Published ahead of print on February 7, 2007
Clin J Am Soc Nephrol 2: 393-400, 2007
© 2007 American Society of Nephrology
doi: 10.2215/CJN.03421006
Report of the First World Transplant Congress
Paolo Cravedi*,
,
Marina Noris, and
Giuseppe Remuzzi*,
* Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo, Mario Negri Institute for Pharmacological Research, and Transplant Research Center, "Chiara Cucchi De Alessandri e Gilberto Crespi," Bergamo, Italy
Address correspondence to: Dr. Giuseppe Remuzzi, Department of Renal Medicine, "Mario Negri" Institute for Pharmacological Research, Negri Bergamo Laboratories, Via Gavazzeni, 11-24125 Bergamo, Italy. Phone: +39-35-319-888; Fax: +39-35-319-331; E-mail: gremuzzi{at}marionegri.it
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Abstract
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During the past 20 yr, new immunosuppressant medications that reduced the rate of acute rejection became available for transplantation. Long-term survival of transplanted organs, however, did not improve to the extent predicted. Chronic immunosuppression is associated with cardiovascular, metabolic, and renal toxicities that negatively affect patient and graft survival. Therefore, there is a pressing need for new approaches to immunosuppression that might better prevent acute rejection with a safety profile that is superior to current regimens. Moreover, the performance of currently available agents should be largely ameliorated by optimizing drug combinations and dosages. The latter goal can be achieved only through the development of specific immune markers of over- and underimmunosuppression to help tailor the immunosuppressive regimen for individual patients and even to allow safe withdrawal of immunosuppression in selected patients. Recent research has resulted in the discovery of new pathways of alloimmune reactivity, thereby offering novel immunologic targets for more specific and minimally toxic antirejection therapies. Finally, recent achievements pushed transplant medicine forward toward its ultimate goal of achieving a condition of tolerance for allogeneic antigens that prevents acute rejection without maintenance immunosuppression. All of these topics were addressed in the more than 3000 abstracts that were presented at the World Transplant Congress, held in Boston July 22 through 27, 2006.
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Introduction
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In this report, we review clinical and experimental data that were presented at the 2006 World Transplant Congress (WTC) by selecting those that, to our knowledge, could have an impact on the treatment of transplant patients in the near future. Priority was given to reports that were highlighted during plenary sections, workshops, and symposia at the meeting.
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Induction Therapy: What’s New?
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Several studies have demonstrated that whenever induction therapy is used, acute rejection rate are lowered (1–3). Among patients who are at low immunologic risk, anti–IL-2 receptor (IL-2R) antibodies provide a better efficacy/safety profile than more toxic polyclonal antibodies, including rabbit anti-human thymoglobulin (RATG) (4,5), and lymphocyte-depleting mAb, such as OKT3 (6). Conversely, among patients who are at high immunologic risk—recipients of second grafts, hypersensitized patients, and black patients—RATG offers better antirejection activity than no induction therapy or induction with nondepleting antibodies (7–9). Preliminary results indicate that RATG is associated with a lower rate of recurrence of immune glomerular diseases than anti–IL-2R antibodies or Campath-1H (10), consistent with its immunomodulatory activity on B cells (11) and its stimulatory effect on regulatory T cells (Treg) (12,13). Whether these effects translate into a better long-term outcome remains to be established. A major shortcoming of RATG, when given at conventional dosages, is an increased risk for cytokine-release syndrome and posttransplantation lymphoproliferative disorders. Attempts have been made to reduce the RATG dosage without affecting its efficacy in preventing acute rejection (14,15). A single pulse of 4 to 6 mg/kg RATG (14) was as effective as a single 6- to 9-mg/kg dose in preventing acute graft rejection in live-donor kidney transplant recipients. To safely reduce the dosages of RATG further, others (16) proposed a novel approach that is based on the combination of an anti–IL-2R antibody and low-dosage RATG (3 mg/kg). Similarly, a prospective study in patients who were at high immunologic risk (17) documented that this combination of induction therapies was as effective as standard-dosage RATG alone in limiting episodes of acute rejection but safer and less expensive. With the use of this strategy, anti–IL-2R antibodies may contribute to overall immunosuppression by inhibiting IL-2–mediated signaling in activated T lymphocytes that are spared from depletion by RATG (17,18), without affecting the function of Treg (19). Future regimens that combine anti–IL-2R antibody and low-dosage RATG might enable use of calcineurin inhibitor or steroid-sparing protocols, saving costs and reducing toxicity.
