Original Article
Randomized Controlled Trial of a Monoclonal Antibody against the Interleukin-2 Receptor (33B3.1) as Compared with Rabbit Antithymocyte Globulin for Prophylaxis against Rejection of Renal Allografts
N Engl J Med 1990; 322:1175-1182April 26, 1990
- Abstract
- Abstract
Interleukin-2 is a major growth factor for activated T lymphocytes, and antibodies reacting with the Tac-chain component of the interleukin-2 receptor can prevent allograft rejection in animals. Because Tac chains are expressed only on a small fraction of activated lymphocytes, monoclonal antibodies against the interleukin-2 receptor may offer a more specific means of immunosuppression than polyclonal antilymphocyte globulin in prophylaxis against graft rejection. Therefore, we compared the immunosuppressive effect of 33B3.1, a rat monoclonal antibody against the human Tac chain, with the effect of a rabbit polyclonal antithymocyte globulin in a randomized study of 100 recipients of first renal transplants.
Injections of 33B3.1 (10 mg per day) were tolerated well, whereas major side effects in 15 of 47 patients (32 percent) receiving antithymocyte globulin required discontinuation of treatment before day 14. The incidence of rejection episodes was not statistically different in the two groups at days 14, 30, 60, and 90 after transplantation. Patient and graft survival was also equal in the two groups at one year (96 and 85 percent, respectively, in both groups), and graft function was similar. The total number of infectious episodes within the first three months was lower in the 33B3.1 group than in the antithymocyte group (47 vs. 72). The drop in peripheral-blood lymphocyte concentrations was significantly larger in the patients treated with antithymocyte globulin. The level of circulating Tac-chain—bearing lymphocytes remained below 1 percent during 33B3.1 treatment, as compared with 4 to 5 percent during antithymocyte-globulin treatment (P not significant).
We conclude that 33B3.1 is as effective as antithymocyte globulin in the prevention of renal-transplant rejection, and its use results in fewer infections and side effects. (N Engl J Med 1990; 322:1175–82.)
Media in This Article
Figure 1
Mean (±SD) Trough Levels of Circulating 33B3.1 during Treatment.Table 1
Characteristics of the Patients.*Article Activity
- Article
TWO strategies are commonly used in the immunosuppressive treatment of patients with kidney allografts. The first consists of a combination of drugs, such as cyclosporine, steroids, and azathioprine, given immediately after surgery. The second consists of an induction treatment with agents such as polyclonal antilymphocyte serum,1 , 2 which is usually administered during the two weeks after transplantation, followed by one or more of the drugs mentioned above. The sequential strategy entailed in the latter approach has gained in popularity because it is efficient in preventing early acute rejection and because it allows the graft to recover from ischemic injury, a state of increased sensitivity to cyclosporine-induced nephrotoxicity.
Recently, the availability of monoclonal antibodies3 , 4 has offered a more specific alternative to the use of antilymphocyte serum in induction treatment and has further contributed to prophylaxis against early rejection, as compared with the regimen involving steroids and azathioprine.4 However, the only monoclonal antibody used clinically to date (Orthoclone OKT3 [Muromonab-CD3], Ortho Pharmaceutical, Raritan, N.J.) interacts with all T lymphocytes in graft recipients, regardless of the degree of their involvement in donor-antigen recognition and the rejection process.
In contrast, a monoclonal antibody that targets a molecule specifically involved in activating the growth signal of a discrete population of lymphocytes (those genetically committed to act against donor antigens) may offer a new opportunity for early immunosuppression. Moreover, by sparing the T-lymphocyte progenitors not involved in the recognition of donor antigen, its use would decrease the hazards of immunosuppression. The interleukin-2 receptor is a good target for such a strategy, insofar as it is expressed early by activated T cells and is necessary for their proliferation.
