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The Journal of Immunology, 1999, 163: 4805-4810.
Copyright © 1999 by The American Association of Immunologists

CD40 Ligand Blockade Induces CD4+ T Cell Tolerance and Linked Suppression1

Karen Honey, Stephen P. Cobbold and Herman Waldmann2

Sir William Dunn School of Pathology, Oxford, United Kingdom


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The CD40-CD40 ligand (CD40L) interaction is a key event in the initiation of an adaptive immune response, and as such the therapeutic value of CD40L blockade has been studied in many experimental models of tissue transplantation and autoimmune disease. In rodents, transplantation of allogeneic tissues under the cover of anti-CD40L Abs has resulted in prolonged graft survival but not tolerance. In this report, we show that failure to induce tolerance probably results from the inability of anti-CD40L Abs to prevent graft rejection elicited by the CD8+ T cell subset. When the CD8+ T cell population is controlled independently, using anti-CD8 Abs, then tolerance is possible. Transplantation tolerance induced by anti-CD4 mAbs can often be associated with dominant regulation, manifested as infectious tolerance and linked suppression, both of which are mediated by CD4+ T cells. We show here that CD4+ T cells rendered tolerant using anti-CD40L therapy exhibit the same regulatory property of linked suppression, as demonstrated by their ability to accept grafts expressing third party Ags only if they are expressed in conjunction with the tolerated Ags. This observation of linked suppression reveals a hitherto undocumented consequence of CD40L blockade that suggests the tolerant state is maintained by a dominant regulatory mechanism. Our results suggest that, although anti-CD40L Abs are attractive clinical immunotherapeutic agents, additional therapies to control aggressive CD8+ T cell responses may be required.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Tolerance in rodents to transplanted tissues, mismatched across both minor and major histocompatibility barriers, can be induced using nonlytic mAbs directed toward CD4 and CD8 molecules (reviewed in Ref. 1). Tolerance so induced has been demonstrated to be dependent on regulatory CD4+ cells. These regulatory CD4+ cells have the ability to suppress graft rejection mediated by naive or primed T cells and, furthermore, are capable of influencing them to become tolerant, i.e., the tolerance is infectious (2, 3, 4, 5). They are also able to prevent rejection of grafts expressing third party Ags if these are presented on the same APC as the Ags to which the animal has been previously tolerized (5, 6). We investigated whether other nonlytic mAbs are able to induce transplantation tolerance, and the experiments documented here describe studies performed using an anti-CD40 ligand (CD40L)3 mAb. Additionally, using linked suppression as the readout, we sought to investigate whether such tolerance is also characterized by regulation.

CD40L is a type II membrane protein of the TNF superfamily (7, 8) that is expressed predominantly by activated CD4+ T cells and a small proportion of CD8+ cells (9, 10, 11). The interaction of CD40 with CD40L has been reported to be pivotal for the induction of both the humoral and cellular immune response (reviewed in Ref. 12). In vivo studies using a blocking anti-CD40L mAb (13), CD40 or CD40L deficient mice (14, 15) demonstrated a role for CD40-CD40L interactions in the generation of both the primary and secondary response to thymus-dependent Ags, in class switching to an Ag-specific IgG1 response, and in development of germinal centers. Furthermore, the Ab and CTL response to Ag can be enhanced in CD40L-deficient mice by administration of activating CD40 mAb (16) and in wild-type mice by administration of a plasmid-encoding trimeric CD40L (17). These effects are thought to be mediated by up-regulation of CD80 and CD86 and induction of IL-12. In vitro experiments have demonstrated that activation of dendritic cells through CD40 induces secretion of high levels of IL-12, up-regulation of CD80, CD86, and ICAM-1, and their prolonged survival (18, 19, 20), and, most recently, that activation of CTLs requires prior "conditioning" of the APC via CD40 on its cell surface (21, 22, 23).

