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`INTERLEUKIN-2 – RECEPTOR BLOCKADE WITH DACLIZUMAB TO PREVENT REJECTION IN RENAL TRANSPLANTATION
`
`INTERLEUKIN-2–RECEPTOR BLOCKADE WITH DACLIZUMAB TO PREVENT
`ACUTE REJECTION IN RENAL TRANSPLANTATION
`
`.D.,
`, M.D., P
` B
`, M.D., G
` L
`, M.D., S
` K
`, M.D., R
` V
`F
`H
`UMGARDNER
`INNY
`IGHT
`USAN
`IRKMAN
`OBERT
`INCENTI
`LAVIO
` P
`, M.D., P
` H
`, M.D., P
`.D., J
` N
`, M.D., A
` W
`, M.D.,
`M
`ESCOVITZ
`ARK
`HILIP
`ALLORAN
`H
`OHN
`EYLAN
`LAN
`ILKINSON
`H
` E
`, M.D., P
`.D., R
` G
`, M.D., L
` B
`, M.D., P
`.D.,
`ENRIK
`KBERG
`H
`OBERT
`ASTON
`ARS
`ACKMAN
`H
` J
` B
`, M.D.,
`
` D
` T
` T
` S
` G
`*
`AND
`AMES
`URDICK
`FOR
`THE
`ACLIZUMAB
`RIPLE
`HERAPY
`TUDY
`ROUP
`
`A
`BSTRACT
`Background
`Monoclonal antibodies that block the
`high-affinity interleukin-2 receptor expressed on al-
`loantigen-reactive T lymphocytes may cause selec-
`tive immunosuppression. Daclizumab is a genetical-
`ly engineered human IgG1 monoclonal antibody that
`binds specifically to the
` chain of the interleukin-2
`a
`receptor and may thus reduce the risk of rejection af-
`ter renal transplantation.
`Methods
`We administered daclizumab (1.0 mg per
`kilogram of body weight) or placebo intravenously
`before transplantation and once every other week af-
`terward, for a total of five doses, to 260 patients re-
`ceiving first cadaveric kidney grafts and immuno-
`suppressive therapy with cyclosporine, azathioprine,
`and prednisone. The patients were followed at regu-
`lar intervals for 12 months. The primary end point
`was the incidence of biopsy-confirmed acute rejec-
`tion within six months after transplantation.
`Results
`Of the 126 patients given daclizumab, 28
`(22 percent) had biopsy-confirmed episodes of acute
`rejection, as compared with 47 of the 134 patients
`(35 percent) who received placebo (P
`0.03). Graft
`⫽
`survival at 12 months was 95 percent in the da-
`clizumab-treated patients, as compared with 90 per-
`cent in the patients given placebo (P
`0.08). The pa-
`⫽
`tients given daclizumab did not have any adverse
`reactions to the drug, and at six months, there were
`no significant differences between the two groups
`with respect to infectious complications or cancers.
`The serum half-life of daclizumab was 20 days, and
`its administration resulted in prolonged saturation of
`interleukin-2
` receptors on circulating lymphocytes.
`a
`Conclusions
`Daclizumab reduces the frequency of
`acute rejection in kidney-transplant recipients. (N Engl
`J Med 1998;338:161-5.)
`©1998, Massachusetts Medical Society.
`
`A
`
`CUTE rejection is a strong risk factor for
`chronic rejection in recipients of renal
` This fact
`grafts from cadaveric donors.
`1
`has prompted the development of new
`immunosuppressive agents designed to reduce the
`incidence and severity of acute rejection.
` All these
`2-6
`agents, however, achieve reductions in the frequency
`and severity of acute rejection at the price of gener-
`alized immunosuppression, with its attendant risks
`of opportunistic infection and cancer.
`One potential target for more specific immuno-
`suppressive therapy with monoclonal antibodies is
`
`the interleukin-2 receptor.
` The high-affinity inter-
`7
`leukin-2 receptor is composed of three noncovalent-
`ly bound chains: a 55-kd
` chain (also referred to
`a
`as CD25 or Tac), a 75-kd
` chain, and a 64-kd
`b
` chain.