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Maintenance Therapy: More Trials, Few Novel Insights
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The most widely used maintenance immunosuppressive regimen is standard triple therapy with a calcineurin inhibitor (cyclosporine A [CsA] or tacrolimus), an antimetabolite (mycophenolate mofetil [MMF] or azathioprine), and corticosteroids.
The SYMPHONY study, presented at the meeting (20), formally compared the efficacy and safety of various triple immunosuppressive strategies in kidney transplantation. In this open-label trial, 1645 patients were randomly assigned either to standard immunosuppression with conventional-dosage CsA (target trough levels 150 to 300 ng/ml for 3 mo, 100 to 200 ng/ml thereafter), MMF (1 g twice daily), and corticosteroids or to one of three regimens that consisted of induction with an anti–IL-2R antibody (daclizumab) and maintenance therapy with MMF and corticosteroids combined with low-dosage CsA (50 to 100 ng/ml) or tacrolimus (3 to 7 ng/ml) or sirolimus (4 to 8 ng/ml). At 1 yr after transplantation, the GFR (the primary end point calculated using the Cockcroft-Gault formula) was significantly higher and the incidence of biopsy-proven acute rejection was lower in the low-dosage tacrolimus group than in all of the others (20). Therefore, it was suggested that immunosuppression with anti–IL-2R antibody induction, MMF, low-dosage tacrolimus, and corticosteroids would provide the best efficacy/safety profile for kidney transplantation. However, follow-up in the trial was very short, and data on the metabolic profiles of the regimens are lacking. The Diabetes Incidence after Renal Transplantation (DIRECT) study (21)—an international, randomized, open-label trial that compared CsA and tacrolimus in 682 kidney transplant recipients—showed that the incidence of new-onset diabetes or impaired fasting glucose at 6 mo after transplantation was significantly lower with CsA than tacrolimus, with no difference in immunosuppressive efficacy. However, in the latter study, the target trough levels of tacrolimus were higher (10 to 15 ng/ml for 3 mo, 5 to 10 ng/ml thereafter) than in the SYMPHONY trial. In addition, the DIRECT study included only a small subgroup of high-risk, nonwhite patients who did not have diabetes and who would be of most interest in examining the extent to which the choice of calcineurin inhibitors influences the incidence of new-onset diabetes. These findings leave unanswered the question of whether CsA- or tacrolimus-based triple immunosuppression should be adopted in kidney transplantation.
The SYMPHONY and the DIRECT studies also exemplify the current trend toward a shift from azathioprine to MMF. MMF was introduced in kidney transplantation in the mid-1990s. Three large registration trials (22–24) that showed MMF to be superior to azathioprine in preventing acute rejection launched this new antimetabolite in clinical transplantation. Since then, its use has grown such that in 2004, 79% of kidney transplant recipients were receiving MMF at the time of hospital discharge (25). Results of the UK registry paired kidney observational analysis, comparing long-term outcomes of kidney transplant recipients who were on MMF or azathioprine combined with CsA, now challenges this approach (26,27). This study shows similar patient and graft survival at 5 yr after transplantation in the two treatment groups. Of note, the incidence of acute rejection between 3 and 12 mo after transplantation was double with MMF compared with azathioprine. One might pinpoint that MMF dosing was suboptimal, with only 49% of patients receiving dosages of 2 g/d or more, which could have affected the outcomes in the MMF group. However, results of this study (26,27) are consistent with those of the Mycophenolate Mofetil Steroid Steering (MYSS) Study, a randomized trial that compared the two drugs directly (28) and convincingly demonstrated that MMF, which is approximately 15 times more expensive, provides no advantages over azathioprine in preventing acute rejection. Discrepancies between these two reports (26–28) and previous registration trials (22–24) could be reconciled considering that the study by Shah et al. (26,27) and the MYSS study compared MMF and azathioprine as part of an immunosuppressive regimen that included Neoral, which is more rapidly, completely, and reproducibly absorbed than Sandimmune, which was used in previous trials. Moreover, papers that published after MMF registration raised concern about its safety profile compared with azathioprine. Indeed, a meta-analysis of 6387 renal transplant patients (29) found a significantly higher incidence of diarrhea, leukopenia, and cytomegalovirus disease among those who were on MMF than among those who were on azathioprine. Moreover, an increased incidence of tuberculosis was reported among renal transplant patients who converted from azathioprine to MMF in geographic regions where tuberculosis is endemic (30).
