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* Department of Medicine, Children’s Hospital,
Laboratory of Immunogenetics and Transplantation, Brigham and Women’s Hospital, and
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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70% of wild type and STAT4-/- mice.
By contrast, there was significantly shorter graft survival in minor
mismatched STAT6-/- mice. Either the adoptive transfer of
STAT4-/- splenocytes or the administration of IL-4Fc
fusion protein into STAT6-/- mice resulted in long term
graft survival. Blocking CTLA-4 signaling accelerated the rejection in
all recipients, but was more pronounced in the minor combination. This
was accompanied by an increased frequency of alloreactive T cells.
Furthermore, CTLA-4 blockade regulated CD4+ or
CD8+ as well as Th1 or Th2 alloreactive T cells. Finally,
while anti-CD25 treatment prolonged graft survival in the major
mismatched combination, the same treatment accelerated graft rejection
in the minor mismatched group. The latter was associated with an
increased frequency of alloreactive T cells and inhibition of T cell
apoptosis. These data demonstrate that cytokine regulation, CTLA-4
negative signaling, and T cell apoptosis play critical roles in
regulating alloimmunity, especially under conditions where the
alloreactive T cell clone size is relatively
small. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CTLA-4 (CD152) is a physiologic terminator of immune responses to pathogens and self-Ags. CTLA-4 is induced on activated T cells and provides a negative regulatory signal by inhibiting IL-2 transcription and cell cycle progression (2, 3, 4). CTLA4 also plays an important role in acquired tolerance to nominal (5, 6, 7) and self Ags (8). More recently, it has been suggested that CTLA4 may play a role in the function of CD4+CD25+ regulatory T cells (9, 10). Thus, its underlying mechanism of immunological down-regulation may be not only induction of anergy, but also active regulation. Although the importance of CTLA-4 negative signaling has been suggested to play an important role in acquired tolerance in some transplant models (11, 12, 13), its precise physiologic role in regulating alloimmune responses in vivo remains unclear.
Cytokine-mediated regulation is a second important mechanism for terminating and regulating immune responses (1). The role of cytokines in alloimmune responses has been extensively investigated. Th1 cells play an important role in allograft rejection, whereas Th2 cells are associated with prolongation of graft survival and tolerance induction in some models (14). However, this simple Th1/Th2 paradigm belies a more complex interaction between the cytokine environment and allograft survival. Recent data demonstrate that in certain transplant models Th1 cytokine knockout mice may reject their allografts (15) and that while some Th1 cytokines are required for tolerance induction (16, 17), Th2 cytokines such as IL-4 are not necessary (18, 19). Thus, the physiological role of cytokines in regulation of alloimmune responses has not been clearly elucidated.
Finally, T cell apoptosis is yet another major mechanism for the
termination of immune responses (1). Fas-mediated
activation-induced cell death
(AICD)3 is critical
for the elimination of Ag-activated cells. Since this process is
potentiated by IL-2, both IL-2- and IL-2R- (
- or 
-chain)
deficient mice have impaired AICD and develop massive
lymphoproliferative disorders with associated autoimmune disease
(20, 21, 22). Furthermore, it appears that deletion of
alloreactive T cells through passive and AICD mechanisms is required
for the development of peripheral transplantation tolerance across MHC
barriers, possibly by allowing a reduction in alloreactive T cell clone
size (23, 24).
In this study we investigated the physiological regulatory role of CTLA-4, Th1/Th2 cytokines, CD25+ T cells, and apoptosis in allograft acceptance and rejection. To this end we used two different mouse heart transplantation models: a fully MHC-mismatched combination (major mismatched combination; C57BL/6 donors into BALB/c recipients) as a model with a large alloreactive T cell clone size and a multiple minor histocompatibilityAg-mismatched combination (minor mismatched combination; B10.D2 donors into BALB/c recipients) as a model with relatively small alloreactive T cell clone size. Wild-type (WT) BALB/c, STAT4-deficient (STAT4-/-, impaired Th1 response) or STAT6-deficient (STAT6-/-, impaired Th2 response) mice were used to investigate the physiologic role of the cytokine environment in alloimmune responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (H-2b) and BALB/c (H-2d) mice, aged 6–8 wk, were purchased from Taconic Farms (Germantown, PA). STAT4-/-, STAT6-/-, and B10.D2 (H-2d H2-T18c Hc1/nSnJ) mice, aged 6–8 wk, were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice homozygous for a targeted disruption of the STAT4 gene (STAT4-/- mice) and the STAT6 gene (STAT6-/- mice) have been previously described (25, 26). We have also previously reported the rejection tempo and cytokine pattern of these mice in response to alloantigen stimulation (27).