The interleukin-2 receptor is composed of two chains, an α chain (P55)5 6 7 and a β chain (P75),8 , 9 combined noncovalently in a molecular complex with a high affinity for interleukin-2.9 The interaction between this P55-P75 complex and interleukin-2 triggers antigen-activated T lymphocytes to enter mitosis and initiates clonal expansion.10 Because the binding of interleukin-2 to both the α chain and the β chain is required in this process, monoclonal antibodies directed at the interleukin-2—binding site of the α chain are potent inhibitors of interleukin-2—driven mitosis.11 , 12 Experiments in animals have demonstrated the capacity of anti–interleukin-2–receptor monoclonal antibody to inhibit13 or delay14 allograft rejection in several species.15 , 16 In addition, an interleukin-2–receptordiphtheria toxin fusion protein, another agent that has been shown in vitro to bind to interleukin-2 receptors and to target activated lymphocytes,17 can also prevent cell-mediated immunity in animals.18 Recently, we have analyzed a series of monoclonal antibodies directed at the human P55 chain11 , 12 and selected a rat IgG2a (33B3.1) with potent interleukin-2–receptor–binding inhibitory activity.11 We observed in a preliminary report that this monoclonal antibody prevented the early rejection of kidney grafts when it was given immediately after kidney transplantation and that it had practically no side effects.4 In this paper, we report on a controlled trial in which 33B3.1 monoclonal antibody was compared with rabbit antithymocyte globulin as prophylactic therapy in 100 recipients of first cadaveric renal transplants.
Methods
Patient Population
From March 1987 through August 1988, 100 consecutive recipients of primary cadaveric renal allografts were studied prospectively in a randomized trial of immunosuppression with either 33B3.1 or antithymocyte globulin. This study was approved by the Academic Ethics Committee, and informed consent was obtained before randomization. Immediately before surgery, the patients were randomly assigned to therapy with either 33B3.1 monoclonal antibody or antithymocyte globulin. The randomization was stratified according to two risk factors: the recipient's age (under 50 or over 50 years) and anti-HLA sensitization before transplantation (sensitivity to 50 percent or more of panel-reactive anti-T antibodies [PRA] or to less than 50 percent). Accordingly, four sets of sealed envelopes (under 50 years old with PRA sensitivity ≥50 percent, under 50 years old with PRA sensitivity <50 percent, over 50 years old with PRA sensitivity ≥50 percent, and over 50 years old with PRA sensitivity <50 percent) containing the treatment assignments were prepared. All patients had negative current crossmatches against the T lymphocytes of the respective donors, and in the 33B3.1 and antithymocyte-globulin groups, 28 and 26 percent, respectively, had positive reactions to the donor's total lymphocytes, B lymphocytes, or both (see Bignon et al.19 for the crossmatch method). The characteristics of the patients are given in Table 1Table 1
Characteristics of the Patients.*. The differences between the two groups with respect to the characteristics listed were not statistically significant. The follow-up period ranged from 5 to 22 months.Treatments
The monoclonal antibody 33B3.1,11 a rat IgG2a, was prepared as described elsewhere.4 The binding of monoclonal antibody to cells positive for interleukin-2 receptor and the 33B3.1-mediated inhibition of interleukin-2 binding to the high-affinity site, as well as the inhibition of interleukin-2—driven growth, have been described in detail elsewhere.11 Quality control corresponding to the requirements of the Food and Drug Administration for the clinical use of monoclonal antibody (with respect to pyrogenicity, sterility, and purity) was carried out by the supplier (Immunotech, Marseille, France). The final product was delivered in vials containing 10 mg of pure 33B3.1 in a saline solution. Rabbit antithymocyte globulin (Thymoglobuline, Institut Mérieux, Lyon, France) was purchased commercially, and no attempt was made to minimize batch-to-batch variations in effect (13 different batches were used).
Immunosuppressive Protocols
The 50 recipients assigned to receive 33B3.1 (the monoclonal-antibody group) were treated as follows: 10 mg per day of 33B3.1 in a 100-ml saline solution was administered intravenously in a peripheral vein for 10 minutes during the first two weeks after transplantation (with the first injection given immediately after surgery); 1 mg of prednisone per kilogram of body weight and 2 mg of azathioprine per kilogram were also given. Cyclosporine was started on day 14 (at the end of monoclonal-antibody therapy) at an oral dose of 8 mg per kilogram per day and then adjusted according to the trough whole-blood cyclosporine levels measured by polyclonal radioimmunoassay three times weekly (accepted range, 300 to 600 ng of cyclosporine per milliliter). The prednisone dose was tapered weekly (by 10 mg) and then withdrawn entirely, as was azathioprine, at day 45 after surgery. After this date the patients received only cyclosporine. Patients who had rejection episodes during 33B3.1 therapy were treated with antithymocyte globulin for seven days, and 33B3.1 treatment was discontinued. Patients with acute rejection episodes were subsequently treated (after day 14) with daily intravenous infusions (pulses) of methylprednisolone (5, 5, 4, 3, and 2 mg per kilogram for five consecutive days, respectively), followed by 1 mg of prednisone per kilogram orally, which was slowly decreased (10 mg per week) and finally withdrawn.