In view of these findings, there has been much interest in the therapeutic application of blocking CD40L in vivo, both to induce Ag-specific transplantation tolerance and to reverse autoimmune disease. Anti-CD40L mAb therapy alone, or in conjunction with donor splenocytes, donor small lymphocytes, or CTLA4Ig, has in most cases been reported to induce prolonged survival of allogeneic cardiac, islet, and skin grafts in mice (24, 25, 26, 27). When administered with a donor specific transfusion (DST), the mAb can tolerize the host to subsequent organ grafts (28). However, anti-CD40L mAb treatment has failed to generate transplantation tolerance (as defined by acceptance of a second challenge graft) where the transplanted organ is itself used as the tolerogen (24, 27). This inability in rodent models to conclusively induce direct tolerance to the organ has limited formal analysis of the mechanisms involved.

In a model of skin transplantation across minor histoincompatibility barriers, we show here that transplantation under the cover of MR1 mAb can induce Ag-specific tolerance in the CD4+ T cell subset, but not in the CD8+ subset, thus providing an explanation for previous reports in which prolongation of graft survival but not tolerance has been observed (24, 25, 26, 27). Tolerance in the CD4+ population could be induced in mice rendered athymic as adults, and so, by definition, must be peripheral in nature. Tolerant mice were also shown to exhibit the phenomenon of linked suppression, thus implicating a regulatory component in the maintenance of tolerance. This finding shows for the first time that CD4+ T cell-mediated dominant regulation may also maintain peripheral tolerance produced by anti-CD40L mAbs, and may explain why cyclosporin A interferes with, and why the continued presence of CD4+ T cells is required for, long-term graft survival induced by CD40L Abs (27, 29).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

CBA/Ca, B10.BR, (AKR x B10.BR)F1, (AKR x CBA/Ca)F1, and BALB/c mice were bred and maintained in conventional facilities at the Sir William Dunn School of Pathology, Oxford University, Oxford, U.K. All groups were age and sex matched, and procedures were conducted in accordance with the Home Office Animals (Scientific Procedures) Act of 1986.

mAbs and CD8+ cell depletion

The mAbs used during these studies were produced in our own laboratory by culture in hollow fiber bioreactors and are listed in Table IGo. mAbs were purified from culture supernatants by 50% ammonium sulfate precipitation, dialyzed against PBS, and purity was checked by native and SDS gel electrophoresis (PhastGel, Pharmacia, St. Albans, U.K.).


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  		Table I. mAbs used in these studies

 
Athymic mice were depleted of CD8+ cells using a mixture of 1 mg each of YTS 156.7 and YTS 169.4, injected i.p. on days -1 and 0, with respect to transplantation. Similarly, CD4+ cells were depleted by i.p. administration of a mixture of 1 mg each of YTA 3.1 and YTS 191.1 on days -1 and 0, with respect to transplantation. Other mAbs were administered as specified in the text.

Thymectomy and skin grafting

Mice were anesthetized with a mixture of 10 mg ml-1 Hypnodil and 2 µg ml-1 Sublimaze (Janssen, Tilburg, Netherlands); 0.12 ml per 20 g of body weight was injected i.p.

Thymectomy was conducted as previously described by Monaco et al. (34). Briefly, a longitudinal incision was made in the ventral surface of the neck, and the thymus was removed as two intact lobes by the application of negative pressure through a glass tip inserted into the anterior mediastinum.

Skin grafting was conducted according to a modified technique of Billingham et al. (35). In short, full thickness tailskin (0.5 x 0.5 cm) was grafted on the lateral flank, and rechallenge grafts were placed on the contralateral flank. Grafts were observed on alternate days after removal of the bandage and considered rejected when no viable donor skin was present. Statistical analysis of graft survival was by the log rank method (36).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Anti-CD40L mAb treatment delays minor mismatched skin graft rejection in euthymic CBA/Ca mice but does not induce tolerance

It has been demonstrated in rodents that anti-CD40L mAb treatment induces long-term survival of allogeneic skin, cardiac grafts, and islets of Langerhans when combined with CTLA4Ig or donor cell infusion (25, 26, 27). We sought to determine whether anti-CD40L mAb alone could induce tolerance to a lesser histoincompatibility, multiple minor transplantation Ag-mismatched skin.

