Advances in immunosuppression for renal transplantation

Nature Reviews Nephrology

Volumn 6, Issue 3, 2010, Pages 160-167

  Durrbach, Antoine ^a   Francois, Helene ^a   Beaudreuil, Severine ^a   Jacquet, Antoine ^a   Charpentier, Bernard ^a  

^a BICÊTRE HOSPITAL   (France)

Author keywords

[No Author keywords available]

Indexed keywords

4 [N [1 (2 CYANO 1 OXOETHYL) 4 METHYL 3 PIPERIDINYL] N METHYLAMINO]PYRROLO[2,3 D]PYRIMIDINE; ABATACEPT; ALEFACEPT; BASILIXIMAB; BELATACEPT; BORTEZOMIB; CALCINEURIN INHIBITOR; CYCLOSPORIN A; ECULIZUMAB; EVEROLIMUS; IMMUNOGLOBULIN; JANUS KINASE 3; LYMPHOCYTE ANTIBODY; MYCOPHENOLIC ACID; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; N BENZYL 2 CYANO 3 (3,4 DIHYDROXYPHENYL)ACRYLAMIDE; PROTEIN KINASE C; PROTEIN KINASE SYK INHIBITOR; R 348; RAPAMYCIN; RITUXIMAB; SOTRASTAURIN; STEROID; TACROLIMUS; UNCLASSIFIED DRUG;

ANTIBODY RESPONSE; AREA UNDER THE CURVE; BLOOD GROUP ABO INCOMPATIBILITY; CANCER RISK; CHRONIC GRAFT VERSUS HOST DISEASE; CLINICAL TRIAL; CYTOMEGALOVIRUS INFECTION; DRUG FATALITY; DRUG MECHANISM; DRUG SUBSTITUTION; DRUG WITHDRAWAL; ENZYME INHIBITION; GRAFT REJECTION; GRAFT SURVIVAL; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; KIDNEY DISEASE; KIDNEY TRANSPLANTATION; LYMPHOMA; MULTIPLE MYELOMA; PAROXYSMAL NOCTURNAL HEMOGLOBINURIA; PLASMAPHERESIS; PRIORITY JOURNAL; PROPHYLAXIS; PSORIASIS; REVIEW; T LYMPHOCYTE ACTIVATION;

ANIMALS; FEMALE; FORECASTING; GRAFT REJECTION; GRAFT SURVIVAL; HAPLORHINI; HUMANS; IMMUNOSUPPRESSION; IMMUNOSUPPRESSIVE AGENTS; KIDNEY TRANSPLANTATION; MALE; PROGNOSIS; RISK ASSESSMENT; SAFETY MANAGEMENT; SURVIVAL ANALYSIS; TRANSPLANTATION IMMUNOLOGY; TRANSPLANTATION TOLERANCE; TREATMENT OUTCOME;

EID: 77649188163     PISSN: 17595061     EISSN: 1759507X     Source Type: Journal    
DOI: 10.1038/nrneph.2009.233     Document Type: Review

References (115)