The other 50 patients were randomly assigned to receive antithymocyte globulin. This treatment was administered intravenously over a 14-day period for 12 to 24 hours per day through a brachial arteriovenous fistula or a central-vein catheter in patients who had not yet undergone dialysis or who were undergoing long-term ambulatory peritoneal dialysis. The doses of antithymocyte globulin were begun at 1.5 mg per kilogram per day and adjusted three times weekly to keep the sheep-erythrocyte—rosette level of circulating mononucleated cells purified by Ficoll–Hypaque centrifugation below 10 percent (the doses never exceeded 2.5 mg per kilogram). After surgery (during the first two weeks and thereafter), the administration of prednisone and azathioprine was similar to that in the 33B3.1 group. Patients with rejection episodes during and after antithymocyte-globulin therapy were treated with corticosteroid pulses, as described in the preceding paragraph.
Diagnosis of Rejection and Cytomegalovirus Infection
The diagnosis of acute rejection episodes was based on the classical clinical criteria (fever, swelling and tenderness of the graft, and oliguria), an increase (≥30 percent) in the serum creatinine level with normal or subtherapeutic trough cyclosporine levels, and a normal graft appearance on ultrasonography. In addition, a biopsy of the graft was performed to confirm the diagnosis of clinical rejection during treatment (the first two weeks) and in case of a clinical pattern that was not obvious thereafter.
Cytomegalovirus infections were defined by a fourfold (or greater) increase in the IgG antibody titer, the seroconversion of a recipient who was previously negative for cytomegalovirus, the isolation of the virus from blood, urine, or bronchoalveolar-lavage fluid, or any combination of these. The serologic status of the donor and recipient was not considered in the decision to perform transplantation. Only clinically overt cytomegalovirus infections confirmed by laboratory findings were taken into account in the study. The infections were stratified according to disease severity on the basis of the classification of Peterson et al.20
Measurement of Circulating Levels of 33B3.1
Serum samples were taken serially before and after grafting (every two to three days during treatment), and aliquots were kept at –20°C until use. The trough 33B3.1 levels were measured in blood collected immediately before the injection of monoclonal antibody. The enzyme-linked immunosorbent assay (ELISA) used to measure 33B3.1 has been described in detail elsewhere.21
Measurement of Anti-33B3.1 Antibodies in the Recipients
Anti-33B3.1 antibodies (IgM and IgG) were detected by ELISA as described elsewhere.21 Anti-33B3.1-idiotype antibodies were detected by the inhibition of 33B3.1 binding to the soluble recombinant Tac chain (soluble interleukin-2 receptor, kindly provided by T-Cell-Science, Boston). In this assay, the ELISA plates were coated with monoclonal antibody 11H2 (Immunotech), another anti-P55 chain antibody directed against an epitope different from that targeted by 33B3.1. Recombinant soluble interleukin-2 receptor was added with peroxidase-linked 33B3.1 (Immunotech) in the presence or absence of serum samples from the recipient, pretreated as described below. Bound labeled 33B3.1 was identified by the addition of peroxidase substrate. In this assay, the serum samples were pretreated to avoid interference in the test with circulating soluble interleukin-2 receptor,22 which was removed by ion-exchange chromatography (diethylaminoethyl trisacryl, IBF, Villeneuve-la-Garenne, France) before testing. However, this test could not be used during treatment with 33B3.1, since 33B3.1 still present after ion exchange would have competed with the peroxidase-linked monoclonal antibody.
