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,
,
Departments of
*
Surgery,
Pathology, and
Molecular Virology, Immunology, and Medical Genetics, and
Comprehensive Cancer Center, Ohio State University College of Medicine, Columbus, OH 43210
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production, but not by IL-10 production. These
data suggest that a donor-reactive, cell-mediated immune mechanism
involving TGF- is associated with the spontaneous acceptance of
renal allografts in mice. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have studied the mechanisms by which anti-CD4 mAb, GN, and
anti-CD40L mAb influence alloimmunity in murine cardiac allograft
recipients. In general, the evidence available to date indicates that
the allograft acceptance caused by these agents is not due to
drug-induced ignorance of donor alloantigens, since the allograft
acceptors continue to make donor-reactive alloantibodies and to
generate donor-induced cytokines (11). Instead, allograft
acceptance is associated with a shift from a proinflammatory to an
anti-inflammatory T cell disposition toward donor alloantigens.
This shift can be demonstrated by monitoring donor-reactive
delayed-type hypersensitivity (DTH) responses. Nonsuppressed cardiac
allograft rejectors mount strong DTH responses to challenge with donor
alloantigens, illustrating a proinflammatory T cell disposition toward
donor alloantigens (12). In contrast, allograft acceptors
fail to mount donor-reactive DTH responses (13). This
failure is an active rather than a passive process, since inclusion of
anti-TGF- or anti-IL-10 Abs at the DTH challenge site
restores donor-reactive DTH responses (14). Hence, the
allograft acceptors are, in fact, sensitized for donor-reactive DTH
responses, but fail to mount them because of dominant,
anti-inflammatory, donor-reactive mechanisms that rely on the
local, alloantigen-induced production of TGF- and IL-10 to block the
proinflammatory donor-reactive T cell responses. Whether the expression
of this anti-inflammatory T cell response is responsible for the
prolonged allograft survival that develops in allograft acceptor mice
remains to be determined.
It has been known since the 1970s that murine renal allografts are often spontaneously accepted (6), yet virtually nothing is known about the immune mechanisms responsible for this acceptance. An attractive hypothesis is that acceptance is due to the spontaneous development of an anti-inflammatory immune regulatory mechanism similar to the one developed by immunosuppressed cardiac allograft acceptor mice. The early studies with renal allograft acceptors were extensive, but they failed to uncover direct evidence of immune regulation (6). DTH studies were not included in this analytic effort. Studies reported in this communication used donor-reactive DTH responses to probe the donor-reactive immune disposition in murine renal allograft acceptors. These studies provided direct evidence that these acceptor mice express an anti-inflammatory, rather than a pro-inflammatory, disposition toward donor alloantigens.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (H-2b) and DBA/2 (H-2d) mice were obtained from Taconic Farms (Germantown, NY). All mice were housed and treated in accordance with animal care guidelines established by the National Institutes of Health and Ohio State University.
Murine kidney transplantation
Murine kidney transplantation was performed as described by Zhang et al. (15). Briefly, the donor left kidney was isolated by ligating and dividing the adrenal and testicular vessels with microsuture. The aorta and inferior vena cava (IVC) were mobilized at their junction, with the left renal artery and vein. The aorta was ligated below the renal vessel. An elliptical patch of bladder containing the left ureterovesical junction was excised. The graft was perfused in situ with 0.2–0.4 ml cold, heparinized Ringer’s lactate. Finally, the kidney with vascular supply and ureter attached to the bladder patch were harvested en bloc. The recipient right native kidney was removed immediately before transplantation. The infrarenal aorta and IVC were carefully isolated and cross-clamped. An end-to-side anastomosis between the donor renal vein and the recipient IVC was performed. Following successful anastomosis the kidney graft perfused instantly. Urinary reconstruction was then performed by a bladder-to-bladder anastomosis. The right native kidney was removed 1 wk post-transplantation. Kidney graft survival was followed by daily examinations of overall animal health. The technical success rate was 85%.
Serum creatinine determination
Quantitative serum creatinine levels were determined using kits from Roche Molecular Biochemicals (Indianapolis, IN). Creatinine reagents and a Roche/Hitachi analyzer were used to perform the analysis. Conventional units (milligrams per deciliter) were converted to Systeme International units by multiplying the conventional units by 88.4. The concentration of creatinine in the serum is expressed as micromoles per liter.