1. Hibberd, A. D. et al. Cancer risk associated with ATG/OKT3 in renal transplantation. Transplant. Proc. 31, 1271-1272 (1999).
2. Danielian, S., Fagard, R., Alcover, A., Acuto, O. & Fischer, S. The tyrosine kinase activity of p56lck is increased in human T cells activated via CD2. Eur. J. Immunol. 21, 1967-1970 (1991).
3. June, C. H., Fletcher, M. C., Ledbetter, J. A. & Samelson, L. E. Increases in tyrosine phosphorylation are detectable before phospholipase C activation after T cell receptor stimulation. J. Immunol. 144, 1591-1599 (1990).
4. Déas, O. et al. Caspase-independent cell death induced by anti-CD2 or staurosporine in activated human peripheral T lymphocytes. J. Immunol. 161, 3375-3383 (1998).
5. Dumont, C. et al. Targeting additional costimulatory pathways: a subtle role for CD2. Transplant. Proc. 33, 199-200 (2001).
6. Mollereau, B., Deas, O., Dumont, C., Charpentier, B. & Senik, A. Effects of anti-CD2 monoclonal antibody: CD2- and CD95-mediated apoptosis of human peripheral T cells. Transplant. Proc. 31, 1245 (1999).
7. Mollereau, B. et al. CD2-induced apoptosis in activated human peripheral T cells: a Fasindependent pathway that requires early protein tyrosine phosphorylation. J. Immunol. 156, 3184-3190 (1996).
8. Rouleau, M. et al. Mitogenic CD2 monoclonal antibody pairs predispose peripheral T cells to undergo apoptosis on interaction with a third CD2 monoclonal antibody. J. Immunol. 152, 4861-4872 (1994).
9. Snanoudj, R. et al. A role for CD2 antibodies (BTI-322 and its humanized form) in the in vivo elimination of human T lymphocytes infiltrating an allogeneic human skin graft in SCID mice: an Fcgamma receptor-related mechanism involving co-injected human NK cells. Transplantation 78, 50-58 (2004).
10. Kaplon, R. J. et al. Short course single agent therapy with an LFA-3-IgG1 fusion protein prolongs primate cardiac allograft survival. Transplantation 61, 356-363 (1996).
11. Majeau, G. R., Meier, W., Jimmo, B., Kioussis, D. & Hochman, P. S. Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/function analysis in vitro and in human CD2 transgenic mice. J. Immunol. 152, 2753-2767 (1994).
12. Miller, G. T. et al. Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J. Exp. Med. 178, 211-222 (1993).
13. Krueger, G. G. et al. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J. Am. Acad. Dermatol. 47, 821-833 (2002).
14. Lebwohl, M. et al. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch. Dermatol. 139, 719-727 (2003).
15. Weaver, T. A. et al. Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat. Med. 15, 746-749 (2009).
16. Shapira, M. Y. et al. Alefacept treatment for refractory chronic extensive GVHD. Bone Marrow Transplant. 43, 339-343 (2009).
17. Stotler, C. J., Eghtesad, B., Hsi, E. & Silver, B. Rapid resolution of GVHD after orthotopic liver transplantation in a patient treated with alefacept. Blood 113, 5365-5366 (2009).
18. Bromley, S. K. et al. The immunological synapse. Annu. Rev. Immunol. 19, 375-396 (2001).
19. Greenwald, R. J., Freeman, G. J. & Sharpe, A. H. The B7 family revisited. Annu. Rev. Immunol. 23, 515-548 (2005).
20. Vincenti, F. et al. Costimulation blockade with belatacept in renal transplantation. N. Engl. J. Med. 353, 770-781 (2005).
21. Linsley, P. S. et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1, 793-801 (1994).
22. Finger, E. B. & Bluestone, J. A. When ligand becomes receptor - tolerance via B7 signaling on DCs. Nat. Immunol. 3, 1056-1057 (2002).
23. Grohmann, U. et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat. Immunol. 3, 1097-1101 (2002).
24. Chavez, H. et al. Absence of CD4CD25 regulatory T cell expansion in renal transplanted patients treated in vivo with belatacept mediated CD28-CD80/86 blockade. Transpl. Immunol. 17, 243-248 (2007).
25. Akalin, E. et al. CD28-B7 T cell costimulatory blockade by CTLA4lg in the rat renal allograft model: inhibition of cell-mediated and humoral immune responses in vivo. Transplantation 62, 1942-1945 (1996).
