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*
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Department of Pathology, Harvard Medical School, Boston, MA 02115; and
Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The ligands for CD28 are CD80 (B7-1) and CD86 (B7-2), both of which are expressed on activated APCs 10, 11, 12 . Blocking interactions between CD28 and its ligands using either mAbs or recombinant fusion proteins (e.g., CTLA4Ig) inhibit a variety of cell-mediated and humoral immune responses including allograft and xenograft rejection, graft-vs-host disease, lupus, experimental allergic encephalomyelitis, and allergic airway inflammation 2, 3, 13, 14, 15, 16, 17 .
The physiologic differences between CD28:CD80 and CD28:CD86 interactions are controversial 15, 18, 19, 20, 21 . Irrespective of potential differences between CD80 and CD86, in most models it has proven necessary to block both of these molecules to suppress CD28-dependent immune responses. In the case of transplantation, we and others have shown that expression of either CD80 or CD86 alone is sufficient to support vigorous allograft rejection, whereas blocking both molecules, even transiently, greatly prolongs allograft survival and in some models can induce transplantation tolerance 6, 22, 23 .
Several studies have been undertaken to address the mechanisms of tolerance by blocking CD28-mediated costimulation. Depending upon the model examined, anergy, deletion, and suppression have all been implicated 21, 24, 25, 26, 27, 28 . Virtually all of the studies that examine the role of CD28-mediated signals in vivo employ blocking agents directed not against CD28 itself but against CD80 and CD86. This somewhat complicates the interpretation of these data, as CD80 and CD86 are also ligands for CTLA-4 (CD152), a negative regulator of T cell function and CD28 costimulation. Thus agents such as anti-B7 mAbs or CTLA4Ig block both CD28 and CD152 ligation. To the extent that CD152 ligation might regulate non-CD28-mediated T cell functions 29, 30 , agents such as CTLA4Ig may also have the unintended "counterproductive" effect of blocking an inhibitory signal to the T cell. The importance of negative regulatory signals through CD152 is illustrated by the perinatal lethality observed in CD152 "knockout" mice, which die of unchecked lymphoid expansion in critical visceral organs 31, 32 .
In addition to the unchecked lymphoid expansion observed in CD152-deficient mice in the absence of a deliberate immune stimulus, active negative signals delivered through CD152 serve to regulate induced responses to Ag. Thus, blocking the CD152-mediated inhibitory signal leads to augmentation of immune responses in vivo, both to exogenous Ags and to autoantigens, and, in the latter model, exacerbates autoimmunity 26, 33, 34 . Furthermore, in some models engagement of CD152 is required for tolerance induction 35, 36 . There are currently very limited data regarding the role of the CD152 pathway during an alloimmune response 37 , and none that address its role in alloresponses in the context of CD28 blockade. Given the suggested requirement for CD152 engagement to induce anergy, this pathway might be required for the induction and/or maintenance phases of transplantation tolerance. Here, we have examined the importance of CD152-mediated signals in the induction of long-term allograft survival.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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C57BL/6 (H-2b), 129/Sv(H-2b), and BALB/c (H-2d) mice (all ages 6–8 wk) were purchased from the Jackson Laboratory (Bar Harbor, ME) and housed in pathogen-free conditions. Mice homozygous for a targeted disruption of the CD80 gene (B7-1-/- mice) have been described previously 38 . C57BL/6 mice and 129/Sv (both wild-type and B7-1-/-) were used as recipients, and BALB/c mice (both wild-type and B7-1-/-) were used as donors. Cardiac allografts were placed in an intraabdominal location using the technique of Corry et al. 39 . Graft function was assessed daily by palpation. Animals received a single dose of mAbs or fusion proteins (at a dose of 200 µg unless otherwise stated) by i.v. injection either on the day of transplantation or 2 days after engraftment. In some instances, animals also received an i.v. injection of 5 x 106 donor splenocytes at the time of transplantation. The day of rejection was defined as the day of cessation of palpable heartbeat, and this was verified by autopsy and selective pathological examination. Loss of graft function within 48 h of transplant was considered a technical failure (<10% on average), and these animals were omitted from further analysis.