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A Novel Immunosuppressant
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In animal models, blocking the co-stimulatory signal for T cell activation using the fusion protein CTLA4-Ig induces tolerance to transplanted organs (31). This approach is particularly interesting, because blockade of co-stimulatory signals specifically acts on activated T cells, thereby avoiding the adverse effects of immunosuppression that result from nonspecific T cell targeting. A modified CTLA4-Ig fusion protein, Belatacept, with increased avidity for its ligands CD80 (B71) and CD86 (B72), was recently developed (32). This agent has been tested in a randomized, parallel-group phase II trial as an alternative to CsA for the prevention of acute rejection in kidney transplantation (33). Results of this trial were repeatedly emphasized during the meeting as representing important progress toward a specific, nontoxic immunosuppressive therapy. Renal transplant patients who were receiving induction therapy with the IL-2R antibody Basiliximab and maintenance immunosuppression with MMF and corticosteroids, were randomly assigned 1:1:1 to intensive (10-mg/kg infusions every 14 to 27 d for 6 mo followed by 5-mg/kg infusions every 4 or 8 wk) or less intensive (10-mg/kg infusions every 14 to 27 d for 3 mo followed by 5-mg/kg infusions every 4 or 8 wk) Belatacept treatment or to oral CsA (target trough levels 150 to 400 ng/ml during month 1 and 150 to 300 ng/ml thereafter). At 6 mo after transplantation, the incidence of biopsy-proven acute rejection was 7, 6, and 8% in the intensive and less intensive Belatacept groups and the CsA group, respectively. Of note, GFR (measured by iohexol clearance) at 12 mo was approximately 9 to 13 ml/min higher in the Belatacept arm than in the CsA arm. These data indicate that Belatacept might have antirejection activity that is comparable to CsA, without its potential nephrotoxic effects.
It is interesting that although B7-CD28 signaling is critical for Treg development in mice (34), preliminary data that were presented at the meeting indicate that Belatacept does not interfere with Treg homeostasis in the clinical setting and might even promote their formation (35). Indeed, higher numbers of infiltrating Treg were detected in the renal grafts with acute rejection from patients who were treated with Belatacept than in those from patients who were treated with CsA (35). On the basis of these data, Belatacept was presented as a new tool for advancement of transplant immunosuppression, although lack of long-term data on large numbers of patients indicates the need for more caution in establishing its real future impact.
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How to Monitor the Effect of Immunosuppression: New Assays
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Great efforts have been dedicated to the development of assays that could allow monitoring of the immune response in transplant patients. These assays have the potential to identify rejection without resorting to invasive tests. The measurement of Foxp3 mRNA, a marker of Treg, in urinary samples was reported recently to be an independent predictor of acute rejection outcome after renal transplantation (36). Increased content of Foxp3 mRNA was associated with a greater likelihood of reversal of rejection and to improved graft survival. An Immune Tolerance Network study has been approved to evaluate the feasibility of using this assay to replace renal biopsy. More important, a reliable index of the immune system activity could allow the customizing of immunosuppressive therapies, an important goal because underimmunosuppression may increase the risk for rejection, whereas overimmunosuppression is associated with severe adverse effects.