Murine cardiac transplantation
Heterotopic cardiac transplantation was performed as described by Corry et al. (16). In general, the native hearts from heparinized donor mice (DBA/2) were anastomosed to recipient B6 abdominal aorta and vena cava using microsurgical techniques. Graft survival was assessed by transabdominal palpation.
Immunosuppression with GN
As described previously (12), GN (Ganite, Fujisawa, Deerfield, IL) was administered as an initial s.c. bolus injection of 2.2 mg 24 h before graft implantation. This was followed by 28 days of continuous delivery via osmotic minipumps (model 2002, Alzet, Palo Alto, CA), which delivered 0.5 µl (12.5 µg GN)/h. Circulating levels of GN fall to subtherapeutic levels within 7 days of pump removal (10).
Murine skin transplantation
Split-thickness ear skin allografts were performed according to
the method of Billingham et al. (1). Briefly, the ears
were removed from anesthetized DBA/2 mice and placed in cold PBS.
Forceps were used to raise a split-thickness epithelial flap from the
cartilaginous bed at the base of the ear; the flap was separated along
the length of the ear and trimmed appropriately. Oval grafts (
8
x 10 mm) were placed on the graft beds prepared on the recipient’s
flank. The graft was covered with a protective bandage for 5 days.
Rejection was considered to occur at the point when the grafts
exhibited dark discoloration, scabbing, and necrotic degeneration.
Subcellular alloantigen
Subcellular alloantigen was prepared according to the method described by Engers et al. (17). Briefly, fresh RBC-depleted DBA/2 splenocytes suspended in PBS were subjected to three rapid freeze/thaw cycles using liquid nitrogen and spun at 13,000 rpm for 30 min to remove the residual debris. The supernatant was adjusted to 3–5 mg protein/ml and used as the source of subcellular alloantigen. For DTH challenge, 25 µl (75–125 µg protein) of this solution was injected into murine pinnae.
Tetanus toxoid (TT)
TT (Wyeth-Ayerst, Marietta, PA) was obtained at a concentration of 10 limits of flocculation (lf)/ml in PBS. To sensitize mice, 0.1 ml (1 lf) TT was injected s.c. at least 14 days before DTH challenge. To challenge mice for DTH reactivity, 25 µl (0.25 lf) TT was injected at the DTH challenge site.
Cytokine Abs used in DTH assay
Polyclonal rabbit anti-TGF-, polyclonal goat
anti-IL-10, control rabbit Ig, and control goat Ig were all
obtained from R&D Systems (Minneapolis, MN).
DTH responses
Direct DTH method. Sensitized mice received pinnae injections containing 25 µl challenge Ag using a 30-gauge insulin syringe.
Transfer DTH method. Kidney acceptor mice, skin rejector mice, and cardiac rejector mice were tested for DTH responses between 60–90 days post-transplant using a transfer DTH assay. For this assay, the pinnae of naive B6 mice were injected using a 30-gauge insulin syringe, with 25 µl containing 8 x 106 syngeneic splenocytes from the transplanted mice plus challenge alloantigen with or without 25 µg neutralizing cytokine Abs. Changes in ear thickness were measured both before injection and 24 h after injection using a dial thickness gauge (Swiss Precision Instruments, Carlstadt, NJ). For reference, changes in the range of 0–30 x 10-4 in. represent background swelling due to injection trauma, changes in the range of 40–60 x 10-4 in represent moderate DTH responses, and changes in the range of 70–100 x 10-4 in represent strong DTH responses.
Alloantibody analysis
The presence of DBA/2- or C57BL/6-reactive IgG Ab was determined
by the ability of serum to bind to DBA/2 or C57BL/6 thymocytes. Binding
was detected by flow cytometry, using FITC-conjugated goat
anti-mouse IgG (
-chain specific; Pierce, Rockford, IL). Results
are shown as the percentage of DBA/2 or C57BL/6 thymocytes that bound
detectable alloantibody. Treatment of DBA/2 thymocytes with serum from
naive C57BL/6 mice resulted in <2% binding.