mAbs and fusion proteins
The GL-1 hybridoma-producing anti-CD86 mAb was obtained from the American Type Culture Collection (Manassas, VA). The 1G10 hybridoma-producing anti-CD80 was a kind gift of Dr. J. D. Powers (Hoffmann-La Roche, Nutley, NJ). The 4F10 hybridoma-producing anti-CD152 mAb was a generous gift of Jeff Bluestone (University of Chicago, Chicago, IL). Both hybridomas were grown as ascites, after which Ab was purified on protein G columns (Pharmacia, Uppsala, Sweden). The anti-CD154 mAb was purchased from TSD Bioservices (Germantown, NY). Control hamster Ig was purchased from Jackson Immunoresearch (West Grove, PA). Human CTLA4Ig has been described previously 11 .
Statistics
Kaplan-Meier survival graphs were constructed and Wilcoxon comparisons of the groups were used to calculate p values.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Previously, using a vascularized murine cardiac allograft model,
we have shown that a single dose of CTLA4Ig administered 2 days after
transplantation prolongs allograft survival to a median of 
75 days,
compared with 8–9 days in mice treated with a control fusion protein
40 . When the recipient mice also receive an i.v. injection of donor
splenocytes on the day of transplantation (donor-specific transfusion
(DST)4), CTLA4Ig almost
invariably induces indefinite allograft survival 40 (Table I
).
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). For these studies, three doses of anti-CD152 mAb were
given, either on consecutive or alternating days. When anti-CD152
mAb was given perioperatively (i.e., days -1, 0, and 1), the ability
of CTLA4Ig plus DST to prevent allograft rejection was severely
compromised. While rejection was delayed when compared with untreated
controls, a majority of the grafts were rejected within 45 days, and
seven of eight grafts were rejected within 88 days. Delay of
administration of the course of anti-CD152 mAb for 1–4 wk
eliminated its effects, i.e., 90% of animals had indefinite graft
survival.
We considered the possibility that the ability of anti-CD152 mAb to
prevent the induction of long-term allograft survival using CTLA4Ig was
due to the trivial effect of the mAb binding to, and neutralizing, the
fusion protein. Although CTLA4Ig was not given until after
anti-CD152 mAb was discontinued, it was possible that residual
anti-CD152 mAb neutralized CTLA4Ig. To address this possibility, we
used anti-CD80 and anti-CD86 mAbs in place of CTLA4Ig. These
two mAbs together have been shown previously to be as effective as
CTLA4Ig in preventing graft rejection 23 . Using this protocol, we
found that anti-CD152 mAb prevented long-term allograft survival by
anti-CD80 plus anti-CD86 mAbs (Table I), indicating that the
ability of anti-CD152 mAb to reconstitute rejection in our model is
due to its ability to block the CD152 receptor on T cells.
Together, these data suggest that negative signals transduced to the T cell through the CD152 molecule are critically important for the induction of long-term allograft survival using CTLA4Ig. We have found previously that tolerance induction using a single dose of CTLA4Ig is optimal if its administration is deliberately delayed until 2 days after transplantation 42 . This finding, along with the current data, suggests that one role for the delay is to allow B7 molecules to engage CD152, as signals through this molecule may be required for tolerance induction 35 . However, other investigators have shown that CTLA4Ig treatment for induction of transplantation tolerance can be initiated on day 0, if treatment is continued over a 12-day period 43 . This raises the possibility that incomplete blockade of B7 molecules by CTLA4Ig allows for selective binding of B7 to CD152 and not to CD28 due to the significantly higher affinity of the CD152:B7 interaction 11 . Alternatively, even if both CD152 and CD28 are activated, dominant negative signaling through CD152 may overcome CD28-mediated costimulation.
The fact that anti-CD152 abrogated long-term allograft survival only when administered at the time of transplantation (and not 1 wk later) highlights the importance of down-regulatory signaling through this pathway very early during the course of T cell activation and the immune response. This is consistent with studies showing that CD152 is functionally expressed on resting T cells 44, 45 . The inability of anti-CD152 mAb to affect graft survival when administered at later time points suggests that CD152 engagement is not critical at that juncture in maintenance of a "tolerogenic" state. Indeed, at least at the 1-wk time point, it is likely that CD152 engagement is already being inhibited by residual circulating CTLA4Ig 46 . By 4 wk, CTLA4Ig levels should have declined enough to allow for B7 binding 2 ; however, CD152 signals no longer appear to be critically important for continued suppression of the alloimmune response. These results are consistent with data showing that CD152 ligation is required for the induction of anergy 35 and that anergy is implicated in the induction but not the maintenance phases of tolerance with CTLA4Ig 25 .