Fusion proteins and Abs
Anti-CTLA-4 mAb (4F10, a gift of Dr. J. Bluestone, San Francisco, CA) and anti-IL-2R mAb (PC-61, a gift of Dr. L. Turka, Philadelphia, PA) were manufactured from their respective hybridomas by Bioexpress Cell Culture Services (West Lebanon, NH). Recipients received anti-CTLA-4 mAb or anti-IL-2R mAb (500 µg i.p. on day 0 plus 250 µg i.p. on days 2, 4, 6, 8, and 10). Some recipients received anti-CTLA-4 mAb (500 µg i.p. on day 30 plus 250 µg i.p. on days 32, 34, 36, 38, and 40). Anti-CD4- and anti-CD8-depleting mAbs were prepared from hybridomas GK1.5 (rat anti-mouse CD4) and 2.43 (rat anti-mouse CD8), respectively, obtained from American Type Culture Collection (Manassas, VA). All treated mice received 0.1 ml i.p. unpurified ascites of the appropriate Ab (roughly equivalent to 100 µg purified Ab) 6, 3, and 1 days before transplantation (28, 29). This regimen insures >95% depletion of the respective cell type in the peripheral blood on the day of transplantation (28, 29). Murine IL-4/Fc fusion protein was prepared as previously described (18). Murine IL-4/Fc was given on days 0–14 (0.2 µg i.p.).
Transplantation
BALB/c mice were used as recipients, and B10.D2 or C57BL/6 mice were used as donors. The cardiac allografts were placed in an intra-abdominal location, as previously described (30). Cardiac graft function was assessed by daily palpation. Rejection was defined as complete cessation of a palpable beat and was confirmed by direct visualization after laparotomy (27, 29). Furthermore, cardiac grafts from rejecting or long term survivors (>100 days) were evaluated histologically for evidence of acute and/or chronic rejection. Grafts were fixed in 10% buffered formalin, embedded in paraffin, coronally sectioned, and stained with H&E for evaluation of cellular infiltrates, Verhoeff’s elastin for vessel arteriosclerosis scoring, or Masson’s Trichrome stain for evaluation of fibrosis by light microscopy. Arteriosclerosis was assessed using light microscopy, and the percentage of luminal occlusion by intimal thickening was determined using the scoring system previously described (27).
ELISPOT
The technique for ELISPOT analysis has been described by our
group and others (27, 29, 31, 32). Briefly, Immunospot
plates (Cellular Technology, Cleveland, OH) were coated with 4 µg/ml
rat anti-mouse IFN-
capture mAb (R4-6A2) in sterile PBS
overnight. The plates were then blocked for 1 h with sterile PBS
containing 1% BSA (fraction V) and washed three times with sterile
PBS. Splenocytes (1 x 106 in 200 µl HL-1
medium containing 1% L-glutamine) were then placed in each
well in the presence of 1 x 106 irradiated
(3000 rad) syngeneic or allogeneic splenocytes and cultured for 24
h at 37°C in 5% CO2. After washing with PBS,
followed by PBS containing 0.05% Tween (PBST), 2 µg/ml biotinylated
rat anti-mouse IFN- detection mAb (XMG1.2) was added overnight.
The plates were then washed four times in PBST, followed by 2-h
incubation with streptavidin-HRP (Dako, Carpenteria, CA) diluted at
1/2000 in PBS/1% BSA. All mAbs were purchased from BD PharMingen (San
Diego, CA). After washing three times with PBST/followed by PBS, the
plates were developed using 800 µl 3-amino-9-ethylcarbazole
(Sigma-Aldrich, St. Louis, MO; 10 mg dissolved in 1 ml
N,N-dimethylformamide) mixed in 24 ml 0.1 M
sodium acetate (pH 5.0) plus 12 µl
H2O2. The resulting spots
were counted on a computer-assisted ELISPOT image analyzer (T Spot
Image Analyzer; Cellular Technology).