` This receptor is present on nearly all acti-
`7
`g
`vated T cells but not on resting T cells. The interac-
`tion of interleukin-2 with this high-affinity receptor
`is required for the clonal expansion and continued
`viability of activated T cells. A variety of rodent
` chain
`monoclonal antibodies directed against the
`a
`of the receptor have been used in animals and
`humans to achieve selective immunosuppression by
`targeting only T-cell clones responding to the al-
`lograft.
` Daclizumab, a molecularly engineered
`8-13
`human IgG1 incorporating the antigen-binding re-
`gions of the parent murine monoclonal antibody,
`offers the potential for greater therapeutic use of in-
`terleukin-2–receptor blockade.
` We compared the
`14-17
`efficacy of daclizumab with placebo for the preven-
`tion of acute rejection in renal-transplant recipients.
`METHODS
`
`Study Design
`We performed a randomized, double-blind, placebo-controlled
`trial at 11 transplantation centers in the United States, 3 in Can-
`ada, and 3 in Sweden. Adults receiving first renal allografts from
`cadaveric donors were eligible for the study. Patients were exclud-
`ed if they were receiving multiple organ transplants or had a pos-
`itive crossmatch for T-cell lymphocytes. The protocol was ap-
`proved by the institutional review board or ethics committee at
`each participating center, and all patients gave written informed
`consent.
`
`Immunosuppressive Treatment
`All patients received cyclosporine, azathioprine, and predni-
`sone. The first dose of cyclosporine was given during the period
`from 12 hours before to 24 hours after transplantation.
`Daclizumab (Zenapax, Hoffmann–LaRoche) or placebo was
`
`From the University of California, San Francisco (F.V.); Brigham and
`Women’s Hospital, Boston (R.K.); Hoffmann–LaRoche, Nutley, N.J.
`(S.L.); Ohio State University, Columbus (G.B.); Indiana University, Indi-
`anapolis (M.P.); the University of Alberta, Edmonton, Alta., Canada
`(P.H.); Emory University, Atlanta (J.N.); the University of California, Los
`Angeles (A.W.); Malmö University Hospital, Malmö, Sweden (H.E.); the
`University of Alabama, Birmingham (R.G.); Sahlgrenska Hospital, Goth-
`enburg, Sweden (L.B.); and Johns Hopkins University, Baltimore (J.B.).
`Address reprint requests to Dr. Vincenti at the Transplant Service, Univer-
`sity of California, San Francisco, 505 Parnassus Ave., Rm. M884, Box
`0116, San Francisco, CA 94143-0116.
`*Other members of the Daclizumab Triple Therapy Study Group are
`listed in the Appendix.
`
`Volume 338 Number 3
`
`ⴢ
`
`161
`
`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on April 24, 2015. For personal use only. No other uses without permission.
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`1 of 5
`
`BI Exhibit 1038
`
`

`

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`
`The New England Journal of Medicine
`
`administered intravenously over a period of 15 minutes. Each pa-
`tient received five doses of either daclizumab (1 mg per kilogram
`of body weight, to a maximum of 100 mg per dose) or placebo
`(0.2 mg of polysorbate 80 per milliliter in 67 mM phosphate
`buffer). The first dose was administered within 24 hours before
`transplantation, with subsequent doses given two, four, six, and
`eight weeks after transplantation.
`
`Primary and Secondary End Points
`The primary end point of the study was the incidence of biop-
`sy-confirmed acute rejection within the first six months after
`transplantation. All patients with an unexplained rise in the serum
`creatinine concentration or one or more symptoms of acute re-
`jection (fever, pain over the graft, or a decrease in urinary volume)
`were required to undergo a renal biopsy within 24 hours after the
`initiation of antirejection therapy, which consisted initially of in-
`travenous methylprednisolone (7 mg per kilogram per day) for
`three days. The histologic diagnosis of rejection was based on the
`presence of acute tubulitis or vasculitis and was made by the pa-
`thologist at each institution. Patients were considered to have
`presumptive rejection if they received a course of antirejection
`therapy in the absence of histologic confirmation of rejection.
`The diagnosis of any subsequent episodes of rejection in patients
`presenting with renal dysfunction was based on clinical criteria,
`such as the absence of evidence of nephrotoxicity or of urinary
`tract obstruction or infection, with a biopsy for confirmation per-
`formed at the investigator’s discretion.