Effects of blocking CD152 on induction of long-term allograft survival by anti-CD154 mAb
CD154 (originally termed as CD40 ligand) is expressed by activated T cells. Its ligand, CD40, is expressed on several cell types including dendritic cells, macrophages, B cells, and endothelial cells. Stimulation of CD40 activates the target cell and, depending upon the cell type, induces the expression of adhesion molecules and cytokines such as IL-12 47, 48 . Several laboratories have used anti-CD154 mAb to induce long-term allograft survival in murine models 4, 5, 6 . In our own studies, a single dose of anti-CD154 mAb plus DST, given together on the day of transplantation, were able to induce long-term graft survival in virtually all recipients 6 . The mechanism by which anti-CD154 mAb prevents graft rejection remains controversial. Signals delivered by CD154 to its ligand CD40 are important inducers of B7 molecule expression on activated APCs 49 . While inhibition of B7 induction may account for the immunosuppressive potency of anti-CD154 mAbs in some models 50 , we have demonstrated that blockade of B7 induction cannot by itself account for the ability of anti-CD154 mAb to prevent graft rejection 6, 22 . Synergistic effects of the combination of anti-CD154 plus CTLA4Ig in studies of skin allograft rejection and cutaneous hypersensitivity are consistent with a nonoverlapping mechanism of action 28, 51 . Therefore, it was of interest to test the effects of anti-CD152 mAb on graft survival in mice treated with anti-CD154.
Unlike the results seen using CTLA4Ig to prevent graft rejection, when
anti-CD154 mAb was used as immunosuppression, blocking CD152 at the
time of transplantation did not inhibit prolongation of allograft
survival (Table II). There was a
suggestion that administration of anti-CD152 mAb at later time
points might adversely affect graft survival, but the effect, if any,
was small. Regardless, the data clearly indicate that negative signals
delivered through CD152 during the onset of the alloimmune response are
not required for the induction of long-term graft survival by
anti-CD154 mAb. This is in striking contrast to a recent report
where CD152 signals were required for tolerance induction in a skin
allograft model using a protocol of pretransplant donor splenocyte
transfusion plus anti-CD154 mAb 37 .
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To study whether CD80 or CD86 might be selectively important for
CD152 ligation in our CTLA4Ig-treatment model, we used mice with
targeted deletion of the CD80 gene as well as anti-B7 mAbs. Our
earlier studies had shown that CD80 deficiency of the donor, the
recipient, or both, did not affect the incidence or timing of cardiac
allograft rejection 22 . Those experiments also demonstrated that
long-term allograft survival could be reliably induced in
CD80-deficient recipients by treatment with CTLA4Ig. In the experiments
in Table III, we tested the ability to
induce long-term survival of CD80-deficient grafts transplanted into
wild-type recipients. For these experiments, we switched the recipient
strain from C57BL/6 to 129/Sv. As our earlier study of CD80-deficient
mice used this recipient strain, this allowed us to compare the current
studies with those results.
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below, anti-CD86 mAb alone given
on day 2 was unable to prevent graft rejection.
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). The role of CD86
Finally, we separately investigated the role of CD86 in this model
(Table IV). We tried to induce long-term allograft survival with
anti-CD86 mAb alone or in combination with DST by giving the
anti-CD86 mAb at day 2, the time point of maximal efficacy of
CTLA4Ig 30 . This led to minimal prolongation of graft survival when
used alone and a comparatively modest effect in combination with DST
(Table IV, as reported in 6 . As we have recently shown that CD86
is selectively expressed at the graft site within 24 h of
transplantation 6 , we next tested the effects of using anti-CD86
mAb on day 0. This maneuver, with or without DST, led to >2-mo
allograft survival in all 15 animals treated, including long-term
survival in 50% of animals not receiving DST, and in all mice that
received donor cells. Furthermore, concurrent administration of
anti-CD152 mAb abrogated the effects of anti-CD86 mAb (Table IV). The fact that CD152 signals appear to be important for induction
of long-term allograft survival despite blockade of CD86 on the day of
transplantation suggests that CD80 may be the dominant CD152 ligand in
this system.
