipated, recipients treated with donor
BMCs alone, with donor BMCs and Bu, or with Bu alone failed to delete
donor-reactive V11+ or
V5+CD4+ T cells (data
not shown). Recipients treated with CB and BMCs (no Bu) showed a
transient decrease in the percentage of
CD4+V11+ and
CD4+V5+ T cells on day
28, but these populations recovered by day 60. This effect was not
observed in recipients treated with CB alone (not shown) or CB and DST
(Fig. 6, A and B).
In contrast, the recipients with CB, BMCs, and Bu developed profound
deletion of CD4+V11+ and
CD4+V5+ T cells in
peripheral blood (Fig. 6C), spleen (Fig. 6D), and
abdominal lymph nodes (Fig. 6E). The deletion process with
this regimen took place over a surprisingly long period of time.
Virtually no peripheral deletion of
CD4+V11+ T cells was
evident in blood, spleen, or lymph node at day 14. Only 50%
depletion was achieved by day 28, and near complete deletion occurred
between days 60 and 90. Similar, but slightly more rapid and complete
deletion (day 28) of
CD4+V5+ T cells was also
observed. Central deletion of CD4+
(CD8-) V11+ and
CD4+ (CD8-)
V5+ thymocytes was only observed in the
recipients treated with CB, BMCs, and Bu, but this deletion was not
apparent until day 60 (Fig. 6F). The percentage of
V8-bearing CD4+ T cells, which are expressed
on 15–20% of BALB/c and B6 CD4+ T cells, was
similar in all groups, indicating that the T cell deletion was donor
specific in nature (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Not surprisingly, we found no statistically significant difference in
primary cardiac graft survival (as assessed by graft palpation) or
cardiac allograft histology (before secondary rechallenge of
alloantigen) between the regimen inducing mixed chimerism and other
regimens including CB alone, CB and BMCs, or CB and DST (Figs. 1 and 3). For example, on day 90, grafts from all of the groups that received
CB continued to beat and showed only rare infiltrating cells equivalent
to that observed in syngeneic grafts in the control group. Consistent
with our earlier work, and that of others, these data suggest that the
combination of CTLA4-Ig and anti-CD40L can protect cardiac
allografts from acute rejection for relatively prolonged periods. These
data are also important in that they demonstrate that enhanced graft
survival that results from this regimen of prolonged CB does not
require the presence of a lymphocytic infiltrate of a significant
number of regulatory cells. Although this does not exclude a role for a
small number of regulatory cells in the graft or a role in the lymphoid
tissues, this knowledge is of practical significance for setting
expectations for protocol allograft biopsies that might be obtained in
the conduct of clinical trials (i.e., an infiltrate cannot be presumed
to be an obligatory feature of the enhanced survival of immunotherapies
directed at T cell costimulation).
In contrast to the effects on primary graft survival, only the chimerism induction regimen (CB, BMCs, and Bu) prevented cardiac allograft rejection after rechallenge with a secondary donor skin graft. It is reasonable to question the importance of the finding that the protocols differ in their ability to protect from rejection that is only evident after a rechallenge with a donor-specific skin graft, as this scenario would not occur in the clinical setting. However, studies conducted using mice housed in highly protected specific pathogen-free conditions also may not accurately reflect the stability of tolerance under normal external environmental circumstances. For example, it is known that T cells specific for pathogens overlap with the allospecific repertoire (28, 29). In the specific pathogen-free conditions used for most murine tolerance studies, activation of cross-reactive T cells might not occur often, if at all, whereas in a clinical setting it is possible, if not likely, that immune responses to environmental pathogens might involve alloreactive cells that could precipitate rejection of grafts maintained by the more tenuous mechanisms that sustain allograft survival in the nonchimerism-based regimens tested in this study. It is noteworthy that one recipient in both the groups receiving CB only and the CB and BMCs group rejected BALB/c grafts with histology typical of severe chronic rejection before placement of the secondary skin graft. Additionally, the sustained presence of the vascularized cardiac graft was not sufficient for the induction of robust tolerance that has been observed with other tolerance regimens (10). In contrast, in the chimeric mice receiving CB, BMCs, and Bu, the inability of donor rechallenge to precipitate rejection suggests that viral infections are unlikely to perturb tolerance established by this regimen. Indeed, although graft histology was not assessed in our skin graft studies, acute lymphocytic choriomeningitis virus infection failed to promote overt rejection of skin grafts after the establishment of hemopoietic chimerism (30).
The findings of this study are in apparent conflict with several reports that have suggested that CB or CB with donor cells can prevent chronic rejection (5, 6, 31, 32, 33). For example, we have previously reported that simultaneous blockade of CD28 and CD40 pathways inhibits the chronic transplant vasculopathy in BALB/c heart grafts in C3H recipients (5), and other groups have demonstrated that blockade of these pathways inhibits transplant vasculopathy in C57BL/10 aortic grafts in C3H recipients (31), rat kidney (32), and heart allograft (33). In addition to role of the secondary skin graft discussed above, there are several other possible reasons for this apparent discrepancy. The strain combination in the current study (B6 recipients and BALB/c donors) has been demonstrated to be vigorous in its ability to overcome the effect of CB, and thus provides a more challenging barrier for the induction of tolerance (34, 35). Second, in the current study, the histological examination of the heart grafts was performed at 300 days after transplant (100 days after rechallenge with a donor skin graft). This is a considerably longer follow-up than in the earlier reports. Third, there are several subtle differences in the treatment regimens between studies, such as the source and timing of blockade or donor cell administration relative to transplantation of the heart graft, that may have contributed to the different outcomes.
