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*
Department of Immunology, National Children’s Medical Research Center, Tokyo;
Department of Internal Medicine, Division of Rheumatology, and
Department of Immunology, Juntendo University School of Medicine, Tokyo; and
§
Department of Immunobiology, Research Institute for Biological Science, Science University of Tokyo, Chiba, Japan
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In a murine acute GVHD model, we previously reported that treatment with anti-CD80+86 mAbs efficiently prevented lethality but did not ameliorate hematologic and histologic abnormalities (16). To investigate the CD28-independent activation mechanism in the development of GVHD, we established an acute GVHD model by transferring allogeneic splenocytes from CD28-deficient mice and investigated alternative activation pathways of alloreactive T cells. In this report, we demonstrate that the CD40L-CD40 pathway may be critical for the pathogenesis of GVHD in the absence of CD28-mediated activation signals.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD28-deficient (CD28(-/-)) mice were generated as previously described (23) and were backcrossed onto a C57BL/6 (B6, H-2b) background for five generations. Female CD28(-/-)B6 mice were used as T cell donors. Wild-type female B6 mice (CD28(+/+)) mice and (BALB/c x C57BL/6)F1(CBF1, H-2d/b) recipient mice were purchased from Japan SLC (Hamamatsu, Shizuoka, Japan). Donors were 6 to 8 wk old and recipients were 8 to 10 wk old at the time of bone marrow transplantation (BMT). For in vitro experiments, female 6-wk-old BALB/c (H-2d) mice were also obtained from SLC.
Monoclonal Abs
Hybridomas producing anti-mouse CD80 (RM80, rat IgG2a) and
CD86 (PO3, rat IgG2b) mAbs were generated as described previously (14, 15). A hybridoma producing anti-mouse CD40L mAb (MR1, hamster IgG)
(24) was obtained from the American Type Culture Collection (Rockville,
MD). These mAbs were purified from ascites as described (15). The
pyrogen level was <0.01 ng/µg protein, as determined by a
Limulus amebocyte lysate assay. mAbs against the following
Ags were used for immunofluorescence analysis: CD3 (145-2C11, hamster
IgG), CD4 (RM4-5, rat IgG2a), CD8
(53-6.7, rat IgG2a), CD45R/B220
(RA3-6B2, rat IgG2a), CTLA-4 (UC10-4F10, hamster IgG), CD40L (MR1),
CD25 (7D4, rat IgM), CD69 (H1.2F3, hamster IgG), and H-2Kd
(SF1-1.1, mouse IgG2a). All FITC-, PE-, cychrome, or biotin-conjugated
mAbs were obtained from PharMingen (San Diego, CA). For staining with
biotinylated mAbs, fluorescence was visualized by R-PE-streptavidin
(Dako-Japan, Kyoto, Japan). Immunofluorescent staining, flow cytometry,
and data analysis were performed as described (25) using FACSort and
CellQuest software (Becton Dickinson Immunocytometry Systems, San
Jose, CA).
Bone marrow transplantation
Recipient CBF1 mice were lethally irradiated with 9.0 Gy using a 60Co irradiator (MBR 1505 R, Hitachi, Tokyo, Japan). Bone marrow (BM) cells were flushed from the shafts of femurs and tibias of B6(+/+) mice, then treated with anti-Thy-1.2 (30-H12, rat IgG2b) mAb (PharMingen) and rabbit complement and used as T cell-depleted (TCD)-BM cells. Single-cell suspensions of splenocytes from either CD28(+/+)B6 or CD28(-/-)B6 mice were used as the source of GVHD-causing T cells. Recipients received 2.5 x 107 TCD-BM cells and 2.5 x 107 splenocytes obtained from either CD28(+/+)B6 or CD28(-/-)B6 mice. Control mice received TCD-BM cells alone. The day of BMT was designated as day 0.
Treatment regimen
Recipients receiving TCD-BM and splenocytes from CD28(-/-)B6 mice were randomly divided into groups of 8 to 10 mice and treated with either control reagents, anti-CD80+86 (RM80 + PO3) mAbs, or anti-CD40L (MR1) mAb. As control reagents, either 100 µg of normal rat Ig (Sigma, St. Louis, MO) or hamster IgG (PharMingen) was administered. One hundred micrograms each of anti-CD80 and anti-CD86 mAb or 200 µg of anti-CD40L mAb per mouse was injected i.p. on day -1, day 0, and then every other day until day 21 post-BMT.