Concluding remarks
Our data indicate a physiologic role for CD152-negative signals
during the induction of long-term allograft survival with CTLA4Ig.
Previously, we have shown that CTLA4Ig is most effective at inducing
transplantation tolerance when its administration is delayed until 2
days after transplantation, while anti-CD154 mAb is best employed
on the day of transplantation 6, 42 . Studies by Abbas and colleagues
demonstrating a role for CD152 engagement in tolerance induction
provided a possible explanation as to why delay of CTLA4Ig was
important, i.e., to allow for engagement of CD152 by B7 molecules 35 .
The data above are consistent with that hypothesis in the case where
CTLA4Ig is used to prevent rejection, although our data also show that
induction of long-term graft survival through anti-CD154 blockade
does not require CD152 engagement as a negative T cell regulator. This
selective requirement for CD152-negative signaling with B7 blockade,
but not with anti-CD154 Abs, further supports a nonoverlapping
mechanism of action of these two strategies, as suggested by earlier
studies 6, 22, 28, 51 . The possible lack of involvement of CD152 in
long-term survival induction with anti-CD154 mAb raises the
possibility that these long-term survivors may be ignorant of, rather
than tolerant of, their grafts. It should be noted that in some models
using anti-CD154 based strategies, CD152 may be required for
tolerance induction 37 , although our data indicates this is not a
universal feature of anti-CD154-based approaches. A role for
negative signals during tolerance induction is also supported by
studies showing that IFN-
-deficient mice are resistant to
immunosuppression by CTLA4Ig and anti-CD154 mAbs 52 .
Recently, it was reported that blockade of CD152 accelerated cardiac allograft rejection in otherwise untreated CD28-knockout mice 30 . This, and a related report 29 , demonstrated the important result that CD152 can function independently of CD28, although neither study addressed the role of CD152 signals as part of strategies to induce transplantation tolerance. It should be noted that both these reports, as well as our present studies, used the same anti-CD152 mAb (4F10), which is generally accepted to act as a blocking agent in vivo 33, 36 . This is consistent with its ability to augment T cell-mediated immune responses and the known negative regulatory capacities of the CD152 molecule 10, 11, 44, 53 . While we believe it unlikely, our observations would also be consistent with 4F10 being a triggering mAb and CD152 being an activating pathway for T cell responses.
Using our protocol of single-dose treatments, it is interesting to note
that CTLA4Ig is most effective when delayed for 2 days following
transplantation 42 , but that anti-CD86 mAb works best when given
on the day of transplantation (Table III). When anti-CD86 is given
alone on day 0, CD80 would still be "available" to interact with
both CD28 and CD152; however, its low level of expression during the
first 48 h post-transplant 6 should favor interaction with
CD152. This interaction may be critical to turn off the immune response
before strong induction of CD80 allows for binding to CD28. In
addition, Pechhold et al. have recently reported that murine
fibroblasts constitutively express CD80 and up-regulate it in response
to inflammatory cytokines 54 . This opens the possibility that
negative signals (through CD80/CD152 interactions) could be delivered
to T cells by nonAPCs in the early post-transplant period.
It is notable that where negative signaling through CD152 is required, it is needed at most only during the first week postengraftment. We do not yet know if this signal is important as a basal immune inhibitor only before administration of CTLA4Ig or if it continues to operate after CTLA4Ig is given. Regarding the latter notion, it is possible that CTLA4Ig is an incomplete blocking agent, and that low level residual B7 expression is sufficient to selectively bind CD152 (and not CD28), allowing CD152 to negatively regulate non-CD28-mediated T cell functions 29, 30 . If so, future strategies designed to selectively block CD28 without inhibiting CD152:B7 interactions might prove even more effective than agents such as CTLA4Ig or anti-B7 mAbs.
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Acknowledgments |
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Footnotes |
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2 The first three authors contributed equally to this manuscript.