Histologic examination of renal tissue
Renal tissues were excised and fixed in 10% neutral buffered formalin, dehydrated in upgraded ethanol (70, 95, and 100%), and embedded in paraffin. For histologic analysis, four to six µ sections were mounted on slides and stained with H&E.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies presented in this communication are based on the
observation that DBA/2
C57BL/6 renal allografts are often
spontaneously accepted without immunosuppression. This is illustrated
in Fig. 1
. In the DBA/2C57BL/6 strain
combination, all cardiac allografts are rapidly rejected within 7–10
days, and all skin allografts are rejected within 15–17 days, yet 80%
of the kidney allografts remain functional for >60 days. Indeed, the
survival of renal allografts is similar to the survival of renal
isografts (Fig. 1). In this model, physiologically effective function
of the allograft is assured, since the native kidneys of the transplant
recipient are removed, making the graft recipient totally dependent on
renal allograft function for survival. Analysis of serum creatinine
levels also demonstrates normal levels of renal function in renal
allograft recipients (Table I). Indeed,
C57BL/6 mice that have spontaneously accepted DBA/2 kidneys for >60
days display the same serum creatinine levels as normal naive C57BL/6
or DBA/2 mice or C57BL/6 isograft recipients (Table I).
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). Further,
alloantibody levels in the recipients of accepted renal allografts are
comparable to those in recipients of rejected cardiac allografts within
the same strain combination. This indicates that at the very least the
immune system of the allograft recipient has recognized and responded
to the allogeneic MHC class I molecules of the renal allograft. Thus,
functional graft-reactive lymphocytes remain present in the renal
allograft acceptor, and the inflammatory responses that develop at the
graft site do not occur in the absence of central alloantigen
recognition by the allograft recipient.
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). At 60 days post-transplant, renal
allografts (Fig. 3A), but not isografts (Fig. 3B), have prominent infiltration by mononuclear leukocytes.
In general, there is a cuffing of leukocytes around the vessels and
small aggregates of mononuclear cells scattered within the cortex of
accepted renal graft tissue. Nevertheless, allografts show no
histologic evidence of tissue destruction, nor do they exhibit
endothelialitis or tubulitis. Studies suggest that the leukocytic
infiltrate of accepted renal allografts is immunologically active.
Real-time PCR analysis reveals that the mRNA levels for IFN-, IL-2,
and IL-10 are much higher in the accepted renal allografts than the
background cytokine mRNA levels found in normal, nontransplanted DBA/2
kidneys (data not shown). Based on these observations, the accepted
renal allografts appear to be the focus of an active immune process.
Accepted renal allografts also demonstrate some histopathologic changes
not seen in renal isografts (Fig. 3). Trichrome staining reveals renal
allografts taken at 70 days post-transplant (Fig. 3, D and
G) have noticeably more interstitial fibrosis than renal
isografts (Fig. 3, E and H) or normal kidneys
(Fig. 3, F and I). Despite this fibrosis and the
presence of circulating donor reactive alloantibodies, no intimal
formation was observed in the arterial structures of these tissue
sections. Thus, accepted renal allografts develop some, but not all,
features of chronic allograft rejection within 70 days of
transplantation.
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As reported previously, a similar immune phenotype is exhibited by
C57BL/6 mice that accept DBA/2 cardiac allografts due to transient
immunosuppression with anti-CD4 mAb (10), GN
(10), or
anti-CD40L.4 These
cardiac allograft acceptors display donor-reactive alloantibodies, but
not donor-reactive DTH responses (13). As shown in Fig. 4, nonimmunosuppressed renal allograft
acceptors also fail to display DTH responses when challenged 60 days
post-transplant with either intact DBA/2 splenocytes (cellular donor
Ag) or a freeze/thawed extract of DBA/2 splenocytes (subcellular donor
Ag). In contrast, nonimmunosuppressed cardiac or skin allograft
rejectors mount potent donor-reactive DTH responses when challenged
with either cellular or subcellular donor alloantigens. Thus, neither
the direct nor the indirect pathway of T cell alloantigen recognition
initiates a proinflammatory, donor-reactive immune response after
cutaneous challenge in renal allograft acceptor mice.
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). When the pinnae of naive
C57BL/6 mice are injected with splenocytes from tetanus-sensitized
renal allograft acceptors plus tetanus, prominent DTH responses
develop. In contrast, an injection with the same splenocytes plus
either cellular or subcellular donor-derived alloantigen results in no
response. Donor-reactive DTH counter-regulation is revealed when the
pinnae are injected with acceptor splenocytes plus a mixture of TT and
either cellular or subcellular donor alloantigen. Under these
conditions, the tetanus-reactive DTH responses are lost. Thus,
splenocytes from renal allograft acceptors display a donor
alloantigen-induced immune mechanism that interferes with DTH
responses. This DTH counter-regulatory mechanism can be induced by
indirect, and possibly direct, donor alloantigen recognition.