Apoptosis assay
Spleens and lymph nodes were harvested from BALB/c recipient mice 5 days after transplantation. A single-cell suspension of spleens and lymph nodes was prepared in HBSS. RBC were lysed by hypotonic shock. Lymphocytes were washed and resuspended in HBSS. Cells were first incubated with the FITC-conjugated anti-mouse CD4 or CD8 mAb for 30 min at 4°C. Then cells were stained with PE-conjugated annexin V and the vital dye 7-amino-actinomycin D (7-AAD) (annexin V apoptosis detection kit; BD PharMingen). Cells were analyzed immediately by flow cytometry. Apoptosis was determined as the percentage of live (7-AAD negative), CD4+ or CD8+ cells staining positively with annexin V.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the fully MHC-mismatched combination (C57BL/6 into BALB/c)
heart grafts were rejected promptly within 10 days in WT recipients,
whereas in the multiple minor histocompatibility Ag-mismatched
combination (B10.D2 into BALB/c) there was spontaneous long term
allograft survival without any manipulation in 70% of animals (Fig. 1
A). Interestingly, long term
surviving grafts were free of pathological features of chronic
rejection, similar to what was observed in syngeneic BALB/c grafts
transplanted into BALB/c recipients. The frequency of alloreactive
IFN--producing recipient splenocytes was measured on day 10
post-transplantation in unmodified recipients of each model. The
frequency of donor-specific alloreactive IFN--producing cells in the
minor mismatched combination was significantly smaller (5.8 ± 2.8
times) than that in the major mismatched combination (Fig. 1B). These data suggest that there may be correlation
between spontaneous allograft survival and alloreactive T cell
clone size.
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As we previously reported, both STAT4-/-
and STAT6-/- mice reject fully mismatched
cardiac allografts with a similar tempo as WT recipients
(27), with all grafts being rejected within 10 days (Fig. 2A). By contrast, in the minor
mismatched combination, graft survival was significantly shorter in
STAT6-/- recipients compared with
STAT4-/- and WT recipients
(p < 0.05; Fig. 2B). These data suggest
that a predominant Th1 environment is less permissive of long term
allograft survival than a Th2 environment in the presence of a small
alloreactive T cell clone size. To confirm the regulatory functions of
Th2 cytokines in the minor mismatched model we used two approaches.
First, we adoptively transferred whole naive splenocytes from
STAT4-/- mice into
STAT6-/- recipients on the day of
transplantation. Interestingly, grafts were accepted indefinitely
without any further manipulation (Fig. 2C). We also tested
the efficacy of systemic administration of IL-4Fc fusion protein (to
supply the deficient Th2 cytokine) in STAT6-/-
recipients. Graft survival was also restored to the same as in WT or
STAT4-/- recipients (Fig. 2C). Both
these experiments suggest that Th2 cytokines play an important
physiological role in spontaneous graft acceptance across minor
histocompatibility barriers.
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To investigate the importance of CTLA-4 in regulating alloimmune
responses, we used a blocking anti-CTLA-4 mAb in both MHC and minor
mismatched combinations. In the former combination anti-CTLA-4 mAb
treatment caused a small, but significant, acceleration of allograft
rejection (median survival time (MST), 6; n = 7;
p = 0.0018 compared with untreated WT recipients; Fig. 3A). To further address the
mechanism by which CTLA-4 accelerated rejection, we employed depleting
anti-CD4 or anti-CD8 mAbs using a previously established
protocol (28, 29). Transient depletion of
CD4+ (MST, 34.5 days; n = 6) and
CD8+ (MST, 14 days; n = 6) T
cells resulted in significant prolongation of graft survival compared
with that of untreated WT mice (MST, 7 days; n = 5;
p < 0.005). CTLA-4 blockade accelerated rejection in
both CD4+ and CD8+ depleted
mice (Fig. 3, B and C). These data establish an
essential physiological role for CTLA-4 in regulating allograft
rejection mediated by either CD4 or CD8+ T
cells.
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A). All
anti-CTLA-4-treated recipients rejected their allografts by 12 days
after transplantation, whereas 70% of untreated recipients accepted
allograft spontaneously for >100 day (p <
0.001). In addition, consistent with the in vivo data, the frequency of
IFN--producing donor-specific T cells determined by ELISPOT was
significantly increased after anti-CTLA-4 mAb treatment (Fig. 4B). However, late introduction of anti-CTLA-4 starting
day on 30 after transplantation did not cause rejection (MST, >100
days; n = 4).