3 Address correspondence and reprint requests to Dr. Laurence A. Turka, University of Pennsylvania, 901 Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104-6100. E-mail address:
4 Abbreviation used in this paper: DST, donor-specific transfusion.
Received for publication August 7, 1998. Accepted for publication November 2, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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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. plus TNF-
induce regulated expression of CD80 (B7-1) but not CD86 (B7-2) on murine fibroblasts. J. Immunol. 158:4921.[Abstract]
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S. L. Blass, E. Pure, and C. A. Hunter A Role for CD44 in the Production of IFN-{{gamma}} and Immunopathology During Infection with Toxoplasma gondii J. Immunol., May 1, 2001; 166(9): 5726 - 5732. [Abstract] [Full Text] [PDF]
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Z.-Q. Wu, A. Q. Khan, Y. Shen, J. Schartman, R. Peach, A. Lees, J. J. Mond, W. C. Gause, and C. M. Snapper B7 Requirements for Primary and Secondary Protein- and Polysaccharide-Specific Ig Isotype Responses to Streptococcus pneumoniae J. Immunol., December 15, 2000; 165(12): 6840 - 6848. [Abstract] [Full Text] [PDF]
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C. Pioli, L. Gatta, V. Ubaldi, and G. Doria Inhibition of IgG1 and IgE Production by Stimulation of the B Cell CTLA-4 Receptor J. Immunol., November 15, 2000; 165(10): 5530 - 5536. [Abstract] [Full Text] [PDF]
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S. TOMASONI, N. AZZOLLINI, F. CASIRAGHI, M. C. CAPOGROSSI, G. REMUZZI, and A. BENIGNI CTLA4Ig Gene Transfer Prolongs Survival and Induces Donor-Specific Tolerance in a Rat Renal Allograft J. Am. Soc. Nephrol., April 1, 2000; 11(4): 747 - 752. [Abstract] [Full Text] [PDF]
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K. A. Frauwirth, M.-L. Alegre, and C. B. Thompson Induction of T Cell Anergy in the Absence of CTLA-4/B7 Interaction J. Immunol., March 15, 2000; 164(6): 2987 - 2993. [Abstract] [Full Text] [PDF]
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J. Sakurai, J. Ohata, K. Saito, H. Miyajima, T. Hirano, T. Kohsaka, S. Enomoto, K. Okumura, and M. Azuma Blockade of CTLA-4 Signals Inhibits Th2-Mediated Murine Chronic Graft-Versus-Host Disease by an Enhanced Expansion of Regulatory CD8+ T Cells J. Immunol., January 15, 2000; 164(2): 664 - 669. [Abstract] [Full Text] [PDF]
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N. N. Iwakoshi, J. P. Mordes, T. G. Markees, N. E. Phillips, A. A. Rossini, and D. L. Greiner Treatment of Allograft Recipients with Donor-Specific Transfusion and Anti-CD154 Antibody Leads to Deletion of Alloreactive CD8+ T Cells and Prolonged Graft Survival in a CTLA4-Dependent Manner J. Immunol., January 1, 2000; 164(1): 512 - 521. [Abstract] [Full Text] [PDF]
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B. Liang, R. J. Gee, M. J. Kashgarian, A. H. Sharpe, and M. J. Mamula B7 Costimulation in the Development of Lupus: Autoimmunity Arises Either in the Absence of B7.1/B7.2 or in the Presence of Anti-B7.1/B7.2 Blocking Antibodies J. Immunol., August 15, 1999; 163(4): 2322 - 2329. [Abstract] [Full Text] [PDF]
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H. GUDMUNDSDOTTIR and L. A. TURKA T Cell Costimulatory Blockade: New Therapies for TransplantRejection J. Am. Soc. Nephrol., June 1, 1999; 10(6): 1356 - 1365. [Abstract] [Full Text]
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F. Luhder, C. Chambers, J. P. Allison, C. Benoist, and D. Mathis Pinpointing when T cell costimulatory receptor CTLA-4 must be engaged to dampen diabetogenic T cells PNAS, October 24, 2000; 97(22): 12204 - 12209. [Abstract] [Full Text] [PDF]
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