Euthymic CBA/Ca mice were transplanted with multiple minor mismatched skin, B10.BR, and perioperatively administered anti-CD40L mAb (MR1) on days 0, 2, and 4, with respect to transplantation. Control mice were transplanted in the absence of mAb and rejected grafts rapidly (Fig. 1Go; median survival time (MST) = 10 days). Although a significant delay in graft rejection was observed in MR1-treated mice (Fig. 1Go; MST = 53 days; p < 0.0028), graft survival was not indefinite. We considered three possibilities for this: 1) MR1 was unable to prevent all the cells involved in graft rejection from carrying out their effector functions. Those that were unaffected brought about rejection with slower kinetics. 2) The effect of MR1 was only transient, with graft-aggressive cells eventually able to execute effector function. 3) The effect of MR1 was permanent, but, following mAb decay, new thymic émigrés became competent to reject the grafts.



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  		FIGURE 1. Anti-CD40L mAb treatment delays minor mismatched skin rejection in euthymic CBA/Ca mice but does not induce tolerance. Euthymic CBA/Ca (H-2k) mice were transplanted with multiple minor mismatched B10.BR tailskin. Three doses of 1 mg of MR1 were administered i.p. on days 0, 2, and 4, with respect to transplantation. Control mice were transplanted in the absence of mAb therapy and rejected B10.BR (H-2k) grafts rapidly ({circ}, MST = 10 days, n = 6). A significant delay in graft rejection (p < 0.0028) was observed in MR1-treated animals (•, MST = 53 days, n = 6). Therefore, anti-CD40L therapy induces immunosuppression in euthymic animals but not Ag-specific tolerance.

 
We attempted to exclude the third possibility by using mice thymectomized in adult life. In addition, since it has previously been demonstrated that CD8+ T cells play a lesser role in rejection of B10.BR skin grafts by CBA/Ca mice (30), we therefore also depleted the recipient CD8+ T cells. This enabled us to ask whether peripheral tolerance could be induced within the CD4+ T cell subset alone.

Anti-CD40L mAb therapy can induce tolerance to minor mismatched skin in CD8+ cell-depleted athymic CBA/Ca mice

CD40L has been reported as being predominantly expressed on activated CD4+ T cells rather than CD8+ T cells (8, 10, 11). We therefore asked whether MR1 could induce tolerance in the CD4+ T cell population. CBA/Ca mice were thymectomized at 5 wk of age and, 2 wk later, were depleted of CD8+ cells. B10.BR tailskin was transplanted under the further umbrella of nondepleting mAb therapy. Three doses of MR1 or the nonlytic anti-CD4 mAb YTS 177.9 were administered on days 0, 2, and 4, with respect to transplantation. Control mice were transplanted in the absence of mAb. All animals receiving mAb therapy accepted the B10.BR graft indefinitely, whereas graft rejection by untreated mice was rapid (data not shown). All animals were rechallenged with a fresh B10.BR graft 70 days after the first graft. Both groups of mAb-treated mice maintained the second B10.BR graft for the duration of the experiment (Fig. 2Go; MST > 100 days), whereas control animals rejected their grafts with second set kinetics (MST = 13 days). A third party allogeneic BALB/c graft (H-2d), transplanted at the same time and in the same graft bed as the second B10.BR graft, was rejected at the same rate by all groups (data not shown), demonstrating immunocompetence in the tolerant mice.



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  		FIGURE 2. Anti-CD40L mAb therapy can induce tolerance to minor mismatched skin in athymic CD8+ cell-depleted CBA/Ca mice. CBA/Ca were thymectomized at 5 wk of age and CD8+ cell-depleted using a mixture of 1 mg each of YTS 156.7 and YTS 169.4, administered i.p. on days -1 and 0, with respect to transplantation. Mice were grafted with B10.BR tailskin and given three doses of either 0.67 mg MR1 or 1 mg YTS 177.9, on days 0, 2, and 4 after transplantation. Seventy days later, mice were regrafted with B10.BR and an allogeneic third party graft, BALB/c (H-2d). Athymic, CD8+ cell-depleted controls rejected the second B10.BR graft rapidly (•, MST = 13 days, n = 6). Indefinite survival of the second B10.BR graft, as well as the first (data not shown), was observed (p < 0.000073) in both MR1 ({circ}, MST > 100 days, n = 7) and YTS 177.9 ({blacksquare}, MST > 100 days, n = 5) treated animals. In all three groups the BALB/c graft was rejected rapidly (data not shown). Therefore, treatment with blocking anti-CD40L or anti-CD4 mAbs induced Ag-specific tolerance.

