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Previous Volume 338:161-165 January 15, 1998 Number 3 Next

Abstract PDF Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited Related Article by Abramowicz, D. PubMed Citation

ABSTRACT

Background Monoclonal antibodies that block the high-affinity interleukin-2 receptor expressed on alloantigen-reactive T lymphocytes may cause selective immunosuppression. Daclizumab is a genetically engineered human IgG1 monoclonal antibody that binds specifically to the chain of the interleukin-2 receptor and may thus reduce the risk of rejection after renal transplantation.

Methods We administered daclizumab (1.0 mg per kilogram of body weight) or placebo intravenously before transplantation and once every other week afterward, for a total of five doses, to 260 patients receiving first cadaveric kidney grafts and immunosuppressive therapy with cyclosporine, azathioprine, and prednisone. The patients were followed at regular intervals for 12 months. The primary end point was the incidence of biopsy-confirmed acute rejection 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 daclizumab-treated patients, as compared with 90 percent in the patients given placebo (P = 0.08). The patients 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.

Conclusions Daclizumab reduces the frequency of acute rejection in kidney-transplant recipients.

One potential target for more specific immunosuppressive therapy with monoclonal antibodies is the interleukin-2 receptor.⁷ The high-affinity interleukin-2 receptor is composed of three noncovalently bound chains: a 55-kd chain (also referred to as CD25 or Tac), a 75-kd chain, and a 64-kd chain.⁷ This receptor is present on nearly all activated T cells but not on resting T cells. The interaction 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 monoclonal antibodies directed against the chain of the receptor have been used in animals and humans to achieve selective immunosuppression by targeting only T-cell clones responding to the allograft.^{8,9,10,11,12,13} Daclizumab, a molecularly engineered human IgG1 incorporating the antigen-binding regions of the parent murine monoclonal antibody, offers the potential for greater therapeutic use of interleukin-2–receptor blockade.^14,15,16,17 We compared the efficacy of daclizumab with placebo for the prevention 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 Canada, and 3 in Sweden. Adults receiving first renal allografts from cadaveric donors were eligible for the study. Patients were excluded if they were receiving multiple organ transplants or had a positive crossmatch for T-cell lymphocytes. The protocol was approved 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 prednisone. 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 administered intravenously over a period of 15 minutes. Each patient 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 biopsy-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 rejection (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 intravenous 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 pathologist 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 performed at the investigator's discretion.

Secondary end points included patient survival and graft survival 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 globulin) 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 concentration 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, 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. Measurements 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 center). 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 probability 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 analyzed with a normal regression model. The serum creatinine concentrations, glomerular filtration rates, and cumulative doses of prednisone administered during the first six months after transplantation 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 biopsy-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 included 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 panel-reactive anti-HLA antibodies, number of HLA-DR mismatches between donor and recipient, and duration of cold ischemia for the graft (Table 1).

View this table: [in this window] [in a new window]   Table 1. Base-Line Characteristics of Renal-Allograft Recipients.

 
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 daclizumab group (21 percent). The early use of prophylactic antilymphocyte therapy for delayed graft function 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 proportion of patients with presumptive or biopsy-confirmed acute rejection and the number of rejection episodes per patient were also lower in the daclizumab 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 episodes and the number receiving antilymphocyte preparations for severe rejection in the daclizumab group. The beneficial effect of daclizumab was not influenced 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).

View this table: [in this window] [in a new window]   Table 2. Acute Rejection Episodes in the First Six Months after Renal Transplantation in the Placebo and Daclizumab Groups.

 
The patient-survival rates at one year were 98 percent 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 daclizumab group but three of those in the placebo group died of infections: one each of aspergillosis, coccidioidomycosis, and pseudomonas sepsis. One patient in the daclizumab group died of lymphoma.

View this table: [in this window] [in a new window]   Table 3. Causes of Death and Renal-Graft Failure at One Year in the Placebo and Daclizumab Groups.