Tests to measure antidonor cellular immunity could potentially identify patients who would benefit from a more aggressive immunosuppression. Indeed, enzyme-linked immunosorbent spot (ELISPOT) evaluation of the frequency of T cells that are reactive toward a panel of alloantigens provides a measure of the reactivity of the preexisting alloreactive T cell repertoire, analogous to how the panel reactive antibodies test functions as a measure of pretransplantation humoral allosensitization. Among patients who received conventional immunosuppression, 44% (37) with a positive antidonor IFN-
ELISPOT before transplantation experienced acute rejection, compared with only 12% with negative ELISPOT. Of interest, no acute rejection occurred in ELISPOT-positive patients who received induction therapy (37). This suggests that pretransplantation assessment of donor reactive cellular immunity by IFN- ELISPOT could also help to identify patients who will benefit the most from induction therapy (37).
The characterization of lymphocyte phenotype and the evaluation of the ratio between TH1/TH2 lymphocytes and Treg could provide useful information on the immune status of transplant patients. An interim report of a multicenter study demonstrated that a higher ratio of Foxp3/
-mannosidase gene expression in circulating lymphocytes (38) identifies patients who will have stable graft function years after discontinuation of the immunosuppressants. These findings represent a major step toward the identification of patients for whom immunosuppression withdrawal is feasible.
Finally, preliminary studies that were presented at the meeting provided the evidence that CYLEX®, a recently developed assay to measure the concentration of ATP in activated CD4 T cells, may help to identify transplant patients who are at greatest risk for infections (39). In both kidney and pancreas transplant recipients, lower lymphocyte ATP content was associated with a higher rate of infections (40,41). Among immunosuppression-related posttransplantation infections, polyoma virus BK is one of the leading causes of nephropathy and graft loss (42). Of interest, highly sensitized renal transplant patients who developed BK viremia had mean T cell CYLEX® results at the time of infection that were significantly lower than those in recipients without infection (43). Whether this assay could represent a prognostic advantage over specific detection of BK by PCR remains to be established.
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Insights from Bench Research into New Potential Targets for Immune Modulation
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A New T cell Activation Pathway
Research has focused on a novel gene family, TIM (T cell, Ig, mucin domain–containing molecules), whose members are differentially expressed on TH1 and TH2 cells. TIM-1 was found on activated T cells, and its stimulation prevented the development of allograft tolerance (44). TIM-1 ligation provides co-stimulatory signals to T cells after a primary MHC class II–T cell receptor signal (45). This finding has been challenged by Strom and colleagues (46), who demonstrated that TIM-1 stimulation is a first signal pathway for T cell activation that is co-stimulation dependent but does not require MHC class II–T cell receptor stimulation. Co-cultures of mouse CD4+ T cells and syngeneic mature dendritic cells (DC) with an agonistic anti–TIM-1 antibody induced rapid T cell activation. Similar results were obtained when mature DC from MHC class II knockout mice were used as stimulators, whereas immature DC that bore low levels of co-stimulatory molecules did not stimulate T cell proliferation (46). Another preliminary report showed that stimulation of the TIM-1 pathway on naïve T cells in the presence of allogeneic DC causes the expansion of both CD4+ and CD8+ T cells (47) and strengthens their TH1 polarization. Importantly, TIM-pathway stimulation on Treg impaired their capability to suppress CD4+ T cells (47). These results support the concept that activation of the TIM-1 pathway exacerbates the allogeneic immune response.