Immunofluorescence Flow-Cytometric Analysis
Fifty microliters of whole blood was incubated for 10 minutes at room temperature with 100 μl of the following monoclonal antibodies at saturating concentrations: anti-CD2 (T11) and anti-CD13 (MY7) (both supplied by Coultronix, Margency, France), anti-CD3 (IOT3), anti-CD4 (IOT4), anti-CD8 (IOT8), anti-CD25 (IOT 14a), and anti-CD37 (IOB1) (Immunotech). After two washings with phosphate-buffered saline, the cells were incubated for five minutes at room temperature with 50 μl of fluorescein-conjugated goat antimouse immunoglobulin (FITC-GAM, Coultronix) or 100 μl of fluorescein-conjugated goat antirat immunoglobulin (FITC-GARA, Immunotech) to detect cell-bound mouse or rat monoclonal antibodies, respectively. The cells were washed twice with phosphate-buffered saline, and the erythrocytes were lysed by incubation with Immunolyse (Coultronix). After three additional washings with phosphate-buffered saline, the cells were fixed with formol (1 percent vol/vol) and kept overnight at 4°C before testing. Flow cytometry was performed on an ATC 3000 cytofluorimeter (ODAM, Wissenbourg, France). The analysis was performed on 1000 lymphocytes selected for their forward and wide-angle light-scatter characteristics. FITC-GARA and FITC-GAM alone did not stain normal lymphocytes.
Statistical Analysis
The comparisons of the 33B3.1 and antithymocyte-globulin groups with respect to clinical tolerance, the incidence of episodes of acute rejection, and the frequency of infectious episodes were evaluated by chi-square analysis. The data from cell counts and circulating levels of 33B3.1 were compared by Student's t-test in the general case, with unequal variances and correction of degree of freedom for small numbers of cases (<20). All P values were two-tailed.
Results
Clinical Tolerance
Table 2Table 2
Clinical Tolerance to Treatment.* summarizes the findings with respect to clinical tolerance. The monoclonal antibody 33B3.1 was tolerated remarkably well as compared with antithymocyte globulin. In only one of the patients treated with 33B3.1 was the monoclonal-antibody treatment discontinued because of clinical intolerance, as compared with 68 percent of the recipients of antithymocyte globulin (P<0.001). A syndrome consisting of fever, chills, diarrhea, and renal dysfunction (with oliguria, massive proteinuria, graft tenderness, and an increase in the serum creatinine level, with a normal renal ultrasonographic scan and without urinary tract infection) led to the discontinuation of monoclonal-antibody treatment on day 7 in the one patient who had intolerance to 33B3.1. The clinical symptoms disappeared 24 hours after 33B3.1 treatment was interrupted, and renal function returned to normal 48 hours later without antirejection treatment. A biopsy was performed, but it could not be interpreted for technical reasons. Despite early mild fever in some patients (possibly due to causes other than the injection of monoclonal antibody), few other side effects were seen in this group. Table 2 shows the frequency and nature of the side effects of antithymocyte globulin. The side effects related to antithymocyte globulin (acute serum sickness in one patient, and high-grade fever with chills in two) that occurred in the patients in the 33B3.1 group who were treated with antithymocyte globulin for rescue are not shown in Table 2.Ten episodes of acute serum sickness and five of major clinical intolerance (high fever and chills) were responsible for the withdrawal of antithymocyte globulin in 32 percent of the recipients assigned to this treatment. Three patients underwent episodes of reversible transplant failure that were related to serum sickness, but there were no signs of rejection in the histologic specimens. The doses of antithymocyte globulin given according to the results of T-cell monitoring (see Methods) ranged from 0.77 to 1.4 mg per kilogram per day (1.25, 1.3, 1, and 0.77 on days, 0, 4, 8, and 13, respectively).
Laboratory Values for Blood
There was no statistical difference in the daily hemoglobin levels between treatments. Significantly lower numbers of total leukocytes (P<0.005) and platelets (P<0.005) were observed in the patients receiving antithymocyte globulin. As early as 48 hours after transplantation, a significant difference in the total number of lymphocytes was observed between the two groups, with declines of 78.4 percent and 51.5 percent in the patients treated with antithymocyte globulin and 33B3.1, respectively (P<0.01). At the end of the second week after transplantation, the lymphocyte counts returned to the values before 33B3.1 therapy, but a persistent drop (84.2 percent on day 14, P<0.001) was still noted in the recipients of antithymocyte globulin.