 
This finding suggested that the failure of anti-CD40L mAbs alone to induce tolerance to skin in euthymic animals (Ref. 24 and here) may have been the result of inadequate control of CD8+ T cell function, or, as a previous report has shown (29), may have been elicited by graft-aggressive T cells exported from the thymus following mAb clearance.

Anti-CD40L mAb therapy does not abrogate the ability of CD8+ T cells to elicit minor histoincompatible skin graft rejection

Having established that anti-CD40L mAb therapy cannot induce tolerance in euthymic mice, but that it is able to do so in adult thymectomized CD8+ T cell-depleted animals, we considered it likely that, in euthymic mice, the anti-CD40L Ab was not adequately controlling the CD8+ T cell population. We therefore directly tested this hypothesis by investigating whether anti-CD40L mAb therapy was able to prevent CD8+ T cell-mediated graft rejection.

CBA/Ca mice were thymectomized at 5 wk of age, and, 2 wk later, were transplanted with B10.BR tailskin. Before grafting, mice were depleted of either CD4+ or CD8+ cells, and half of the CD4+ cell-depleted animals were also perioperatively administered three doses of MR1. Control animals were grafted in the absence of T cell depletion or subsequent mAb therapy. T cell subset depletion was assessed by flow cytometry of the peripheral blood lymphocytes, and the number of residual cells was shown to be <1% (data not shown). Mice depleted of CD8+ cells rejected B10.BR tailskin rapidly, with the same kinetics as undepleted animals (Fig. 3Go; MST = 13 and 14 days, respectively; p < 0.99), whereas animals depleted of CD4+ cells also rejected their grafts, but more slowly (MST = 34 days). Although anti-CD40L mAb therapy significantly delayed B10.BR skin graft rejection in CD4+ cell-depleted mice when compared with such mice not administered MR1 (Fig. 3Go, p < 0.0037), it did not induce indefinite survival or transplantation tolerance, as observed in athymic CD8+ cell-depleted animals treated with anti-CD40L mAb (Fig. 2Go).



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  		FIGURE 3. Anti-CD40L mAb therapy does not prevent rejection of minor histoincompatible skin in athymic CD4+ cell-depleted mice. CBA/Ca mice were thymectomized at 5 wk of age and transplanted with B10.BR tailskin 2 wk later. Before transplantation, one group of mice was depleted of CD8+ cells using a mixture of 1 mg each of YTS 156.7 and YTS 169.4, and two further groups were CD4+ cell depleted using 1 mg each of the lytic mAbs YTA 3.1 and YTS 191.1. Depleting mAbs were administered i.p. on days -1 and 0, with respect to transplantation. One group of CD4+ cell-depleted mice was given a course of three doses of 0.67 mg MR1 on days 0, 2, and 4, with respect to transplantation. Control animals were grafted in the absence of subset depletion or MR1 treatment. Control mice ({blacksquare}, MST = 14 days, n = 5) and CD8+ cell-depleted mice ({square}, MST = 13 days, n = 6) rejected the B10.BR graft with the same kinetics (p < 0.99) whereas CD4+ cell-depleted mice rejected the graft at a slower rate (•, MST = 34 days). Anti-CD40L mAb significantly delayed graft rejection by CD4 cell-depleted animals (p < 0.0037) but did not prevent it ({circ}, MST = 59 days). Therefore, both CD4+ and CD8+ T cells can elicit B10.BR graft rejection, but anti-CD40L mAb cannot prevent graft rejection in athymic CD4+ cell-depleted mice.

 
These observations indicate that both CD4+ and CD8+ T cells are able to elicit rejection of minor disparate skin grafts and that anti-CD40L mAb therapy is unable to prevent CD8+ T cell-mediated rejection. This provides evidence to support our hypothesis that the ability of anti-CD40L mAb therapy to induce tolerance in athymic CD8+ cell-depleted mice but not in euthymic animals (Ref. 24 and here) is due to an inability of the mAb to control CD8+ T cell-mediated graft rejection. However, since these experiments were performed in athymic animals, these results do not formally eliminate a role for new thymic émigrés in graft rejection by euthymic mice administered anti-CD40L mAb.