`Secondary end points included patient survival and graft sur-
`vival at one year, the time to the first episode of acute rejection,
`the number of acute rejection episodes per patient, the need for
`antilymphocyte therapy (OKT3 or polyclonal antithymocyte glob-
`ulin) because of glucocorticoid-resistant rejection (defined as the
`absence of a response to intravenous methylprednisolone pulse
`therapy), graft function (as indicated by the serum creatinine con-
`centration and glomerular filtration rate), and the cumulative
`dose of prednisone in the first six months after transplantation.
`
`Pharmacokinetic Measurements
`Blood samples were collected immediately before and after (for
`trough and peak concentrations, respectively) the first and fifth
`infusions of daclizumab or placebo and on days 70 and 84 after
`transplantation. A sandwich enzyme-linked immunosorbent assay
`was used to measure daclizumab in serum.
`18
`In 20 consecutive patients at one U.S. center (University of
`California, San Francisco), lymphocyte analysis was performed to
`determine the saturation of the interleukin-2–receptor
` chain,
`a
`with the use of methods reported previously.
`17
`
`Glomerular Filtration Rate
`The glomerular filtration rate was measured in all patients with
`functioning grafts six months after transplantation. Measure-
`ments were based on iohexol, radioisotope, or inulin clearance.
`
`Statistical Analysis
`Differences in categorical variables between the two groups
`were determined with the use of the Mantel–Haenszel test (with
`stratification according to center). Differences in the time to the
`first biopsy-confirmed episode of rejection were determined with
`the use of the log-rank test (with stratification according to cen-
`ter). The log-rank test was also used to analyze the time to graft
`failure (or death with a functioning graft) because of the small
`number of events reported. Kaplan–Meier estimates of the prob-
`ability of patient survival and graft survival and the cumulative
`probability of biopsy-confirmed rejection were plotted over time.
`Differences in the number of presumptive or biopsy-confirmed
`rejection episodes per patient in the first six months were ana-
`lyzed with a normal regression model. The serum creatinine con-
`centrations, glomerular filtration rates, and cumulative doses of
`prednisone administered during the first six months after trans-
`
`162
`
`ⴢ
`
`Januar y 15, 1998
`
`plantation in the two groups were compared with the use of the
`Wilcoxon rank-sum test. Logistic-regression analysis was used to
`determine the effects of various factors on the probability of bi-
`opsy-confirmed rejection. Proportional-hazards analysis was used
`to determine the effects of various factors on the time to biopsy-
`confirmed rejection. The results of lymphocyte and interleukin-
`2–receptor assays were compared with the use of Student’s t-test.
`All statistical tests were two-sided.
`All patients randomly assigned to a treatment group were in-
`cluded in the primary analyses of efficacy and safety, according to
`the intention-to-treat principle. Values are reported as means
`SD.
`⫾
`RESULTS
`A total of 260 patients were enrolled in the study:
`134 patients were assigned to the placebo group,
`and 126 to the daclizumab group. The two groups
`were similar with respect to age, sex, race, cause of
`end-stage renal disease, presence or absence of pan-
`el-reactive anti-HLA antibodies, number of HLA-
`DR mismatches between donor and recipient, and
`duration of cold ischemia for the graft (Table 1).
`All patients received at least one dose of the study
`drug, and 107 of the patients in the placebo group
`(80 percent) and 107 of those in the daclizumab
`group (85 percent) received all five doses. Graft
`function was delayed in 39 patients in the placebo
`group (29 percent) and 27 patients in the daclizu-
`mab group (21 percent). The early use of prophy-
`lactic antilymphocyte therapy for delayed graft func-
`tion led to the discontinuation of the study drug in
`nine patients in the placebo group (7 percent) and
`nine in the daclizumab group (7 percent).
`
`Efficacy
`Daclizumab prophylaxis resulted in a significant
`reduction in the incidence of biopsy-documented
`acute rejection during the first six months after
`transplantation (22 percent, vs. 35 percent in the
`placebo group; P
`0.03; odds ratio, 0.5; 95 percent
`⫽
`confidence interval, 0.3 to 0.9) (Table 2). The pro-
`portion of patients with presumptive or biopsy-con-
`firmed acute rejection and the number of rejection
`episodes per patient were also lower in the daclizu-
`mab group, and the time to the first rejection was
`longer. There was a trend toward a reduction in the
`number of patients with two or more rejection epi-
`sodes and the number receiving antilymphocyte prep-
`arations for severe rejection in the daclizumab group.