Significant differences in T-cell subsets were noted between treatment groups. The drops in the CD2+, CD3+, CD4+, and CD8+ cell counts were significantly larger (P<0.001) in the patients treated with antithymocyte globulin, beginning as early as day 2 and throughout the 14-day course of treatment (fewer than 5 percent of the lymphocytes remained for any of the indicated markers), than those in the patients receiving 33B3.1, whose counts returned to the pretreatment levels at the end of the course of monoclonal-antibody treatment. No significant differences in the CD37+ cell counts were found between the two groups. The CD25+ cell counts remained almost undetectable during the first 12 days of 33B3.1 treatment. The patients receiving antithymocyte globulin had somewhat higher proportions of circulating cells positive for interleukin-2 receptor (4 percent vs. <1 percent and 5 percent vs. <1 percent in the antithymocyte-globulin and 33B3.1 groups on days 6 and 12, respectively), although the differences did not reach statistical significance.
Rejection Episodes
No subacute "vascular" or hyperacute rejections occurred in either of the groups (Table 3Table 3
Incidence of Episodes of Acute Rejection.*). Rejection episodes were more frequent in the 33B3.1 group (six) than in the antithymocyte-globulin group (one) during the first two weeks after surgery, although the difference was not statistically significant. The incidence of acute rejection was not statistically different after one, two, and three months. The six rejection episodes that occurred during the two weeks of monoclonal-antibody therapy (mean [±SD] time to the diagnosis of rejection, 10±3 days) were all histologically documented ("cellular" acute rejections). They were completely reversible after the discontinuation of monoclonal-antibody treatment and during rescue treatment. The serum creatinine levels reverted to the prerejection levels in 9±5 days. However, in two cases the creatinine returned to the prerejection levels within 24 hours of the cessation of 33B3.1 treatment and before the initiation of rescue treatment, suggesting that mechanisms other than simple rejection were involved. Four of the six patients who had a rejection episode during 33B3.1 treatment and received rescue treatment with antithymocyte globulin now have functioning grafts. Only one patient in the antithymocyte-globulin group had an episode of acute rejection (on day 9) that was proved at biopsy and that was reversible. In this case, antithymocyte globulin had been discontinued on day 6 because of major clinical intolerance. Thereafter, the number of rejection episodes noted during the first three months was roughly similar in both groups (15 in the 33B3.1 group and 12 in the antithymocyte-globulin group). Only one patient in the 33B3.1 group (and none in the antithymocyte-globulin group) had a second rejection crisis (at day 80) during the first three months after transplantation.Patient and Graft Survival
Patient survival was the same in both groups (96 percent) at 12 months. There were two deaths in the 33B3.1 monoclonal-antibody group (from fulminant endocarditis with mitral-valve perforation on day 35, and from cryptococcal meningitis with a reactivation of cytomegalovirus disease on day 120) and two in the antithymocyte-globulin group (from massive gastric bleeding on day 7 and from cytomegalovirus disease with legionnaires' disease on day 210). Three grafts were functional at death (creatinine levels, 460, 400, and 300 μmol per liter). One death occurred during acute tubular necrosis on day 7. No differences in actuarial graft survival were noted: survival was 85 percent at one year in both groups.
A total of 15 grafts were lost: 7 in the monoclonal-antibody group (14 percent) and 8 in the antithymocyte-globulin group (16 percent). No graft was lost because of acute rejection in either group. Graft loss occurred in the monoclonal-antibody group because of death (in two patients), recurrent urinary fistula (two), venous thrombosis in the graft (one), a histologically proved recurrence of native glomerulonephritis (one), and an indeterminate cause (one) in a patient who was hyperimmunized (anti-T alloantibodies, 95 percent) and who received a transplant involving a positive "historical" T-cell crossmatch. A reversible episode of cellular acute rejection occurred on day 6. The patient received a cardiac graft six months after kidney transplantation because of idiopathic irreversible heart failure, and she resumed hemodialysis four months after heart transplantation, with normal cardiac-graft function. No renal biopsy was performed at that time. The causes of graft loss in the antithymocyte-globulin group were death (in two patients), graft venous thrombosis (one), arterial thrombosis in the graft (one), a possible recurrence of uremic hemolytic syndrome (one), a histologically proved recurrence of native glomerulonephritis (one), a never-functioning graft, with no symptoms of rejection on three successive renal biopsies (one), and a nephrectomy for bleeding after a core biopsy of the kidney (histologic examination showed cyclosporine-induced toxicity; serum creatinine level, 180 μmol per liter) (one).