 
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 µmol per liter]). The mean glomerular filtration rate was 55±23 ml per minute in the daclizumab group and 52±22 ml per minute in the placebo group. The average 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 associated with any immediate side effects. There was no significant difference in reported adverse events between 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.

View this table: [in this window] [in a new window]   Table 4. Adverse Events at Six Months in the Placebo and Daclizumab Groups.

 
Pharmacokinetic Data

Pharmacokinetic data were available for 92 patients in the daclizumab group. The mean serum half-life of daclizumab was 20 days.

Circulating Peripheral-Blood Lymphocytes and Interleukin-2 -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 subgroups 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-CD25 antibody starting 10 hours after transplantation and lasting up to four months in the daclizumab group (data not shown). Similarly, there was a significant decrease in the percentage of circulating lymphocytes that stained with the fluorescein-conjugated antibody 7g7, which binds to an interleukin-2 -chain–receptor epitope distinct from the epitope recognized by daclizumab and reflects total interleukin-2–receptor expression (data not shown).

Discussion

We found that the patients receiving daclizumab in addition to maintenance therapy with three immunosuppressive agents had a lower frequency of biopsy-confirmed acute rejection in the first six months after transplantation than the patients receiving 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 infectious complications or cancers. The efficacy of daclizumab is probably related to its selective target, the -chain component of the high-affinity interleukin-2 receptor, which is present almost exclusively on activated T cells. Use of the drug thus spares other immunocompetent cells.⁷

Only 10 percent of daclizumab is composed of murine sequences, which are from the antigen-binding 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 -chain receptors but does not activate the receptors, and the cells therefore have no free interleukin-2 -chain receptors available for activation by interleukin-2. In addition, the decline in the percentage of circulating lymphocytes expressing CD25 (measured by staining with 7g7 antibody) without an accompanying decrease in the absolute number of lymphocytes suggests that the expression of interleukin-2 receptors is down-regulated or the shedding of the daclizumab-bound interleukin-2 chain is increased.

In conclusion, when added to therapy with cyclosporine, azathioprine, and prednisone, daclizumab reduces the frequency of acute rejection and improves 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 contribution to the development of daclizumab, and to Ms. Peggy Millar for her assistance in the preparation of the manuscript.

^* Other members of the Daclizumab Triple Therapy Study Group are listed in the Appendix.

Source Information

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, Indianapolis (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, Gothenburg, Sweden (L.B.); and Johns Hopkins University, Baltimore (J.B.).

Address reprint requests to Dr. Vincenti at the Transplant Service, University of California, San Francisco, 505 Parnassus Ave., Rm. M884, Box 0116, San Francisco, CA 94143-0116.