`The beneficial effect of daclizumab was not influ-
`enced by delayed graft function, initial use of other
`antilymphocyte therapies, or exclusion of patients
`who did not receive all five infusions of the study
`drug (data not shown).
`The patient-survival rates at one year were 98 per-
`cent in the daclizumab group and 96 percent in the
`placebo group (Table 3). The graft-survival rates in
`the daclizumab and placebo groups were 95 and 90
`percent, respectively. None of the patients in the da-
`clizumab group but three of those in the placebo
`group died of infections: one each of aspergillosis,
`
`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on April 24, 2015. For personal use only. No other uses without permission.
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`2 of 5
`
`BI Exhibit 1038
`
`

`

`INTERLEUKIN-2 – RECEPTOR BLOCKADE WITH DACLIZUMAB TO PREVENT REJECTION IN RENAL TRANSPLANTATION
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`T
`
` 1.
`ABLE
`
`B
`-L
`ASE
`INE
`
` C
`
`HARACTERISTICS
`R
`.*
`ECIPIENTS
`
` R
`-A
`
`OF
`ENAL
`LLOGRAFT
`
`TABLE 3. CAUSES OF DEATH AND RENAL-GRAFT
`FAILURE AT ONE YEAR IN THE PLACEBO
`AND DACLIZUMAB GROUPS.
`
`CAUSE
`
`PLACEBO
`(Nⴝ134)
`
`DACLIZUMAB
`(Nⴝ126)
`
`no. of patients (%)
`
`Death
`Infection or lymphoma
`Cardiovascular cause
`Pulmonary embolism
`Intracerebral bleeding
`Suicide
`Graft failure
`Death
`Rejection
`Technical cause
`Primary nonfunction
`
`5 (4)
`3 (2)
`1 (1)
`1 (1)
`0
`0
`13 (10)
`5 (4)
`3 (2)
`4 (3)
`1 (1)
`
`3 (2)
`1 (1)
`0
`0
`1 (1)
`1 (1)
`6 (5)
`3 (2)
`1 (1)
`2 (2)
`0
`
`coccidioidomycosis, and pseudomonas sepsis. One
`patient in the daclizumab group died of lymphoma.
`The mean serum creatinine concentrations six
`months after transplantation were the same in the
`two groups (1.7
`0.7 mg per deciliter [150
`60
`mol
`⫾
`⫾
`m
`per liter]). The mean glomerular filtration rate was
`23 ml per minute in the daclizumab group and
`55
`⫾
`52
`22 ml per minute in the placebo group. The av-
`⫾
`erage daily doses of prednisone and cyclosporine did
`not differ between the groups at any time during the
`study, nor was there a difference in the mean trough
`whole-blood cyclosporine concentrations at any time.
`
`Adverse Events
`The administration of daclizumab was not associ-
`ated with any immediate side effects. There was no
`significant difference in reported adverse events be-
`tween the two groups (Table 4). One patient in the
`placebo group and two patients in the daclizumab
`group had lymphoma during the first year after
`transplantation.
`
`Pharmacokinetic Data
`Pharmacokinetic data were available for 92 pa-
`tients in the daclizumab group. The mean serum
`half-life of daclizumab was 20 days.
`
`Circulating Peripheral-Blood Lymphocytes
`and Interleukin-2 a
`-Chain Receptor
`There were no differences in absolute lymphocyte
`numbers between the placebo and daclizumab groups
`before transplantation or for six months afterward.
`Circulating CD3
` cell concentrations and T-cell sub-
`⫹
`groups were not measured, because they were not
`affected by daclizumab therapy in an earlier study.