Anti-CD40L mAb therapy can induce tolerance to multiple minor histoincompatible skin in euthymic mice if combined with a nonlytic anti-CD8 mAb

Having established that anti-CD40L mAb therapy can induce tolerance in athymic mice depleted of CD8+ cells but not CD4+ cells, we sought to further investigate whether the delayed graft rejection observed in euthymic animals (Ref. 24 and here) was due to an inability of anti-CD40L mAbs to control CD8+ T cells or whether, following mAb decay, new thymic émigrés were able to elicit graft rejection. Euthymic CBA/Ca mice were transplanted with B10.BR tailskin and perioperatively administered three doses of nonlytic mAb. Animals received MR1 alone or in combination with the anti-CD8 mAb YTS 105.18. Further groups of mice received YTS 105.18 alone or in combination with an anti-CD4 mAb YTS 177.9. Control mice were transplanted in the absence of mAb therapy. Mice receiving no mAb treatment and MR1 or YTS 105.18 alone rejected the graft rapidly whereas indefinite graft survival was observed in animals administered a combination of mAbs (data not shown). All animals were rechallenged with a fresh B10.BR graft and an allogeneic third party BALB/c graft 70 days after the first B10.BR transplant. Both groups of mice treated with a combination of mAbs were tolerant of B10.BR, as demonstrated by maintenance of the second B10.BR graft for the duration of the experiment (Fig. 4Go; MST > 60 days). Animals receiving a single mAb or no treatment rejected the graft with second set kinetics (Fig. 4Go, MST = 12 days). The third party BALB/c graft was rejected at the same rate by all groups (data not shown), demonstrating immunocompetence in the tolerant mice.



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  		FIGURE 4. Anti-CD40L mAb can induce tolerance in euthymic mice to minor disparate skin when combined with a nonlytic anti-CD8 mAb. Euthymic mice were transplanted with B10.BR tailskin under the cover of a course of nonlytic mAb therapy, administered i.p. on days 0, 2, and 4, with respect to transplantation. Animals received three doses of 0.67 mg MR1 alone or in combination with three doses of 1 mg of YTS 105.18. Further groups of mice were administered YTS 105.18 alone or in combination with three doses of 1 mg of YTS 177.9. Control mice were grafted in the absence of mAb therapy. All animals were rechallenged with B10.BR tailskin and a third party BALB/c graft seventy days after the first transplant. Mice receiving a combination therapy maintained the first (data not shown) and second B10.BR graft indefinitely (MR1 + YTS 105.18: {blacktriangledown}, MST > 60 days, n = 8; YTS 105.18 + YTS 177.9: {diamondsuit}, MST > 60 days, n = 5) whereas both first (data not shown) and second grafts were rejected rapidly by control animals (•, MST = 12 days, n = 8) and MR1 ({circ}, MST = 12 days, n = 7) or YTS 105.18 ({blacksquare}, MST = 12 days, n = 8) treated mice. All groups rejected the BALB/c graft with the same kinetics (data not shown). Therefore, tolerance can be induced in euthymic mice using an anti-CD40L mAb if CD8+ T cell-mediated graft rejection is controlled using a nonlytic anti-CD8 mAb.

 
Therefore, tolerance can be induced in euthymic animals using anti-CD40L mAb therapy if it is combined with a nonlytic anti-CD8 mAb. This indicates that the minor disparate graft rejection by euthymic animals treated with anti-CD40L mAb alone is not a result of graft-aggressive cells emerging from the thymus following mAb clearance, but that it is due to an inability of the mAb to control CD8+ T cell-mediated graft rejection.