References

1. Ferguson R. Acute rejection episodes -- best predictor of long-term primary cadaveric renal transplant survival. Clin Transplant 1994;8:328-331. [Medline]
2. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995;60:225-232. [Medline]
3. Vincenti F, Laskow DA, Neylan JF, Mendez R, Matas AJ. One-year follow-up from an open-label trial of FK506 in primary kidney transplantation: a report of the U.S. Multicenter FK506 Kidney Transplantation Group. Transplantation 1996;61:1576-1581. [CrossRef][Medline]
4. Morris RE. Mechanisms of action of new immunosuppressive drugs. Kidney Int Suppl 1996;53:S-26. 
5. Kahan BD. Sirolimus: a new agent for clinical renal transplantation. Transplant Proc 1997;29:48-50. [CrossRef][Medline]
6. Gruber SA, Chan GLC, Canafax DM, Matas AJ. Immunosuppression in renal transplantation. II. Corticosteroids, antilymphocyte globulin, and OKT3. Clin Transplant 1991;5:219-232.
7. Taniguchi T, Minami Y. The IL-2/IL-2 receptor system: a current overview. Cell 1993;73:5-8. [CrossRef][Medline]
8. Kupiec-Weglinski JW, Diamantstein T, Tilney NL, Strom TB. Therapy with monoclonal antibody to interleukin 2 receptor spares suppressorT cells and prevents or reverses acute allograft rejection in rats. Proc Natl Acad Sci U S A 1986;83:2624-2627. [Free Full Text]
9. Reed MH, Shapiro ME, Strom TB, et al. Prolongation of primate renal allograft survival by anti-Tac, an anti-human IL-2 receptor monoclonal antibody. Transplantation 1989;47:55-59. [Medline]
10. Soulillou J-P, Cantarovich D, Le Mauff B, et al. Randomized controlled trial of a monoclonal antibody against the interleukin-2 receptor (33B3.1) as compared with rabbit antithymocyte globulin for prophy-laxis against rejection of renal allografts. N Engl J Med 1990;322:1175-1182. [Abstract]
11. Kirkman RL, Shapiro ME, Carpenter CB, et al. A randomized prospective trial of anti-Tac monoclonal antibody in human renal transplantation. Transplantation 1991;51:107-113. [Medline]
12. van Gelder T, Zietse R, Mulder AH, et al. A double-blind, placebo-controlled study of monoclonal anti-interleukin-2 receptor antibody (BT563) administration to prevent acute rejection after kidney transplantation. Transplantation 1995;60:248-252. [Medline]
13. Reding R, Vraux H, de Ville de Goyet J, et al. Monoclonal antibodies in prophylactic immunosuppression after liver transplantation: a randomized controlled trial comparing OKT3 and anti-IL-2 receptor monoclonal antibody LO-Tact-1. Transplantation 1993;55:534-541. [Medline]
14. Queen C, Schneider WP, Selick HE, et al. A humanized antibody that binds to the interleukin 2 receptor. Proc Natl Acad Sci U S A 1989;86:10029-10033. [Free Full Text]
15. Hakimi J, Mould D, Waldmann TA, Queen C, Anasetti C, Light S. Development of Zenapax: a humanized anti-Tac antibody. In: Harris WJ, Adair JR, eds. Antibody therapeutics. New York: CRC Press, 1997:277-300.
16. Hakimi J, Chizzonite R, Luke DR, et al. Reduced immunogenicity and improved pharmacokinetics of humanized anti-Tac in cynomolgus monkeys. J Immunol 1991;147:1352-1359. [Abstract]
17. Vincenti F, Lantz M, Birnbaum J, et al. A phase I trial of humanized anti-interleukin 2 receptor antibody in renal transplant recipients. Transplantation 1997;63:33-38. [CrossRef][Medline]
18. Fayer BE, Soni PP, Binger MH, Mould DR, Satoh H. Determination of humanized anti-Tac in human serum by a sandwich enzyme linked immunosorbent assay. J Immunol Methods 1995;186:47-54. [Medline]
19. Brown PS Jr, Parenteau GL, Dirbas FM, et al. Anti-Tac-H, a humanized antibody to the interleukin 2 receptor, prolongs primate cardiac allograft survival. Proc Natl Acad Sci U S A 1991;88:2663-2667. [Free Full Text]
20. Anasetti C, Hansen JA, Waldmann TA, et al. Treatment of acute graft-versus-host disease with humanized anti-Tac: an antibody that binds to the interleukin-2 receptor. Blood 1994;84:1320-1327. [Free Full Text]

In addition to the authors, the following investigators participated in the Daclizumab Triple Therapy Study Group: Victoria General Hospital, Halifax, 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 Hoffmann–LaRoche, Nutley, N.J. — A. Lin, I. Patel, K. Nieforth, A. Wolitzky, and J. Hakimi.