Hematologic and pathologic examination
Peripheral blood was obtained by retro-orbital venipuncture. The total number of lymphocytes, white blood cells, and RBC were counted by an automated cell counter (Toa Medical Electronics, Tokyo, Japan), and the hemogram was assessed by Wright-Giemsa staining. For pathologic examination, formalin-fixed, paraffin-embedded tissue sections were stained with hematoxylin-eosin.
Measurement of anti-host proliferative responses and cytotoxicity
Splenocytes were obtained from three to four spleens in each group of mice, and T cells were purified as described previously (16). For measurement of T cell proliferative responses against host alloantigen, purified splenic T cells (2 x 105/well) were cocultured with irradiated (20 Gy) BALB/c splenocytes (4 x 105/well) in 96-well flat-bottom plates. Cultures were pulsed with [3H]thymidine (1 µCi/well) (New England Nuclear, Boston, MA) for 18 h and harvested at day 5. To generate allospecific CTL, purified splenic T cells (2 x 106/ml) were cocultured with the same number of irradiated (20 Gy) BALB/c splenocytes in the presence of rIL-2 (40 U/ml) in 24-well plates. After 6 days of culture, viable cells were isolated by Ficoll-Hypaque gradient centrifugation and used as effector cells for cytotoxic assay. Cytotoxicity against A20 (H-2d) cells was measured by a standard 4 h 51Cr release assay.
Statistical analyses
Significant differences between experimental groups were analyzed by Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previously, we and others have shown that the in vivo
administration of CTLA4Ig (8, 9) or anti-CD80+86 mAbs (16) could
prevent the lethality of acute GVHD, but did not completely ameliorate
hematologic or histologic abnormalities. To investigate the reason for
the incomplete protection against GVHD, we focused on the
CD28-independent activation pathways in the development of GVHD. We
established a CD28-independent acute GVHD model by transferring
allogeneic splenocytes from CD28(-/-) mice. Splenocytes (2.5 x
107) from either CD28(+/+)B6 or CD28(-/-)B6 mice
were coinjected with 2.5 x 107 TCD-BM cells from
wild-type B6 mice into lethally irradiated CBF1 recipient
mice. As shown in Figure 1
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CBF1 mice receiving TCD-BM cells alone (referred to as BM
mice) survived more than 150 days, with a gradual increase in body
weight, and did not exhibit visible signs of GVHD. In contrast, all of
the CBF1 mice that received TCD-BM cells and splenocytes
from CD28(+/+)B6 mice (referred to as CD28(+/+)BMS mice) died by day
50, after demonstrating severe weight loss. All of the CBF1
mice that received BM cells and splenocytes from CD28(-/-)B6 mice
(referred to as CD28(-/-)BMS mice) also survived, with a smaller
increase in body weight as compared with the BM mice.
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). However,
in the other target organs such as the liver, the intestine, and the
skin, the manifestations of acute GVHD in the CD28(-/-)BMS mice were
much milder than in the CD28(+/+)BMS mice (not shown). This
result suggests that the manifestation of GVHD that developed in the
CD28(-/-)BMS mice was preferentially apparent in the lymphoid
organs.
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). The peripheral blood in the
CD28(-/-)BMS mice also exhibited a typical pattern of acute GVHD,
although it was slightly milder than in CD28(+/+)BMS mice. Clear
reductions in the total splenocyte number and in the ratio of CD4 to
CD8 were seen in the CD28(-/-)BMS mice, similar to
CD28(+/+)BMS mice (Table II A). The reduction in
the number of B cells was more moderate than in CD28(+/+)BMS mice, but
still far from the percentage in the GVHD-free BM mice.
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B). Proliferative
responses and cytotoxicity were also observed in the CD28(-/-)BMS
mice, although the magnitude of responses in proliferation and
cytotoxicity was clearly lower than in CD28(+/+)BMS mice. Overall,
manifestations observed in the CD28(-/-)BMS mice seemed similar to
those observed in the anti-CD80+86 mAb-treated BMS mice (16),
albeit with a slightly improved body weight curve and survival ratio.