Tolerance induced by anti-CD40L mAb involves linked suppression

Having established peripheral transplantation tolerance in the CD4+ T cell population, we were then able to investigate whether a dominant mechanism was involved in its maintenance by testing for the existence of linked suppression (6). Athymic, CD8+ cell-depleted CBA/Ca mice were transplanted with B10.BR tailskin under the cover of MR1 while control animals received a graft in the absence of mAb. Seventy days later, mice were regrafted with either (AKR x B10.BR)F1 + CBA/Ca tailskin or (AKR x CBA/Ca)F1 + B10.BR tailskin; in each case, both grafts were placed in the same graft bed. Mice receiving no mAb therapy rejected all grafts except the syngeneic CBA/Ca (Fig. 5Go). MR1-tolerized mice demonstrated long-term acceptance of (AKR x B10.BR)F1 grafts and rapid rejection of (AKR x CBA/Ca)F1 grafts (Fig. 5Go). Therefore, MR1-induced Ag-specific tolerance to minor mismatched skin grafts has a dominant regulatory phenotype, characterized by linked suppression. Since CD8+ T cells had been depleted and the recipients thymectomized, we suggest that the regulation was dependent on CD4+ T cells.



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  		FIGURE 5. Tolerance induced by anti-CD40L mAb involves linked suppression. CBA/Ca were thymectomized and CD8+ cell depleted, as specified in Materials and Methods. Mice were rendered tolerant of B10.BR using three doses of 0.67 mg MR1, administered on days 0, 2, and 4, with respect to transplantation. Seventy days later, mice were regrafted with either (AKR x B10.BR)F1 + CBA/Ca or (AKR x CBA/Ca)F1 + B10.BR; in each case, both grafts were placed in the same graft bed. Athymic and CD8+ cell-depleted control animals rejected (AKR x B10.BR)F1 (•, MST = 12 days, n = 8), (AKR x CBA/Ca)F1 ({blacksquare}, MST = 12 days, n = 7) and B10.BR (data not shown) grafts rapidly while accepting syngeneic CBA/Ca grafts (data not shown). Groups of mice tolerized to B10.BR using MR1 demonstrated indefinite survival of (AKR x B10.BR)F1 grafts ({circ}, MST > 100 days, n = 8, p < 0.000073). Control grafts of (AKR x CBA/Ca)F1 were rejected rapidly by MR1-tolerized mice ({square}, MST = 16 days, n = 7). These data indicate that MR1-induced tolerance exhibits a suppressive phenotype, as demonstrated here by linked suppression.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Previous studies have shown that anti-CD40L mAb prophylaxis in rodents can achieve prolonged graft survival (25, 26, 27). Tolerance to organ transplants, as defined by acceptance of a rechallenge graft and rejection of a third party graft, has been documented in only one report in which hosts were pretreated with anti-CD40L and DST (28). Therefore, opportunities to study the induction and maintenance mechanisms of such tolerance have been limited. We show here, for the first time, that an anti-CD40L mAb is capable of inducing Ag-specific transplantation tolerance using the transplanted tissue as the tolerogen if the CD8+ T cell population is controlled independently, either by thymectomy coupled with CD8+ cell depletion or by combining anti-CD40L and a nonlytic anti-CD8 mAb in euthymic mice. These data, coupled with the observation that MR1 failed to induce tolerance in athymic CD4+ cell-depleted mice, demonstrate that anti-CD40L mAb preferentially induces tolerance in the CD4+ T cell population. Although anti-CD40L mAb did not induce tolerance in athymic CD4+ cell-depleted mice, a significant delay in graft rejection was observed, suggesting anti-CD40L mAb can delay CD8+ cell-mediated graft rejection. This may be a direct effect on the CD8+ T cells, or, more likely, an indirect effect of anti-CD40L mAb abolishing help from residual (<1%) CD4+ T cells. Our results indicating that anti-CD40L mAb therapy is unable to prevent CD8+ T cell-mediated graft rejection have profound clinical implications that may limit the use of such mAbs or require their combination with drugs eliciting CD8+ T cell control.

It has previously been reported that prolonged allogeneic skin graft survival but not tolerance can be observed in athymic mice infused with donor-specific splenocytes under the cover of anti-CD40L mAb (29). In that study, euthymic animals did not demonstrate prolonged graft survival, thereby implicating new thymic émigrés, following the cessation of mAb therapy, as mediators of graft rejection. Although our own studies in athymic CD8+ cell-depleted mice could not rule this out as a possibility, we were able to induce tolerance in euthymic animals by combining MR1 with a nonlytic anti-CD8 mAb. This indicates that the inability of anti-CD40L mAb alone to induce transplantation tolerance in euthymic mice is a result of its failure to abrogate CD8+ T cell-mediated graft rejection and not that rejection-competent cells emerge from the thymus following mAb decay.