Abstract PDF Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited Related Article by Abramowicz, D. PubMed Citation

Related Letters:

Daclizumab to Prevent Acute Rejection in Renal Transplantation
Abramowicz D., Vincenti F., The Daclizumab Triple Therapy Study Group
Extract | Full Text  
N Engl J Med 1998; 338:1700-1701, Jun 4, 1998. Correspondence

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• Pascual, J., Marcen, R., , J. O. (2001). Anti-interleukin-2 receptor antibodies: basiliximab and daclizumab. Nephrol Dial Transplant 16: 1756-1760 [Full Text]  
• Ryan, E. A., Lakey, J. R.T., Rajotte, R. V., Korbutt, G. S., Kin, T., Imes, S., Rabinovitch, A., Elliott, J. F., Bigam, D., Kneteman, N. M., Warnock, G. L., Larsen, I., Shapiro, A.M. J. (2001). Clinical Outcomes and Insulin Secretion After Islet Transplantation With the Edmonton Protocol. Diabetes 50: 710-719 [Abstract] [Full Text]  
• Phillips, K. E., Herring, B., Wilson, L. A., Rickford, M. S., Zhang, M., Goldman, C. K., Tso, J. Y., Waldmann, T. A. (2000). IL-2R{{alpha}}-Directed Monoclonal Antibodies Provide Effective Therapy in a Murine Model of Adult T-Cell Leukemia by a Mechanism other than Blockade of IL-2/IL-2R{{alpha}} Interaction. Cancer Res. 60: 6977-6984 [Abstract] [Full Text]  
• Morris, J. C, Waldmann, T. A (2000). Advances in interleukin 2 receptor targeted treatment. Ann Rheum Dis 59: i109-114 [Abstract] [Full Text]  
• Cantarovich, D., Giral-Classe, M., Hourmant, M., Dantal, J., Blancho, G., Lerat, L., Moreau, A., Soulillou, J.-P. (2000). Prevention of acute rejection with antithymocyte globulin, avoiding corticosteroids, and delaying cyclosporin after renal transplantation. Nephrol Dial Transplant 15: 1673-1676 [Abstract] [Full Text]  
• Whitcup, S. M. (2000). The Double-Edged Ocular Immune Response: The Cogan Lecture. IOVS 41: 3243-3248 [Full Text]  
• TRAN, H. T. B., ACHARYA, M. K., MCKAY, D. B., SAYEGH, M. H., CARPENTER, C. B., AUCHINCLOSS, H. JR., KIRKMAN, R. L., MILFORD, E. L. (2000). Avoidance of Cyclosporine in Renal Transplantation: Effects of Daclizumab, Mycophenolate Mofetil, and Steroids. J. Am. Soc. Nephrol. 11: 1903-1909 [Abstract] [Full Text]  
• Smith, X. G., Bolton, E. M., Ruchatz, H., Wei, X.-q., Liew, F. Y., Bradley, J. A. (2000). Selective Blockade of IL-15 by Soluble IL-15 Receptor {alpha}-Chain Enhances Cardiac Allograft Survival. J. Immunol. 165: 3444-3450 [Abstract] [Full Text]  
• Ponticelli, C. (2000). Calcineurin-inhibitors in renal transplantation. Too precious to be abandoned. Nephrol Dial Transplant 15: 1307-1309 [Full Text]  
• Shapiro, A.M. J., Lakey, J. R.T., Ryan, E. A., Korbutt, G. S., Toth, E., Warnock, G. L., Kneteman, N. M., Rajotte, R. V. (2000). Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen. NEJM 343: 230-238 [Abstract] [Full Text]  
• O'CONNOR, T.M., O'HALLORAN, D.J., SHANAHAN, F. (2000). The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia. QJM 93: 323-333 [Abstract] [Full Text]  
• Sharma, A., Davis, C. B., Tobia, L. A. P., Kwok, D. C., Tucci, M. G., Gore, E. R., Herzyk, D. J., Hart, T. K. (2000). Comparative Pharmacodynamics of Keliximab and Clenoliximab in Transgenic Mice Bearing Human CD4. J. Pharmacol. Exp. Ther. 293: 33-41 [Abstract] [Full Text]  