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A). In all experiments rejected
grafts from CTLA4 mAb-treated animals showed extensive and massive
interstitial infiltration. Taken together these data confirm the
important regulatory functions of CTLA-4 in alloimmune responses,
especially across minor histocompatibility barriers. Role of CD25+ T cells in physiological termination of alloimmune responses
Next, we studied the physiological role of
CD25+ T cells in alloimmune responses. We used
the lytic anti-CD25 mAb (PC61) in vivo. While 6% of
CD4+ T cells expressed CD25 in the peripheral
blood of naive BALB/c mice, an increased number of
CD25+ T cells was seen at 10 days after cardiac
transplantation in both major mismatched and minor mismatched
recipients (11.3 and 8%, respectively). After anti-CD25 mAb
treatment, the number of cells expressing CD25 was markedly reduced in
major and minor mismatched recipients (1.2 and 1.3%, respectively).
Thus, as previously reported, the mAb (PC-61) used in this study
markedly reduced the number of CD25+ T cells in
peripheral blood (33). Consistent with previous studies
(34, 35, 36), anti-CD25 mAb treatment significantly
prolonged allograft survival in the MHC-mismatched combination (Fig. 5A). By sharp contrast, this
treatment accelerated graft rejection in the minor mismatched
combination (Fig. 5C). Interestingly, these data suggest a
dual role of CD25+ cells according to
alloreactive T cell clone size. These in vivo data were confirmed by
ELISPOT. While lower frequencies of donor-specific, IFN--producing
cells were seen after anti-CD25 mAb treatment in recipients of
major mismatched grafts, significantly elevated frequencies were
observed after anti-CD25 mAb treatment in recipients of minor
mismatched grafts compared with controls (Fig. 5, B and
D).
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Finally, to investigate the role of apoptosis in terminating the
alloimmune response in vivo, leukocytes were isolated from spleens and
lymph nodes of transplanted mice. Cells were stained with annexin V,
7-AAD, and CD4 or CD8 mAb as previously described and were analyzed by
flow cytometry. Interestingly, in the minor mismatched combination, a
significant number of both CD4 and CD8 cells from untreated
transplanted mice expressed annexin V. Following anti-CD25 mAb
treatment the number of cells undergoing apoptosis was markedly reduced
(Fig. 6). However, unlike in the minor
combinations, in at least five different experiments we could not
detect any significant and consistent changes when comparing apoptosis
results before and after anti-CD25 mAb treatment in recipients of
major mismatched grafts. These data suggest that anti-CD25 mAb
treatment inhibited AICD and caused accelerated graft rejection in the
minor combination. Thus, apoptosis may be a key mechanism contributing
to spontaneous graft acceptance in the minor mismatched
combination.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present studies we have shown that a blocking anti-CTLA-4 mAb accelerated allograft rejection mediated by either CD4+ or CD8+ T cells and in a predominantly Th1 or Th2 environment. These data, therefore, clearly demonstrate that CTLA-4 is a critical physiologic regulator of in vivo alloimmune responses and is capable of regulating both CD4+ and CD8+ T cells regardless of their cytokine milieu, especially when the alloreactive T cell clone size is relatively small. Indeed, based on our results in the minor mismatched combination, intact CTLA-4 signaling appears to be critical for spontaneous allograft acceptance. Recent studies have demonstrated the constitutive expression of CTLA-4 on CD4+CD25+ regulatory T cells and have thus suggested a central role for the molecule in the action of these cells (9, 10, 43). In addition, CD4+CD25+ T cells have been reported to prevent the development of autoimmunity and alloimmunity (44, 45, 46, 47, 48). However, since CD4+CD25+ T cells from CTLA-4-deficient mice also demonstrate some regulatory activity, the precise role for CTLA-4 in the function of regulatory T cells remains to be defined (10). Interestingly, we found that the late introduction (starting on day 30 after transplantation) of anti-CTLA-4 mAb did not result in rejection in the minor Ag-mismatched combination, in which spontaneous allograft acceptance occurred in the majority of cases. This suggests that while CTLA4 plays a vital role in the induction phase of the alloimmune response, it plays little regulatory role in the maintenance phase of the alloimmune response. Therefore, early CTLA4 blockade in our model may, on the one hand, be inhibiting the functions of a regulatory T cell population or preventing alloreactive T cells from being rendered anergic, thus leading to a higher frequency of activated/effector alloreactive T cells (as demonstrated by ELISPOT) that mediate accelerated allograft rejection.