Our results on CD28(-/-)BMS mice have confirmed previous observations
(8, 9) that CD28 blockade alone was not sufficient for complete
protection against acute GVHD, suggesting that CD28-independent
pathways of T cell activation might be involved in the development
of GVHD. CTLA4 and CD40L are expressed on T cells in the GVHD mice induced by CD28- T cells
To investigate alternative activation pathways in CD28(-/-)BMS
mice, we examined cell surface expression of CTLA4, CD40L, CD25, and
CD69 on splenic T cells at 28 days post-BMT. An apparently higher
percentage of T cells expressed CTLA-4 and CD40L in the
CD28(+/+)BMS mice, while a few T cells expressed both Ags in the BM
mice (Table II B). Interestingly, T cells from
CD28(-/-)BMS mice expressed these Ags at an intermediate level. We
have not observed any differences in CD25 and CD69 expression between
the three groups (not shown). These data suggest a possible
involvement of CTLA4 and CD40L in the development of GVHD.
Treatment with anti-CD40L mAb ameliorates the manifestations of GVHD induced by CD28- T cells, while treatment with anti-CD80+86 mAbs exacerbates these manifestations
To directly investigate the involvement of the CTLA4-B7 or
CD40L-CD40 pathway in the development of GVHD, we examined the effects
of in vivo treatment with either anti-CD40L mAb or anti-CD80+86
mAbs in CD28(-/-)BMS mice. As shown in Figure 3, the anti-CD40L mAb-treated mice
showed an increase in body weight similar to BM mice. To the contrary,
in the anti-CD80+86 mAb-treated mice, one mouse died at 9 days, and
the recovery of body weight after BMT was clearly delayed. This was
further indicated by analyzing the hematologic reconstitution of the
peripheral blood (Fig. 4). The
administration of anti-CD40L mAb significantly augmented the number
of lymphocytes above the level found in BM mice, reaching the highest
level at day 60. In the anti-CD80+86 mAb-treated mice,
the recovery of lymphocytes was clearly delayed compared with
the untreated-CD28(-/-)BMS mice. The RBC count at 90 days post-BMT,
which is a good indicator for assessment of late phase GVHD, was
ameliorated by the anti-CD40L mAb treatment, whereas it was
not recovered by the treatment with anti-CD80+86 mAbs. In
histopathology, the anti-CD40L mAb treatment showed an apparent,
but still incomplete, improvement of tissue destruction in the spleen.
In contrast, irreversible destruction and atrophy were caused by the
anti-CD80+86 mAb treatment (not shown). Taken together, our data
suggested that the in vivo clinical manifestations of GVHD in
the CD28(-/-)BMS mice were substantially improved by treatment with
anti-CD40L mAb. In contrast, these GVHD manifestations
were exacerbated by anti-CD80+86 mAb treatment.
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To investigate the effects of mAb treatment on T cell phenotype
and function, we analyzed splenic T cells at 28 days post-BMT. The
total numbers of splenocytes and B cells were efficiently improved by
the anti-CD40L treatment (not shown). In contrast, the
reconstitution of splenocytes was clearly delayed by treatment with
anti-CD80+86 mAbs (not shown). T cells from each group of mice were
analyzed for CTLA4, CD40L, and CD25 expression (Fig. 5). The anti-CD40L mAb treatment
reduced the expression of both CTLA-4 and CD40L, while the
anti-CD80+86 mAb treatment clearly enhanced the expression of
CTLA4, CD40L, and CD25 on T cells. The induction of these activation
Ags was observed on the residual H-2Kd+ host-derived T
cells, as well as on the H-2Kd- donor-derived T cells (not
shown). In the in vitro assay for T cell responses, the reduced
host-alloantigen-specific T cell proliferative responses in the
CD28(-/-)BMS mice was further diminished by the anti-CD40L mAb
treatment (Fig. 6A).