26. Larsen, C. P. et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 381, 434-438 (1996).
27. Lenschow, D. J. et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science 257, 789-792 (1992).
28. Pearson, T. C. et al. Transplantation tolerance induced by CTLA4-Ig. Transplantation 57, 1701-1706 (1994).
29. Turka, L. A. et al. T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. Proc. Natl Acad. Sci. USA 89, 11102-11105 (1992).
30. Kirk, A. D. et al. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc. Natl Acad. Sci. USA 94, 8789-8794 (1997).
31. Kirk, A. D. et al. Induction therapy with monoclonal antibodies specific for CD80 and CD86 delays the onset of acute renal allograft rejection in non-human primates. Transplantation 72, 377-384 (2001).
32. Durrbach, A. et al. A Phase III Study of Belatacept vs Cyclosporine in Kidney Transplants from Extended Criteria Donors (BENEFIT-EXT Study). Am. J. Transplant. (in press).
33. Vincenti, F. et al. A Phase III Study of Belatacept-based Immunosuppression Regimens vs Cyclosporine in Renal Transplant Recipients (BENEFIT Study). Am. J. Transplant. (in press).
34. Evenou, J. P. et al. The potent protein kinase C selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation. J. Pharmacol. Exp. Ther. 330, 792-801 (2009).
35. Takai, Y., Kishimoto, A., Inoue, M. & Nishizuka, Y. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem. 252, 7603-7609 (1977).
36. Baier, G. The PKC gene module: molecular biosystematics to resolve its T cell functions. Immunol. Rev. 192, 64-79 (2003).
37. Spitaler, M. & Cantrell, D. A. Protein kinase C and beyond. Nat. Immunol. 5, 785-790 (2004).
38. Tan, S. L. & Parker, P. J. Emerging and diverse roles of protein kinase C in immune cell signalling. Biochem. J. 376, 545-552 (2003).
39. Long, A., Kelleher, D., Lynch, S. & Volkov, Y. Cutting edge: protein kinase C beta expression is critical for export of Il-2 from T cells. J. Immunol. 167, 636-640 (2001).
40. Pfeifhofer, C. et al. Defective IgG2a/2b class switching in PKC alpha-/-mice. J. Immunol. 176, 6004-6011 (2006).
41. 2+ mobilization and NFAT cell activation in primary mouse T cells. J. Exp. Med. 197, 1525-1535 (2003).
42. Sun, Z. et al. PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes. Nature 404, 402-407 (2000).
43. Volkov, Y., Long, A., McGrath, S., Ni Eidhin, D. & Kelleher, D. Crucial importance of PKC-beta(I) in LFA-1-mediated locomotion of activated T cells. Nat. Immunol. 2, 508-514 (2001).
44. Marsland, B. J. & Kopf, M. T-cell fate and function: PKC-theta and beyond. Trends Immunol. 29, 179-185 (2008).
45. Monks, C. R., Kupfer, H., Tamir, I., Barlow, A. & Kupfer, A. Selective modulation of protein kinase C-theta during T-cell activation. Nature 385, 83-86 (1997).
46. Anderson, K. et al. Mice deficient in PKC theta demonstrate impaired in vivo T cell activation and protection from T cell-mediated inflammatory diseases. Autoimmunity 39, 469-478 (2006).
47. Kovarik, J. M., Huang, H. L., Slade, A., Sfikas, N. & Chandler, P. A. The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole. Br. J. Clin. Pharmacol. 68, 381-385 (2009).
48. Vincenti, F. & Kirk, A. D. What's next in the pipeline. Am. J. Transplant. 8, 1972-1981 (2008).
49. Budde, K. et al. AEB071, a novel protein kinase C-inhibitor: first clinical results of an AEB071 (sotrastaurin) plus tacrolimus regimen in renal transplant recipients [abstract]. AST 391 (2009).
50. Friman, S. et al. AEB071 (sotrastaurin) a novel protein kinase C-inhibitor: evaluation of an AEB071 plus mycophenolate regiman in renal transplant recipients [abstract]. AST 458 (2009).
51. Abraham, R. T. Mammalian target of rapamycin: immunosuppressive drugs uncover a novel pathway of cytokine receptor signaling. Curr. Opin. Immunol. 10, 330-336 (1998).
52. Denton, M. D., Magee, C. C. & Sayegh, M. H. Immunosuppressive strategies in transplantation. Lancet 353, 1083-1091 (1999).