Recently, Russell et al. (4) have reported that successful
chimerism induction strategies may, in certain circumstances, induce
tolerance, but not prevent chronic rejection. In their studies, mixed
chimerism was induced in B6 recipients from B10.A donors using a
regimen consisting of total body irradiation, depletion of CD4 and CD8
cells and a single dose anti-mouse CD40L, followed by confirmation
of tolerance by a challenge of donor-specific skin graft. Afterward,
heart allografts were transplanted into the recipients with no further
immunotherapy. Chronic vascular rejection was observed in allografts
transplanted to these chimeric recipients. There are several
possibilities for different results between Russell’s and ours. First,
it is possible that immune responses to heart-specific polymorphic
Ag(s) might play a role in the rejection observed in their experiments.
In our experiments, the induction of mixed chimerism and
transplantation of the heart were performed simultaneously under the
cover of CB, while in Russell’s experiments mixed chimerism was
established at least 100 days before heart transplantation. Thus, it is
possible that transplantation of the heart under the cover of
CB might tolerize Ag-specific T cells to heart-specific polymorphic
Ag(s) not expressed by the bone marrow, whereas in the Russell
experiments delayed heart transplantation would expose the recipient to
these putative Ags in the absence of any immunosuppression, perhaps
contributing to the observed vasculopathy. Second, not only
alloantigen-dependent, but also alloantigen-independent factors can
cause chronic rejection (36). Previous reports have
suggested that cold ischemia/reperfusion injury can provoke chronic
organ dysfunction and vascular remodeling and that administration of
CTLA4-Ig can prevent these lesions (37, 38). Thus, it is
possible that in our experiments CB could protect the heart graft from
not only T cell-mediated responses, but also inhibit
ischemia/reperfusion injury via mechanisms that are not completely
understood. Third, as suggested by Russell’s group, NK cells might be
involved in the pathogenesis of obliterative vasculopathy in cardiac
allografts. Several studies have provided evidence that the CD40/CD154
and CD28/B7 pathways may play an important role in the activation of NK
cells (39). However, the recent report that NK cells play
an important role in cardiac allograft rejection in
CD28-/- mice suggests that blockade of this
pathway alone is insufficient to inhibit NK-induced rejection. Thus,
the incorporation of agents to block both the CD40 and CD28 pathways in
the peritransplant period in our studies may synergistically inhibit NK
cell-mediated injury that contributes to chronic vasculopathy. Finally,
the duration of CB in our studies was considerably longer than in most
earlier studies. Given the surprisingly long period of time (60
days) to promote complete deletion of donor-reactive T cells, it is
possible that prolonged CB plays an important role by protecting the
allograft until the deletion process is complete.
In summary, the data presented have shown that several regimens incorporating CD28 and CD40 blockade with donor cell infusions prolong cardiac allograft survival and protect the allografts from peritransplant infiltration and immunologic injury. However, we have found that only a regimen consisting of CD28 and CD40 blockade together with a minimally myelosuppressive dose of Bu and donor BMCs promoted robust deletional tolerance. Importantly, this regimen also prevented the development of chronic allograft vasculopathy. These data suggest that further development of regimens targeting the CD40 and CD28 pathways to promote chimerism and tolerance may have a significant impact on chronic rejection, an untreatable cause of clinical transplant failure.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Christian P. Larsen or Dr. Thomas C. Pearson, Emory University Woodruff Memorial Building, 1639 Pierce Drive, Atlanta, GA 30322. E-mail address: clarsen@emory.org or tpearson{at}emory.org
3 Abbreviations used in this paper: BMC, bone marrow cell; Bu, busulfan; CB, costimulation blockade; CD40L, CD40 ligand; DST, donor splenocyte; MST, median survival time.
Received for publication February 15, 2002. Accepted for publication June 11, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and CTLA4. J. Clin. Invest. 101:2446.[Medline]
production by dendritic cells. J. Immunol. 164:64.11-bearing T cells. J. Exp. Med. 169:1405.11 T cells cosegregate with mammary tumor virus genomes. Nature 349:531.[Medline]
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,
n = 5); CB, DST (
, n = 4);
CB, BMCs (•, n = 5); CB (
,
n = 6); isotype control (
, n
= 5); or no treatment (
, n = 10). All animals
(B6) received fully allogeneic cardiac grafts (BALB/c) on day 0.
Control groups (no treatment, or isotype control) promptly rejected the
BALB/c cardiac grafts (MST = 8 days, respectively). Recipients
treated with CB-based regimens (i.e., recipients with CB alone; CB and
BMCs; CB and DST; or CB, BMCs, and Bu) showed prolonged survival of
primary cardiac allografts with MST >180 days, while one recipient
each from group with CB alone or with CB and BMCs rejected the grafts
on days 147 and 60, respectively. Additional groups performed with
these regimens yielded similar survival results, but were harvested for
histologic assessment on day 14, 28, 60, or 90.