Interestingly, anti-CD80+86 mAb treatment clearly augmented
alloantigen-specific T cell proliferative responses. In contrast
with proliferative responses, no obvious difference in the generation
of alloantigen-specific CTL was observed between nontreated,
anti-CD40L mAb-treated, and anti-CD80+86 mAb-treated mice
(Fig. 6B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Our results demonstrated the disparity
between the lethality and the lymphocyte abnormalities in the spleen
and blood, suggesting that abnormalities in the lymphoid organs were
mediated more by the CD28-independent mechanism. Wallace et al. (9)
also suggested that the lethality of acute GVHD was more dependent upon
CD28 costimulation than the other GVHD-associated
abnormalities. In this study, anti-CD40L mAb treatment in the CD28(-/-)BMS mice efficiently ameliorated the delay of hematologic reconstitution and reduced the expression of activation Ags (such as CD40L, CTLA4, and CD25) and allogeneic T cell proliferative responses. These results suggest that the CD40L-CD40 pathway may be a potent CD28-independent activation pathway. Prior reports (27, 28) demonstrated that treatment with anti-CD40L mAb inhibited the tissue-destructive properties of allogeneic CD4+ T cells and allogeneic CTL responses when splenocytes were injected into sublethally or nonirradiated recipients. These findings are compatible with an active involvement of the CD40L-CD40 pathway in the pathogenesis of acute GVHD. In a highly immunogenic organ allograft model, the simultaneous blockade of the CD28-B7 and CD40-CD40L pathways was required for long term acceptance of grafts (29). Furthermore, Tang et al. (30) reported that successful tolerance induction in Th2-mediated contact hypersensitivity required blockade of CD40L and CTLA4Ig treatment. We previously suggested that the delay of hematologic reconstitution by treatment with anti-CD80+86 mAbs may come from the incomplete inhibition of Th2 cell activation (16). The fact of excellent recovery in hemopoiesis, especially in lymphogenesis, by the anti-CD40L treatment in the CD28(-/-)BMS mice strongly supports our previous proposal. CD40 signaling via CD40L in the APC induces not only B7 but also the expression of other costimulatory molecules that may result in augmentation of the APC function. CD44H and ICAM-1 are possible candidates for alternative costimulators induced by CD40L (21, 22). The CD28 and CD40 pathways are critical independent regulators of T cell mediated immune responses.
It should be noted that treatment with the anti-CD40 mAb significantly increased peripheral blood lymphocytes in the GVHD mice. At present, we are unable to understand the reason why the blockade of CD40-CD40L enhances the number of peripheral lymphocytes. The same schedule of administration of anti-CD40L mAb in syngeneic BMT did not show a significant increase of peripheral lymphocytes (J.O., unpublished observations), and therefore, this manifestation might be associated with allogeneic T cell transfer. It has been shown that CD40L can induce both Fas expression and susceptibility to Fas-mediated apoptosis (31). But CD40 ligation also counteracts apoptosis of B cells and dendritic cells by up-regulating Bcl-xL or bcl-2 (32, 33). Thus, CD40 can act as either a negative or positive regulator in APC. If the former situation is dominant in our GVHD model, the blockade of CD40 signaling may inhibit apoptosis of B cells and other APC and consequently may enhance T and B lymphocyte expansion. Further studies will be required to clarify this issue.
Treatment with anti-CD80+86 mAbs in the CD28(-/-)BMS mice revealed that CTLA4 acted protectively in the development of acute GVHD, since the blockade of CTLA4 signal by anti-CD80+86 mAbs clearly exacerbated the manifestations of acute GVHD. Interestingly, blockade of the CTLA-4 signal in the CD28(-/-)BMS mice strongly enhanced the expression of CD40L and CTLA4 on donor T cells, indicating that the CD28-mediated activation pathway was not essential for induction of CD40L and CTLA-4. These observations are consistent with previous findings (34, 35). The enhancement of CD40L expression in the anti-CD80+86 mAb-treated CD28(-/-)BMS mice suggested that the development of GVHD may be mediated mainly by the CD40-dependent activation pathway in these mice. Our results also suggested that the use of anti-CD80 and/or CD86 mAbs, or possibly CTLA4Ig, could interfere with negative signals through CTLA4, resulting in an incomplete blockade of T cell activation. Therefore, the selective manipulation of the CD28 signal alone may be a better approach to preventing acute GVHD. Otherwise, the combination of CD28 and CD40 antagonists might be desirable for attenuating the disadvantage of blockade of CTLA4 regulatory signals.
In conclusion, our results suggested that CD28-B7 and CD40L-CD40 may be two crucial pathways in the pathogenesis of acute GVHD. In addition, the regulatory mechanism through CTLA4-B7 may protect the development of GVHD.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Miyuki Azuma, Department of Immunology, National Children’s Medical Research Center, 3-35-31 Taishido, Setagaya-ku, Tokyo 154, Japan. E-mail address:
3 Abbreviations used in this paper: anti-CD80+86, anti-CD80 plus anti-CD86; GVHD, graft-vs-host disease; BMT, bone marrow transplantation; B6 mice, C57BL/6 mice; CBF1, (C57BL/6 x BALB/c)F1, CD40L, CD40 ligand; BM, bone marrow; BMS, bone marrow cells and splenocytes; PE, phycoerythrin; TCD, T cell-depleted.
Received for publication August 8, 1997. Accepted for publication December 31, 1997.
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