`17
`There was a significant decrease in the percentage
`of circulating lymphocytes that stained with anti-
`
`Volume 338 Number 3
`
`ⴢ
`
`163
`
`C
`HARACTERISTIC
`
`P
`LACEBO
`(N
`134)
`ⴝ
`
`D
`ACLIZUMAB
`(N
`126)
`ⴝ
`
`47
`⫾
`
`13
`
`81 (60)
`53 (40)
`
`81 (60)
`27 (20)
`26 (19)
`
`40 (30)
`29 (22)
`20 (15)
`19 (14)
`26 (19)
`
`47
`13
`⫾
`
`74 (59)
`52 (41)
`
`84 (67)
`24 (19)
`18 (14)
`
`33 (26)
`32 (25)
`24 (19)
`18 (14)
`19 (15)
`
`121 (90)
`10 (7)
`3 (2)
`
`113 (89)
`12 (10)
`1 (1)
`
`22 (16)
`62 (46)
`40 (30)
`21
`9
`⫾
`
`19 (15)
`49 (39)
`50 (40)
`22
`8
`⫾
`
`Age — yr
`Sex — no. of patients (%)
`Male
`Female
`Race or ethnic group —
`no. of patients (%)
`White
`Black
`Other
`Cause of renal failure —
`no. of patients (%)
`Glomerulonephritis
`Diabetes mellitus
`Hereditary or polycystic kidney disease
`Hypertension
`Other
`Panel-reactive serum antibodies —
`no. of patients (%)†
`0–10%
`11–49%
`50–100%
`No. of HLA-DR mismatches —
`no. of patients (%)‡
`
`012
`
`Graft cold-ischemia time — hr
`
`⫾
`
`SD. Percentages may not sum to 100
`
`*Plus–minus values are means
`because of rounding.
`†Panel-reactive antibodies are anti-HLA antibodies that have a cytotoxic
`effect on lymphocytes obtained from a panel of donors from the general
`population.
`‡Data were missing for some patients.
`
`T
`
` 2.
` M
` F
`
` E
`A
` R
`
` S
`
`ABLE
`IX
`THE
`IN
`EJECTION
`CUTE
`PISODES
`IRST
`ONTHS
` R
` T
`
`
` P
`AFTER
`ENAL
`RANSPLANTATION
`IN
`THE
`LACEBO
` D
` G
`.
`AND
`ACLIZUMAB
`ROUPS
`
`REJECTION
`
`One or more biopsy-confirmed
`episodes — no. of patients (%)
`One or more biopsy-confirmed or
`presumptive episodes — no. of
`patients (%)
`Two or more biopsy-confirmed or
`presumptive episodes — no. of
`patients (%)
`Mean no. of episodes/patient
`Time to first episode — days*
`Episode requiring antilymphocyte
`therapy — no. of patients (%)†
`
`PLACEBO
`(Nⴝ134)
`
`DACLIZUMAB
`(Nⴝ126)
`
`P VALUE
`
`47 (35)
`
`28 (22)
`
`52 (39)
`
`32 (25)
`
`0.03
`
`0.04
`
`18 (13)
`
`9 (7)
`
`0.08
`
`0.6
`30⫾27
`19 (14)
`
`0.3
`73⫾59
`10 (8)
`
`0.01
`0.008
`0.09
`
`*Plus–minus values are means
`SD.
`⫾
`†Antilymphocyte therapy consisted of OKT3 or polyclonal antithy-
`mocyte globulin.
`
`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on April 24, 2015. For personal use only. No other uses without permission.
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`3 of 5
`
`BI Exhibit 1038
`
`

`

`The New England Journal of Medicine
`
`TABLE 4. ADVERSE EVENTS AT SIX MONTHS
`IN THE PLACEBO AND DACLIZUMAB GROUPS.
`
`ADVERSE EVENTS
`
`Serious event*
`Fever
`Sepsis and bacteremia
`Pneumonia
`Fungal infection
`Fungemia
`Local infection
`Local infection†
`Cellulitis and wound
`infection
`Urinary tract infection
`Other
`Any viral infection†
`Viremia
`Local infection
`Cytomegalovirus
`infection
`Viremia
`Tissue infection
`
`PLACEBO
`(Nⴝ134)
`
`DACLIZUMAB
`(Nⴝ126)
`
`no. of patients (%)
`
`13 (10)
`16 (12)
`9 (7)
`4 (3)
`27 (20)
`2 (1)
`25 (19)
`70 (52)
`4 (3)
`
`44 (33)
`38 (28)
`32 (24)
`12 (9)
`21 (16)
`14 (10)
`
`10 (7)
`4 (3)
`
`6 (5)
`11 (9)
`4 (3)
`3 (2)
`21 (17)
`0
`21 (17)
`59 (47)
`7 (6)
`
`34 (27)
`36 (29)
`29 (23)
`12 (10)
`20 (16)
`15 (12)
`
`12 (10)
`3 (2)
`
`*Serious adverse events were defined as complications
`other than death or rejection that prolonged or required
`hospitalization and were possibly or probably related to the
`study drug.