By controlling CD8+ T cell-mediated graft rejection, we have been able to reveal the tolerogenic effects of the anti-CD40L mAb MR1. Thymectomized CD8+ cell-depleted mice were rendered tolerant to skin mismatched for multiple minor transplantation Ags, and all tolerant animals were shown to exhibit linked suppression, presumably mediated by CD4+ T cells.

The generation of CD4+ regulatory cells has previously been demonstrated by the observation of the phenomena of infectious tolerance (2, 3, 4, 5) and linked suppression (5, 6) following tolerance induction using nonlytic anti-CD4 mAbs. A role for CD4+ regulatory cells has also been demonstrated during the maintenance phase of tolerance induced using a lytic anti-CD4 mAb combined with DST (37), CTLA4Ig (38), and an anti-CD3 mAb (M. Wise, L. Chatenoud, and H. Waldmann, manuscript in preparation). In this paper we show for the first time that blockade of the CD40-CD40L costimulator pathway achieves a similar outcome, manifested as linked suppression (6). These observations suggest a final common pathway of dominant regulation for the maintenance of peripheral transplantation tolerance induced by a variety of nonlytic Ab-based therapeutics.

In summary, we have shown here that an anti-CD40L mAb is able to induce Ag-specific tolerance only in CD4+ T cells and that it has little impact on CD8+ T cell-mediated destruction. These results predict that monotherapy with anti-CD40L mAb is unlikely to be sufficient to induce tolerance to allogeneic organ transplants and that combination therapies with a component that controls CD8+ T cell effector function may be needed. In addition, although the mechanism by which anti-CD40L induces tolerance was not investigated here, we have provided evidence to indicate that such tolerance is maintained by regulation.


   Footnotes
 
1 This work was supported by grants from the Medical Research Council, Wellcome Trust, and EU Network PL962151. Back

2 Address correspondence and reprint requests to Dr. Herman Waldmann, Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, United Kingdom. E-mail address: Back

3 Abbreviations used in this paper: CD40L, CD40 ligand; DST, donor-specific transfusion; MST, median survival time. Back

Received for publication January 11, 1999. Accepted for publication August 19, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Long-term induction of immune tolerance after blockade of CD40-CD40L interaction in a mouse model of hemophilia A
Blood, May 1, 2001; 97(9): 2750 - 2757.
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H. Ito, J. Kurtz, J. Shaffer, and M. Sykes
CD4 T Cell-Mediated Alloresistance to Fully MHC-Mismatched Allogeneic Bone Marrow Engraftment Is Dependent on CD40-CD40 Ligand Interactions, and Lasting T Cell Tolerance Is Induced by Bone Marrow Transplantation with Initial Blockade of this Pathway
J. Immunol., March 1, 2001; 166(5): 2970 - 2981.
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T. Wekerle, J. Kurtz, M. H. Sayegh, H. Ito, A. D. Wells, S. Bensinger, J. Shaffer, L. A. Turka, and M. Sykes
Peripheral Deletion After Bone Marrow Transplantation with Costimulatory Blockade Has Features of Both Activation-Induced Cell Death and Passive Cell Death
J. Immunol., February 15, 2001; 166(4): 2311 - 2316.
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R. S. Lee, J. R. Rusche, M. E. Maloney, D. H. Sachs, M. H. Sayegh, and J. C. Madsen
CTLA4Ig-Induced Linked Regulation of Allogeneic T Cell Responses
J. Immunol., February 1, 2001; 166(3): 1572 - 1582.
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L. Graca, K. Honey, E. Adams, S. P. Cobbold, and H. Waldmann
Cutting Edge: Anti-CD154 Therapeutic Antibodies Induce Infectious Transplantation Tolerance
J. Immunol., November 1, 2000; 165(9): 4783 - 4786.
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N. D. Jones, A. Van Maurik, M. Hara, B. M. Spriewald, O. Witzke, P. J. Morris, and K. J. Wood
CD40-CD40 Ligand-Independent Activation of CD8+ T Cells Can Trigger Allograft Rejection
J. Immunol., July 15, 2000; 165(2): 1111 - 1118.
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