Toll-Like Receptors: A Link between Innate and Adaptive Immunity
Innate immunity represents the first line of defense against invading pathogens and noxious stimuli. Initially, adaptive and innate immunities were thought to be temporally separable processes that involve different cell types (48). However, as highlighted by Lakkis in his lecture on tolerance and the innate immune system, evidence is emerging that a link exists between innate immunity and the initiation of the adaptive alloimmune response. His work with hydroactinia documented that this little polyp does not possess an adaptive immune response but nevertheless is fully capable of mounting a rejection response against implantation of cells from other colonies (49). Actually, Lakkis’s studies exemplified the concept that emerged from the meeting that the innate immune system and particularly the Toll-like receptors (TLR) are involved in alloreactivity. Cheng et al. (50,51) observed that a common feature of transplanted organs—lung, intestine, and skin—that are resistant to tolerance induction by co-stimulatory blockade is their continuous exposure to commensal and environmental bacteria and hypothesized that these agents could stimulate TLR and promote alloimmune response. Indeed, TLR-signaling blocking by knocking out MYD-88 led to successful skin allograft acceptance in anti-CD154–treated mice, whereas the graft was rejected in wild-type mice (50,51). Conversely, a "sterile" heart graft became resistant to tolerance when either TLR9 or TLR2 stimulation occurred during transplantation (50,51). Of note, TLR engagement (50,51) abolished intragraft recruitment of Treg.
TLR can be also activated by ischemia/reperfusion (I/R) (52,53). Indeed, endogenous TLR4 ligands are released during I/R injury in mouse liver grafts; conversely, livers from TLR4 knockout mice are protected from postischemic inflammation and injury. Similar results were achieved in a kidney I/R model (54).
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Toward Tolerance
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The achievement of immunologic tolerance has been the focus of transplant medicine since the first successful kidney transplant programs in the 1950s. Despite success in experimental models, translation of these results into the clinical setting has been slower than predicted as new barriers to tolerance have been encountered. Difficulties and hopes emerge also from the overview of ongoing studies on tolerance induction in humans that were presented at the WTC. Most of the work in this field has been done on behalf of the Immune Tolerance Network. Induction of mixed chimerism by a nonmyeloablative conditioning regimen has been attempted in patients who were given combined bone marrow and kidney transplantation from one-haplotype–mismatched, related donors (55). The preparative regimen consisted of cyclophosphamide, thymic irradiation, anti-CD2 mAb, and a 9- to 14-mo course of calcineurin inhibitor. Of the five enrolled patients, two experienced acute humoral rejection that in one case resulted in graft loss. Three patients are currently without any immunosuppressive therapy, with stable graft function >1 yr after transplantation. These results are encouraging, because they represent one of the first demonstrations of the feasibility of tolerance induction in humans. However, some concern remains about the safety and the routine clinical applicability of such intensive conditioning regimens, and their advantages over chronic maintenance immunosuppression remain ill defined.
Alternative protolerogenic regimens are those that are based on progressive tapering and eventually discontinuation of maintenance immunosuppressants after induction therapy with lymphocytotoxic antibodies. On this line is the ongoing trial on 10 kidney transplant patients (56) who are treated with Campath-1H, tacrolimus (discontinued 2 mo after transplantation), and sirolimus. At the time of the meeting, all patients were rejection-free, but only two of them had reached 1 yr of follow-up. For those with ex vivo evidence of donor-specific hyporesponsiveness 1 yr after transplantation, the gradual weaning from sirolimus has been planned. Other small studies have shown that minimization of immunosuppressive therapy is feasible in selected transplant recipients (57–59).
Immunologic tolerance that is induced by T cell depletion or co-stimulation blockade in rodents depends on the formation of Treg (60). Promotion of Treg formation may represent a tool to achieve tolerance in clinical settings. However, current maintenance immunosuppressive drugs may have an impact on Treg induction and function. Alloantigen injection into Foxp3-IRES-EGFP knock-in mice under protolerogenic conditions that were promoted by anti-CD40L resulted in de novo formation of EGFP+ Foxp3–expressing Treg (61,62). This event was blocked by CsA but not by sirolimus, which enhanced Treg formation. In another study, high dosages of CsA (63) abrogated the development of Treg and prevented donor blood transfusion–induced tolerance to heart allografts in rats. Altogether, these data document that calcineurin inhibitor–based immunosuppression negatively affects Treg-dependent tolerogenic strategies.