Graft Function
Follow-up after transplantation ranged from 5 to 22 months (mean, 12±4) and 6 to 22 months (mean, 13±4) in the monoclonal-antibody and antithymocyte-globulin groups, respectively. The incidence of a need for at least one episode of dialysis in patients with acute tubular necrosis was similar in both groups (32 and 30 percent, respectively). The mean number of times patients underwent dialysis was 3±2 (range, 1 to 9) and 2±1 (range, 1 to 5) in the monoclonal-antibody and antithymocyte-globulin groups, respectively (P not significant). The mean serum creatinine levels, as well as the mean doses of cyclosporine, were not significantly different between the groups at 3, 6, and 12 months (Table 4Table 4
Mean Serum Creatinine Levels and Cyclosporine Dosages at 1, 3, 6, and 12 Months.*). The incidence of proteinuria (defined as >0.5 g of urinary protein per 24 hours) was similar in the patients treated with 33B3.1 and antithymocyte globulin (17 and 15 percent, respectively). There was no statistical difference in the incidence of high blood pressure (43 and 65 percent in the 33B3.1 and antithymocyte-globulin groups, respectively).Circulating Levels of 33B3.1
Figure 1Figure 1
Mean (±SD) Trough Levels of Circulating 33B3.1 during Treatment. shows the serum levels of 33B3.1 in the treated patients. The mean circulating levels of 33B3.1 became stable as early as day 4 (approximately 3 μg per milliliter). At that time, although no anti-33B3.1 antibodies could be detected in the recipients, large individual variations were nevertheless noted. Later, even though injections of monoclonal antibody were given daily, the mean serum 33B3.1 levels remained stable, but the standard deviations increased. When curves were drawn separately for the patients with and without an anti-33B3.1 response (as described in the next section), the two groups had significantly different mean levels on and after day 8, with a drop in the circulating levels of 33B3.1 in the immunized patients (Fig. 1). The nonimmunized recipients had increasing mean serum 33B3.1 levels (to 4 μg per milliliter on day 14).Anti-33B3.1 Immune Response of Recipients
The immunization of recipients against 33B3.1 increased with time. Forty percent of the patients had detectable anti-33B3.1 antibodies as early as days 12 to 17. At one month, 81 percent of the patients had detectable IgG and IgM antibodies against 33B3.1. The timing of the appearance of IgG and IgM antibodies was roughly similar. Antiidiotype antibodies were tested in 34 of 46 patients who had detectable antirat IgG antibodies. Because the test could not detect antiidiotype antibodies during the period of 33B3.1 infusion (see Methods), only two or three determinations were made from day 20 through day 27. All but one patient had an unambiguously positive test.
Of the six patients who had acute graft-rejection crises during 33B3.1 treatment, three were found to have anti-33B3.1 antibodies that appeared simultaneously or at a closely related time and decreases (of 93, 96, and 61 percent) in the circulating levels of 33B3.1 at the time the rejection was diagnosed. However, in two other patients, neither anti-33B3.1 antibodies nor a significant (>50 percent) drop in the level of monoclonal antibody could be detected at the time of rejection. As compared with other patients, the patients who had rejection episodes during 33B3.1 treatment produced IgG anti-33B3.1 antibodies earlier (12.7± 5.7 vs. 18.1±5.4 days, respectively).