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and IL-10
(14). This can be demonstrated by including Abs that bind
either TGF- or IL-10 along with donor alloantigens at DTH challenge
sites. Under these conditions, donor-reactive DTH responses are
restored. Splenocytes from renal allograft acceptor mice display a
similar, cytokine-mediated DTH counter-regulatory mechanism (Fig. 6). When the pinnae of naive mice are
injected with donor alloantigens plus anti-TGF- Abs,
donor-reactive DTH responses are restored. Interestingly, when they are
injected with donor alloantigens plus anti-IL-10 Abs, only
background levels of swelling develop. Thus, it appears that the
regulation of donor-reactive cell-mediated immunity in
nonimmunosuppressed DBA/2C57BL/6 renal allograft acceptor mice is
mediated by TGF-, but not by IL-10. This contrasts with the
regulation of cell-mediated immunity in immunosuppressed
DBA/2C57BL/6 cardiac allograft acceptor mice, which is mediated by
both TGF- and IL-10 (14).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 strain combination
support the original observations of Russell and colleagues by
demonstrating the >60- to 100-day survival of renal allografts in the
absence of immunosuppression (Fig. 1
). This strain combination
represents one of the most potent murine MHC mismatches and routinely
results in cardiac allograft rejection within 10 days of implantation
(12). Spontaneous renal allograft acceptance appears to be
a species-specific phenomenon, since rat (23, 24) and
canine (18) renal allografts are rapidly rejected in the
absence of immunosuppression, and years of clinical experience have
demonstrated that the same is true for human renal allografts. It is
possible that the phenomenon of spontaneous renal allograft acceptance
in mice may also be strain specific, but this has not been
systematically evaluated. Russell and colleagues observed spontaneous
renal allograft acceptance in (C57BL/6 x
A/J)F1 recipients of B10.D2 allografts
(6), but not in (C3H x DBA/2)F1 recipients of
C576BL/6 grafts. Others have reported 7-day renal allograft survival in
the BALB/cC57BL/6 system (21) and 14- to 20-day
survival in the C57BL/6C3H system (22). We have not
explored this issue, except to determine that 50% of
BALB/coutbred CD1 renal allografts are spontaneously accepted
(unpublished observation).
We note that renal allografts represent an interesting and unusual
allograft model in that they are concurrently subject to two types of
allograft rejection responses, one that is cardiac-like and one that is
skin-like. As immediately revascularized organs, renal allografts are
quite similar to cardiac allografts, and one might expect them to
induce similar immune responses. However, unlike cardiac allografts,
renal allografts require a second anastomosis with the recipient at the
level of the bladder. This bladder connection is not immediately
revascularized. Rather, it requires a period of angiogenesis during
which the microvasculature of the donor and recipient bladder wall must
form a functional interface. This component of renal engraftment is
similar to early events that occur in skin allografts. The immunologic
significance of this component is unclear, but graft-compromising
problems with bladder anastomoses are observed in approximately 20% of
the allograft recipients around 2–3 wk post-transplant (Fig. 1). These
are often considered as technical failures. However, they could also
result from acute rejection responses in the bladder wall. Indeed, such
technical failures are somewhat less common in renal isografts (Fig. 1). Interestingly, the pathobiology of the bladder anastomosis has been
completely ignored in favor of the pathobiology within the kidney
itself. The concern is that two different immune responses, one in the
immediately revascularized kidney and one in the slowly revascularized
bladder, may be associated with renal allograft rejection. Although
either of these mechanisms could compromise renal allograft function,
only one of them is studied, while the other is completely ignored. The
possibility that two mechanisms of acute rejection operate in renal
allografts raises the possibility that they may be differentially
regulated. Clearly, this could complicate studies of immune regulation
in this experimental system.
Fortunately, the majority of renal allografts avoid acute rejection
regardless of its mechanism. The obvious question is why renal
allografts are spontaneously accepted while cardiac allografts are
spontaneously rejected despite identical MHC disparities and allograft
location within the abdomen. According to current immunologic thinking,
there are three possibilities: ignorance (clonal deletion), anergy, or
immune regulation. Ignorance due to clonal deletion is excluded because
the grafts of the acceptor mice have striking leukocytic infiltration
(19) (Fig. 2) that involves T cells (19).
Further the allograft acceptors exhibit donor-reactive MLC activity
(6) and sufficient in vivo donor-reactive T cell function
to produce donor-reactive IgG (19) (Fig. 2).