We were intrigued with the novel data showing that that there is a discrepancy in the effect of anti-CD25 mAb treatment on graft survival in recipients of fully allogeneic vs minor mismatched allografts. In sharp contrast to the MHC-mismatched combination, in which graft survival was prolonged, there was remarkable acceleration of graft rejection in the minor Ag-mismatched combination. The mechanisms of this observation are probably complex and not necessarily mutually exclusive. On the one hand, the anti-CD25 mAb may be reducing the number of CD25+ alloreactive effector T cells, while, on the other, the same treatment may be depleting CD25+ regulatory T cells. This is supported by our data showing markedly decreased number of peripheral CD25+ T cells after mAb therapy. In addition, our apoptosis data suggest that the mechanism underlying the accelerated rejection following anti-CD25 mAb treatment in the minor mismatched combination may have been at least in part related to the inhibition of programmed cell death. This is probably related to decreased IL-2 secretion. Therefore, the net result may depend on the balance between effector and regulatory cells as a function of the size of the alloreactive T cell. In the major mismatched combination, in which T cell death and regulatory cells play minor roles in physiologically regulating the alloimmune response, a dominant effect of anti-CD25 mAb was reduction of the alloreactive T cell clone size and prolongation of graft survival. In the minor mismatched combination, in which apoptosis and regulation play critical roles in regulating alloimmunity, anti-CD25 mAb therapy accelerated allograft rejection. These findings may have relevant clinical implications. First, recent data from our group showed that calcineurin inhibitors or anti-CD25 mAb therapy abrogated the beneficial effects of CD154 blockade in promoting long term allograft survival (49). Second, the use of anti-CD25 mAb for induction therapy may have a detrimental effect in cases of transplantation using well-matched donor-recipient combinations. Since the use of anti-CD25 mAb has recently become more common in clinical transplantation, further careful evaluation of its impact on graft survival under these circumstances is warranted.
Accumulating data have confused the role of Th1 cells as solely being mediators of allograft rejection (15). Previous studies using cytokine gene knockout mice clearly showed that certain Th1 cytokines were required for peripheral tolerance induction (16, 17). Moreover, data on the role of Th2 cells in tolerance induction have been conflicting (32). Some studies have shown that tolerance correlated with increases in Th2 cytokines, and that Th2 cytokines were necessary for neonatal tolerance (14, 50). However, there is no direct evidence that Th2 cells are involved in alloimmune tolerance in adult animals (46). Li et al. (51) reported that Th1 to Th2 immune deviation using anti-IL-12 mAb in an islet transplantation model induced prolonged engraftment only when there was multiple minor Ag mismatches, but not in fully MHC-mismatched grafts. Our study corroborates these findings in a physiological model. We found that a Th1 environment was less permissive for allograft acceptance and that Th2 cytokines are critical in minor Ag-mismatched combinations. These conclusions were highlighted by the results of our adoptive transfer experiments with either splenocytes of STAT4-/- mice or administration of IL-4Fc fusion protein into STAT6-/- mice. The restoration of immune deviation from a Th1 to a Th2 environment resulted in spontaneous graft acceptance. Hence, in an analogous manner to CD25+ T cells, cytokine-mediated regulation may play a more significant role when the alloreactive T cell clone size is limited. This is further supported by recent work from our laboratory using a model of experimental autoimmune encephalomyelitis in which the clone size of pathogenic CD4 cells is of a similar magnitude to the minor mismatched transplant model and in which disease is only inducible in a Th1 (WT and STAT6-/-), but not Th2 (STAT4-/-), environment (52).
In conclusion, we have provided important principles for the physiologic regulation of alloimmune responses in vivo. In the presence of low frequency of alloreactive T cell CTLA-4 negative signaling, Th2 cytokines, CD25+ cells, and T cell apoptosis play critical roles in the physiological termination of the alloimmune response. Of course, these mechanisms may not be mutually exclusive. These principles have important clinical implications for future design of novel strategies for the induction of transplantation tolerance (53).
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mohamed H. Sayegh, Laboratory of Immunogenetics and Transplantation, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail address: msayegh{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: AICD, activation-induced cell death; MST, median survival time; WT, wild type; 7-AAD, 7-amino-actinomycin D.
Received for publication May 21, 2002. Accepted for publication August 1, 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]
is critical for long-term allograft survival induced by blocking the CD28 and CD40 ligand T cell costimulation pathways. J. Immunol. 160:2059. chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3:521.[Medline]
. Science 268:1472.) monoclonal antibody. Cancer Res. 59:3128. chain and chain. Transplant. Proc. 29:2301.[Medline]
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; n = 5,
MST, 7 days), whereas in the multiple minor histocompatibility
Ag-mismatched combination (B10. D2 into BALB/c, minor mismatch),
;
n = 7; MST, >100 days). B,
Frequency of IFN-