Infections
Fewer episodes of infection were observed in the monoclonal-antibody group than in the antithymocyte-globulin group (47 vs. 72, respectively). In addition, a lower incidence of urinary tract infections was noted in the 33B3.1-treated patients (21 vs. 66 percent; P<0.001). Table 5Table 5
Number of Infectious Episodes. shows the causes of the infectious episodes. In the 33B3.1 group, eight of nine cases of cytomegalovirus disease were mild (with fever and leukopenia, without visceral involvement). Only one patient had severe reactivation of cytomegalovirus, with altered mentation, diarrhea, severe leukopenia, and thrombocytopenia. At the same time, cryptococcal meningitis was diagnosed, and the patient died (creatinine level at death, 400 μmol per liter). Four of the nine patients had primary cytomegalovirus infections, and five had reactivations of cytomegalovirus disease. In the antithymocyte-globulin group, a higher incidence (50 percent) of severe cytomegalovirus disease (three primary and two reactivated infections) with visceral involvement was observed. One patient died of legionnaires' disease and cytomegalovirus pneumonitis on day 210 (creatinine level at death, 300 μmol per liter).Discussion
The results of this study support and extend our previous preliminary data indicating that treatment with the monoclonal antibody 33B3.1 against interleukin-2 receptor, when compared with the use of only azathioprine and prednisone in historical controls,4 was effective in preventing early episodes of acute kidney-graft rejection, without important side effects. In this study we compared the results obtained with 33B3.1 in a larger, randomized group of patients with those attained with polyclonal rabbit antithymocyte globulin, a highly effective treatment in preventing early episodes of acute rejection.4 , 23
With regard to clinical tolerance, 33B3.1 was well tolerated as compared with antithymocyte globulin, and treatment was interrupted in only one case because of clinical intolerance. This was in sharp contrast to the data on antithymocyte globulin, clinical intolerance to which led to a 32 percent incidence of treatment interruption. Acute serum sickness (in 28 percent) seemed much more frequent than is usually reported, possibly as a result of the specific preparations of antithymocyte globulin used. The low incidence of side effects of 33B3.1 also suggests that this monoclonal antibody may offer an interesting alternative to the only other monoclonal antibody available for clinical use (Orthoclone OKT3). Indeed, Orthoclone OKT3, which has also been used recently for prophylactic purposes in humans,3 is associated with a high incidence of cytokine-mediated toxic syndrome.24
Although less than 3 percent of 33B3.1-labeled circulating mononuclear cells were routinely found in the patients immediately before transplantation, we observed a surprising 51 percent drop in the lymphocyte counts 48 hours after the first injection of monoclonal antibody. However, this drop was probably due to associated therapy with prednisolone. Indeed, when a double (20-mg) initial dose of 33B3.1 was given to treat ongoing episodes of acute rejection in graft recipients who had been given only cyclosporine, there was no change in the lymphocyte counts.25
The fact that less than 1 percent of the circulating lymphocytes were positive for interleukin-2 receptor during 33B3.1 treatment is no indication that cellular expansion against donor cells did not take place, at least at the graft level, since rejection crises occurred in some patients during 33B3.1 treatment without an increment in the peripheral cells positive for interleukin-2 receptor. The somewhat increased number of such cells (P not significant) in the patients treated with antithymocyte globulin may reflect some degree of lymphocyte activation by antilymphocyte serum, as has already been reported in the literature.26
The incidence of rejection episodes at three months was nearly the same in both groups (31 percent in the 33B3.1 group vs. 26 percent in the antithymocyte-globulin group). More patients rejected their grafts in the 33B3.1 group (six) than in the antithymocyte-globulin group (one) during the 14-day treatment period. This difference did not reach statistical significance; however, it probably would have done so if a larger number of patients had been studied. Although the rejection episodes during the first two weeks were treated differently (antithymocyte globulin was considered ethically preferable for the treatment of rejection episodes occurring during the evaluation of a new reagent), all of them were reversible. Four of six rejections occurring during monoclonal-antibody treatment were associated with early immunization with antirat immunoglobulin in the recipient and a variable drop in circulating levels of 33B3.1. This suggests that anti–interleukin-2–receptor monoclonal antibody might have been fully protective against rejection if it had been present at high enough concentrations in plasma. However, it is more likely that the patients who had early increases in the level of antibodies to monoclonal antibody represented a "responder" population at a higher risk of rejection and that there was no direct relation between the rejection episode and the drop in circulating levels of monoclonal antibody. This interpretation is supported by the fact that decreases in the 33B3.1 levels were concomitant with but did not precede rejection. For reasons of the test design (see Methods), the anti-33B3.1 idiotypic responses of the recipients could not be determined during monoclonal-antibody therapy, so that it was impossible to assess their presence before early episodes of rejection occurred. An early increase in levels of antiidiotype antibodies (within the first week in the immunosuppressed patients) would have been uncommon and is not suggested, since almost undetectable levels of circulating lymphocytes positive for interleukin-2 receptor were found during 33B3.1 therapy, particularly before rejection. However, because the percentage of circulating lymphocytes bearing interleukin-2 receptors has been reported to be low during rejection episodes in the patients not receiving any bioreagent,27 no definitive conclusion can be drawn.