Anergy as a cause of allograft acceptance remains subject to debate. Anergy at the CD4+ T cell level is excluded by the persistence of alloantibody production, as described above. Anergy at the CD8+ T cell level remains a possibility. Early studies indicated that renal allograft acceptors display a significant depression in donor-reactive CTL activity (6), although they did not determine whether normal numbers of CD8+ T cells were present in allograft acceptor mice. Interestingly, a similar depression of donor-reactive CTL has been reported in transiently immunosuppressed cardiac allograft acceptor mice (20, 25). Further, renal allograft acceptor mice can reject donor-matched skin allografts (a process thought to involve both CD4 and CD8 T cells) without losing renal function (6). Thus, the case for T cell anergy as a mechanism of renal allograft acceptance remains open.
In contrast, a case can now be made for immune suppression. Detailed
initial studies with renal allograft acceptors uncovered little or no
evidence of donor alloantigen-associated immune suppression. In their
analytic tests they observed 1) induction of skin allograft rejection
by naive mice that received lymph node cells from renal allograft
acceptor mice, 2) induction of graft-vs-host disease in neonatal mice
after transfer of lymph node and spleen cells from renal allograft
acceptor mice, 3) neutralization of donor alloantigen-matched tumor
cells in vivo by spleen and lymph node cells from renal allograft
acceptor mice, and 4) induction of in vitro donor-reactive CTL
generation by mixtures of splenocytes from normal naive mice and
allograft acceptor mice (6). Yet, treatment of renal
allograft acceptors with donor-sensitized lymphocytes results in
transient graft damage, but not in graft rejection (26),
suggesting the possible engagement of active suppressor mechanisms.
Nevertheless, our studies demonstrated donor alloantigen-linked DTH
nonresponsiveness in renal allograft acceptor mice similar to that
observed in transiently immunosuppressed cardiac allograft acceptor
mice. This DTH nonresponsiveness could be induced by either subcellular
donor alloantigen or intact viable donor splenocytes (Fig. 4),
suggesting that it involved the indirect, and possibly the direct,
pathway of donor alloantigen presentation. Although induction of DTH
counter-regulation was donor alloantigen dependent, its effects were
not Ag specific. Thus donor-induced DTH inhibition could impair DTH
responses to a third party Ag, such as tetanus toxoid (Fig. 5). This is
in keeping with the nature of the agent that mediates DTH regulation,
TGF-, which is a nonselective inhibitor of DTH responses
(27). The fact that active TGF- was produced after DTH
challenge with donor alloantigens was suggested by the recovery of
donor-reactive DTH responses when local TGF- was neutralized with
Abs (Fig. 6).
Given that renal allografts develop immune suppression and thus avoid
acute allograft rejection, it becomes necessary to explain how this is
associated with their development of at least one feature of chronic
rejection, interstitial fibrosis. One possibility is that escape from
acute rejection does not reflect the induction of allograft tolerance.
Rather, it reflects immune deviation toward an immune response with
different pathologic consequences, i.e., chronic tissue remodeling. In
this regard it is intriguing that renal allograft acceptors develop
donor-reactive IgG (Fig. 2), since such alloantibodies can mediate the
development of chronic rejection-like tissue remodeling in cardiac
allografts (28). Studies are ongoing to determine the
extent of this remodeling that develops over longer periods of time
than those evaluated in the reported studies (60 days). The goal of
future studies will be to determine whether the development of immune
regulation will lead to stable, long term renal allograft function, or
whether it permits eventual compromise of the graft function due to an
unregulated immune phenomenon such as chronic allograft rejection.
Several features of this anti-inflammatory response to
donor alloantigens are worthy of mention. First is the observation that
this anti-inflammatory T cell behavior can develop spontaneously in
response to an allograft, and immunosuppressive agents are not
necessarily required to artificially force the immune system to adopt
this pattern of immune behavior. Apparently both proinflammatory and
anti-inflammatory T cell responses are normal options of the murine
immune system. This may help to explain why an identical pattern of
TGF-/IL-10-mediated, anti-inflammatory immune behavior develops
when cardiac allograft recipients are treated with such disparate
immunosuppressants as deleting anti-CD4 mAb (13),
deleting anti-CD40L mAb,4 and nondeleting GN
(14).
A second feature is the fact that renal allograft acceptors display
TGF--mediated DTH regulation, but not IL-10-mediated DTH regulation.