• Beniaminovitz, A., Itescu, S., Lietz, K., Donovan, M., Burke, E. M., Groff, B. D., Edwards, N., Mancini, D. M. (2000). Prevention of Rejection in Cardiac Transplantation by Blockade of the Interleukin-2 Receptor with a Monoclonal Antibody. NEJM 342: 613-619 [Abstract] [Full Text]  
• Carpenter, C. B. (2000). Improving the Success of Organ Transplantation. NEJM 342: 647-648 [Full Text]  
• Waldmann, T. A., Levy, R., Coller, B. S. (2000). Emerging Therapies: Spectrum of Applications of Monoclonal Antibody Therapy. ASH Education Book 2000: 394-408 [Abstract] [Full Text]  
• Przepiorka, D., Kernan, N. A., Ippoliti, C., Papadopoulos, E. B., Giralt, S., Khouri, I., Lu, J.-G., Gajewski, J., Durett, A., Cleary, K., Champlin, R., Andersson, B. S., Light, S. (2000). Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood 95: 83-89 [Abstract] [Full Text]  
• Maes, B. D., Vanrenterghem, Y. F. (1999). Anti-interleukin-2 receptor monoclonal antibodies in renal transplantation. Nephrol Dial Transplant 14: 2824-2826 [Full Text]  
• DICK, A. D, ISAACS, J. D (1999). Immunomodulation of autoimmune responses with monoclonal antibodies and immunoadhesins: treatment of ocular inflammatory disease in the next millennium. Br. J. Ophthalmol. 83: 1230-1234 [Full Text]  
• Stein, C. M., Murray, J. J., Wood, A. J.J. (1999). Inhibition of Stimulated Interleukin-2 Production in Whole Blood: A Practical Measure of Cyclosporine Effect. Clin. Chem. 45: 1477-1484 [Abstract] [Full Text]  
• NICKERSON, P., JEFFERY, J., GOUGH, J., GRIMM, P., MCKENNA, R., BIRK, P., RUSH, D. (1999). Effect of Increasing Baseline Immunosuppression on the Prevalence of Clinical and Subclinical Rejection: A Pilot Study. J. Am. Soc. Nephrol. 10: 1801-1805 [Abstract] [Full Text]  
• Nussenblatt, R. B., Fortin, E., Schiffman, R., Rizzo, L., Smith, J., Van Veldhuisen, P., Sran, P., Yaffe, A., Goldman, C. K., Waldmann, T. A., Whitcup, S. M. (1999). Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-Tac mAb: A phase I/II clinical trial. Proc. Natl. Acad. Sci. USA 96: 7462-7466 [Abstract] [Full Text]  
• GUMMERT, J. F., IKONEN, T., MORRIS, R. E. (1999). Newer Immunosuppressive Drugs: A Review. J. Am. Soc. Nephrol. 10: 1366-1380 [Abstract] [Full Text]  
• van den Berg, J W K, Postma, D S, Koëter, G H, van der Bij, W (1999). New immunosuppressive drugs and lung transplantation: last or least?. Thorax 54: 550-553 [Full Text]  
• GAO, Z., ZHONG, R., JIANG, J., GARCIA, B., XING, J. J., WHITE, M. J., LAZAROVITS, A. I. (1999). Adoptively Transferable Tolerance Induced by CD45RB Monoclonal Antibody. J. Am. Soc. Nephrol. 10: 374-381 [Abstract] [Full Text]  
• Abramowicz, D., Vincenti, F., The Daclizumab Triple Therapy Study Group, (1998). Daclizumab to Prevent Acute Rejection in Renal Transplantation. NEJM 338: 1700-1701 [Full Text]  
• Marom, E. M., Choi, Y. W., Palmer, S. M., DeLong, D. M., Stuart, M. D., McAdams, H. P. (2001). Reperfusion Edema after Lung Transplantation: Effect of Daclizumab. Radiology 221: 508-514 [Abstract] [Full Text]