The doses of antithymocyte globulin were adjusted to keep the levels of circulating E-rosetting lymphocytes below 10 percent. This search for the optimal doses of antithymocyte globulin could have favored the patients treated with antithymocyte globulin as compared with those treated with monoclonal antibody, since no simple predictive test to monitor 33B3.1 levels is yet available. Moreover, since the modulation of the antithymocyte-globulin dose led to the use of a much lower dose than is usually given without monitoring (60 percent less than the recommendations of the supplier at day 10), the incidence of infectious episodes may have been reduced in this group as compared with the incidence expected at the recommended doses. Furthermore, because antithymocyte globulin was withdrawn on account of clinical intolerance before day 14 in 32 percent of the recipients and cyclosporine was started earlier, these patients with high response levels may not have had a risk of graft rejection by the end of the treatment period that was equal to that in the 33B3.1-treated recipients for whom cyclosporine was introduced, except in one case, on day 15.
Similar graft function and similar actuarial survival of patients and grafts were found at all follow-up times. However, the total number of episodes of infection (particularly infections of the urinary tract) was lower in the patients treated with 33B3.1 than in those treated with antithymocyte globulin. The incidence of cytomegalovirus disease, including primary cytomegalovirus, was roughly similar in both groups. Assuming that 33B3.1 is specific for activated T lymphocytes and that cytomegalovirus contamination is mostly transmitted by donor organs, the growth of clones committed to act against cytomegalovirus should in theory be as depressed as that of any other lymphocyte similarly committed. The fact that some infectious episodes recorded in the 33B3.1 group occurred in the patients who received rescue treatment with antithymocyte globulin may have minimized the possible minor difference in the incidence of infection between the two groups.
The monitoring of total 33B3.1 levels showed that high levels of circulating monoclonal antibody were achieved by day 6. At that time, the mean serum 33B3.1 concentration (approximately 20 nM) exceeded by 30-fold the dissociation constant of 33B3.1 (<1 nM11), suggesting that in vivo interaction between interleukin-2 and interleukin-2 receptor was inhibited. However, the concentration of 33B3.1 in the graft tissue may have been lower, and the local concentration of ligand (interleukin-2) in the rejected organ concomitantly higher. All these unknown factors could have contributed to a decrease in effectiveness against interleukin-2 receptor, and they reinforce the importance of the dose delivered, as noted in the pilot study.4 In addition, soluble truncated interleukin-2 receptor bearing the epitope recognized by 33B3.122 is found in low amounts in the serum samples of normal healthy persons, and its production has been shown to be increased in allogeneic conflicts.28 This soluble receptor might thus contribute to counteracting the efficacy of 33B3.1. Unfortunately, the level of soluble interleukin-2 receptor could not be measured during 33B3.1 therapy because of competition from circulating monoclonal antibody in the assay. The monoclonal antibody 33B3.1 appeared to be strongly immunogenic: half the recipients had detectable IgG or IgM antibodies against 33B3.1 by the end of the second week of treatment. This high incidence of sensitization may argue for a shorter time for the administration of antibody (10 days, for instance), since sequential therapies (as with polyclonal or monoclonal antibodies followed by cyclosporine) have proved efficient in initial courses of 7 days.29
We conclude that induction treatment with 33B3.1 in recipients of first cadaveric renal allografts was without major clinical side effects and led to a three-month incidence of rejection episodes that was roughly similar to that observed in the patients treated with antithymocyte globulin. These results indicate that interleukin-2 receptor may be an important target for interactions on the surface of activated T lymphocytes in order to prevent the alloimmune response.
Supported by a grant from the Caisse Nationale d'Assurance Maladie.
Presented in part at the 12th International Congress of the Transplantation Society, Sydney, Australia, August 14 to 19, 1988.
We are indebted to Dr. M. Denis of the Centre Hospitalier, Nantes, for help in measuring circulating levels of 33B3.1, to F. Boeffard for excellent technical assistance, and to A. Bertho and D. Douillard for assistance in the preparation of the manuscript and the figure.
Source Information
From the Service de Néphrologie et d'immunologic Clinique, Centre Hospitalier Régional Universitaire (J.-P.S., D.C., B.L.M., M.G., M.H.), and the Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine (J.-P.S., B.L.M., M.G., N.R., Y.J.), both in Nantes; and the Immunotech et Faculté de Sciences, Luminy, Marseille (M.H.); all in France. Address reprint requests to Dr. Soulillou at the INSERM U.211, 1 rue Gaston Veil, 44035 Nantes, France.
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