`†Some patients had more than one type of infection.
`
`CD25 antibody starting 10 hours after transplanta-
`tion and lasting up to four months in the daclizu-
`mab group (data not shown). Similarly, there was a
`significant decrease in the percentage of circulating
`lymphocytes that stained with the fluorescein-conju-
`gated antibody 7g7, which binds to an interleukin-2
`a-chain–receptor epitope distinct from the epitope
`recognized by daclizumab and reflects total interleu-
`kin-2a–receptor expression (data not shown).
`DISCUSSION
`We found that the patients receiving daclizumab
`in addition to maintenance therapy with three im-
`munosuppressive agents had a lower frequency of
`biopsy-confirmed acute rejection in the first six
`months after transplantation than the patients re-
`ceiving placebo with the three immunosuppressive
`agents. In addition, the time to the first episode of
`acute rejection was significantly prolonged, and the
`mean number of episodes per patient significantly
`reduced in the daclizumab group. These results were
`obtained without a concomitant increase in infec-
`tious complications or cancers. The efficacy of da-
`clizumab is probably related to its selective target,
`the a-chain component of the high-affinity interleu-
`kin-2 receptor, which is present almost exclusively
`
`164 ⴢ
`
`Januar y 15, 1998
`
`on activated T cells. Use of the drug thus spares oth-
`er immunocompetent cells.7
`Only 10 percent of daclizumab is composed of
`murine sequences, which are from the antigen-bind-
`ing regions of the parent antibody. These sequences
`are inserted into human immunoglobulin with the
`use of molecular biologic techniques.14 Our study
`highlights the advantages of this type of antibody,
`including its prolonged serum half-life, approaching
`that of human IgG, and the absence of functional
`immunogenicity associated with its use.15,16,19,20
`The exact mechanism or mechanisms of action of
`daclizumab are not known. A likely mechanism is that
`it binds to circulating lymphocytes with interleukin-2
`a-chain receptors but does not activate the receptors,
`and the cells therefore have no free interleukin-2
`a-chain receptors available for activation by interleu-
`kin-2. In addition, the decline in the percentage of
`circulating lymphocytes expressing CD25 (measured
`by staining with 7g7 antibody) without an accompa-
`nying decrease in the absolute number of lympho-
`cytes suggests that the expression of interleukin-2 re-
`ceptors is down-regulated or the shedding of the
`daclizumab-bound interleukin-2 a chain is increased.
`In conclusion, when added to therapy with cyclo-
`sporine, azathioprine, and prednisone, daclizumab
`reduces the frequency of acute rejection and im-
`proves short-term graft survival in renal-transplant
`recipients.
`
`Supported by a grant from Hoffmann–LaRoche.
`
`We are indebted to Dr. Thomas A. Waldmann for his contribu-
`tion to the development of daclizumab, and to Ms. Peggy Millar for
`her assistance in the preparation of the manuscript.
`APPENDIX
`In addition to the authors, the following investigators participated in the
`Daclizumab Triple Therapy Study Group: Victoria General Hospital, Hali-
`fax, N.S., Canada — B. Kibert; Huddinge Hospital, Huddinge, Sweden —
`G. Tyden; University of Minnesota, Minneapolis — A. Matas; Beth Israel
`Deaconess Medical Center, Boston — M. Shapiro; Tampa General Hospital,
`Tampa, Fla. — G. Chan; Vancouver General Hospital, Vancouver, B.C.,
`Canada — P. Keown; University of California, San Francisco — M. Lantz;
`University of Alberta, Edmonton, Alta., Canada — K. Solez; and Hoff-
`mann–LaRoche, Nutley, N.J. — A. Lin, I. Patel, K. Nieforth, A. Wolitzky,
`and J. Hakimi.
`
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`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on April 24, 2015. For personal use only. No other uses without permission.
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
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`INTERLEUKIN-2 – RECEPTOR BLOCKADE WITH DACLIZUMAB TO PREVENT REJECTION IN RENAL TRANSPLANTATION
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`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on April 24, 2015. For personal use only. No other uses without permission.
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
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