The mechanistic basis for this is unknown. This pattern makes them
different from immunosuppressed cardiac allograft acceptor mice, which
concurrently display both DTH regulatory systems. It clearly
demonstrates that the TGF--mediated and IL-10-mediated regulatory
mechanisms can develop independently. Additional support for this comes
from studies with B cell knockout mice. These mice can accept cardiac
allografts if treated transiently with GN and display only the
IL-10-mediated pathway of DTH regulation, not the TGF--mediated
pathway (A. A. Bickerstaff, manuscript in preparation). Thus,
different immune mechanisms may be responsible for the induction or
expression of TGF--mediated and IL-10-mediated immune regulation. In
turn, the differential expression of TGF- or IL-10 at a graft site
may have significant impact on graft pathobiology. TGF- and IL-10
have different arrays of biologic activity. For example, TGF- is
fibrogenic, while IL-10 is not. It is interesting to note that accepted
renal allografts, which presumably endure prolonged intragraft TGF-
production, also display chronic rejection-like tissue remodeling
(6). It might be beneficial to find therapeutic strategies
that favor IL-10-mediated regulation and discourage TGF--mediated
immune regulation.
An outstanding question is why this anti-inflammatory disposition
toward donor Ag develops spontaneously in kidney allograft recipient,
but needs the help of selected immunosuppressants in cardiac allograft
recipients? What is different about the two allograft systems that tips
the immune decision-making process in opposite directions? Our current
thinking develops from observations made in the anterior
chamber-associated immune deviation model (29), where a
similar TGF--mediated immunoregulatory mechanism develops in
response to Ag challenge. There, local conditions define the spectrum
of immune responses that are permissible. We postulate that features
inherent in kidney tissues promote the development of TGF--mediated
anti-inflammatory T cell behavior. Either these features are
missing from cardiac tissues, or cardiac tissues express other tissue
features that promote proinflammatory T cell behavior and are missing
from renal tissues. Studies are underway that directly address this
issue.
We note that while spontaneous renal allograft acceptance is exhibited by mice and not by humans, the same is not true for the expression of anti-inflammatory T cell behavior. We recently demonstrated that several transplant patients who unilaterally discontinued immunosuppression but retained allograft function display an anti-inflammatory disposition toward donor alloantigens (30), as revealed in the trans-vivo DTH assay (31). Further, we have found that approximately 20% of our renal transplant patients who remain on immunosuppression develop a similar anti-inflammatory disposition toward donor alloantigens (C. G. Orosz, manuscript in preparation). Thus, the anti-inflammatory DTH phenotype may be relatively common in humans and completely unappreciated. Observations regarding the induction and expression of this phenotype in murine experimental systems may have direct relevance to human transplantation. The critical question that remains is whether this anti-inflammatory phenotype is causal for allograft acceptance or an epiphenomenal event that occurs in transplant recipients under conditions that favor allograft acceptance over rejection. No data yet exist to definitively answer this question.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Alice A. Bickerstaff, Ohio State University Transplant, 357 Means Hall, 1654 Upham Drive, Columbus, OH 43210. E-mail address: bickerstaff-1{at}medctr.osu.edu
3 Abbreviations used in this paper: GN, gallium nitrate; CD40L, CD40 ligand; DTH, delayed-type hypersensitivity; IVC, inferior vena cava; lf, limits of flocculation; TT, tetanus toxoid.
4 A. A. Bickerstaff, J. J. Wang, D. Xia, and C. G. Orosz. Allograft acceptance despite differential strain-specific induction of TGF/IL-10–mediated immunoregulation. Submitted for publication.
Received for publication March 13, 2001. Accepted for publication August 20, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and interleukin-10 subvert alloreactive delayed type hypersensitivity in cardiac allograft acceptor mice. Transplantation 69:1517.[Medline]
and IL-10, along with administration of CHO cells expressing the regulatory molecule OX-2. Clin. Immunol. 95:182.[Medline]
1 inhibits murine immediate and delayed type hypersensitivity. J. Immunol. 149:521.[Abstract]
2 alters antigen-presenting abilities of macrophages on T cell activation. Eur. J. Immunol. 27:1648.[Medline]
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;
n = 10), heterotopic DBA/2 cardiac allografts (
;
n = 10), or DBA/2 skin grafts (
;
n = 10). Graft survival was monitored as recipient
survival (kidney grafts), transabdominal palpation (heart allografts),
or tissue necrosis (skin allografts).
) or
subcellular (
) donor alloantigen (DBA/2). DTH responses were
measured after 24 h as the change in ear thickness (mean ±
SD). The dashed line, background (BKG), represents the mean change in
ear thickness + SD when naive C57BL/6 mice are challenged with cellular
DBA/2 alloantigen (n = 4).