These experimental findings were confirmed by clinical data. Among a group of stable renal transplant patients who were under conventional immunosuppressive regimens, those who received calcineurin inhibitors had lower frequencies of circulating Treg than those who were given sirolimus (64). In renal transplant patients (65) who underwent profound T cell depletion with Campath-1H, sirolimus but not CsA was associated with Treg peripheral expansion during immune reconstitution. Consistently, in sirolimus- but not CsA-treated patients, T cell hyporesponsiveness to alloantigens was reversed by Treg depletion. These data suggest that lymphopenia and calcineurin-dependent signaling are instrumental to achieving protolerogenic Treg expansion (65).
Administration of Treg preformed in vitro could represent a new tool to induce tolerance. Functional Treg were obtained by retroviral transfection of mouse CD4+CD25– T cells with Foxp3 (66,67). Injection of these cells in recipient mice prolonged heart and skin allograft survival. Moreover, functional Treg were generated by co-culturing naïve T cells with tolerogenic DC. "Alternatively" activated DC, generated in the presence of TGF-ß, then exposed to the TLR4 ligand LPS, were resistant to maturation and capable of generating CD4+Foxp3+ cells on incubation with allogeneic T cells (68). These Treg suppressed autoimmune diabetes when co-transplanted with syngeneic islets in previously diabetic NOD mice (69). Another study documented that rat DC, made immature by adenoviral transfection with dnIKK2, induced the formation of Treg from allogeneic CD4+ T cells (70). Pretransplantation infusion of Treg significantly prolonged the survival of a fully mismatched kidney graft without any immunosuppressive therapy (70).
Human Treg can be formed and expanded in vitro, as well. Treg (71) with indirect allospecificity for an HLA-A2 peptide were generated from purified human naïve CD4+ T cells by priming with HLA-A2– autologous DC pulsed with the A2 peptide. Antigen-specific Treg could be selected by A2-specific tetramers and expanded 1600-fold, maintaining their suppressive properties. In vitro expansion of Treg has been achieved by incubating human lymphocytes with RATG. This was due mainly to conversion of CD4+CD25– into CD4+CD25+ T cells (12,13). Taken together, these studies provide the proof of principle for clinical studies using in vitro–generated and –expanded human Treg to promote transplantation tolerance.
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Conclusions
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Overall, this first joint international transplant meeting cannot be noted for the reporting of novel breakthroughs, at least clinically. Except for Belatacept, no other novel drugs/biologics are in the pipeline of early clinical trials. Clinical tolerance trials are still limited to very controlled proof-of-concept studies, but a pharmacologically promoted state of antigen-specific tolerance may finally be achieved in the near future. In the meantime, transplant physicians should continue optimizing the immunosuppressive regimens, using available immunosuppressants to minimize toxicities and improve long-term outcomes. One example is the use of induction therapy that has been demonstrated to be an effective mean of achieving low rates of acute rejection in most transplant recipients.
Immunosuppressive regimens should be individualized, specifically pairing induction agents on the basis of their mechanism of action to the specific clinical need and combining them with complementary maintenance therapies. New assays to monitor the immune response have now been shown to be promising for the identification of transplant recipients who could safely undergo drug withdrawal or, conversely, who are at high immunologic risk and require more aggressive immunosuppression.
Innovative highlights are emerging from experimental studies of immune system function that permit new potential targets such as TIM and TLR to be defined and drive the development of a number of novel immunosuppressive drugs. Hopefully, these experimental findings, together with emerging cellular therapies with Treg, will yield treatment strategies that enhance tolerance among transplant recipients.
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Disclosures
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None.
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Acknowledgments
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This work was supported by Association for Research in Transplantation.
We deeply thank Dr. Norberto Perico for invaluable help in critical discussion and editing of the manuscript.
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Footnotes
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Published online ahead of print. Publication date available at www.cjasn.org.
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Abstract
Introduction