53. Schorle, H., Holtschke, T., Hünig, T., Schimpl, A. & Horak, I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352, 621-624 (1991).
54. Steiger, J., Nickerson, P. W., Steurer, W., Moscovitch-Lopatin, M. & Strom, T. B. IL-2 knockout recipient mice reject islet cell allografts. J. Immunol. 155, 489-498 (1995).
55. Thèze, J., Alzari, P. M. & Bertoglio, J. Interleukin 2 and its receptors: recent advances and new immunological functions. Immunol. Today 17, 481-486 (1996).
56. Giri, J. G. et al. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 13, 2822-2830 (1994).
57. Willerford, D. M. et al. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521-530 (1995).
58. Liu, K. D., Gaffen, S. L. & Goldsmith, M. A. JAK/STAT signaling by cytokine receptors. Curr. Opin. Immunol. 10, 271-278 (1998).
59. Nelson, B. H. & Willerford, D. M. Biology of the interleukin-2 receptor. Adv. Immunol. 70, 1-81 (1998).
60. Thomis, D. C. & Berg, L. J. The role of Jak3 in lymphoid development, activation, and signaling. Curr. Opin. Immunol. 9, 541-547 (1997).
61. Hofmann, S. R. et al. Cytokines and their role in lymphoid development, differentiation and homeostasis. Curr. Opin. Allergy Clin. Immunol. 2, 495-506 (2002).
62. Leonard, W. J. & O'Shea, J. J. Jaks and STATs: biological implications. Annu. Rev. Immunol. 16, 293-322 (1998).
63. O'Shea, J. J., Pesu, M., Borie, D. C. & Changelian, P. S. A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat. Rev. Drug Discov. 3, 555-564 (2004).
64. Nosaka, T. et al. Defective lymphoid development in mice lacking Jak3. Science 270, 800-802 (1995).
65. Park, S. Y. et al. Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity 3, 771-782 (1995).
66. Thomis, D. C., Gurniak, C. B., Tivol, E., Sharpe, A. H. & Berg, L. J. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270, 794-797 (1995).
67. Macchi, P. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377, 65-68 (1995).
68. Russell, S. M. et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270, 797-800 (1995).
69. Gazit, A. et al. Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases. J. Med. Chem. 34, 1896-1907 (1991).
70. Kirken, R. A. et al. Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells. J. Leukoc. Biol. 65, 891-899 (1999).
71. Meydan, N. et al. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379, 645-648 (1996).
72. Säemann, M. D. et al. Suppression of primary T-cell responses and induction of alloantigenspecific hyporesponsiveness in vitro by the Janus kinase inhibitor tyrphostin AG490. Transplantation 70, 1215-1225 (2000).
73. Wang, L., Chen, J. J., Gelman, B. B., Konig, R. & Cloyd, M. W. A novel mechanism of CD4 lymphocyte depletion involves effects of HIV on resting lymphocytes: induction of lymph node homing and apoptosis upon secondary signaling through homing receptors. J. Immunol. 162, 268-276 (1999).
74. Behbod, F. et al. Concomitant inhibition of Janus kinase 3 and calcineurin-dependent signaling pathways synergistically prolongs the survival of rat heart allografts. J. Immunol. 166, 3724-3732 (2001).
75. Paniagua, R. et al. Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts. Transplantation 80, 1283-1292 (2005).
76. Conklyn, M., Andresen, C., Changelian, P. & Kudlacz, E. The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing. J. Leukoc. Biol. 76, 1248-1255 (2004).
77. Borie, D. C. et al. Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates. Transplantation 79, 791-801 (2005).
78. Borie, D. C. et al. Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates. Transplantation 80, 1756-1764 (2005).
79. Rousvoal, G. et al. Janus kinase 3 inhibition with CP-690,550 prevents allograft vasculopathy. Transpl. Int. 19, 1014-1021 (2006).
80. Velotta, J. B. et al. A novel JAK3 inhibitor, R348, attenuates chronic airway allograft rejection. Transplantation 87, 653-659 (2009).
81. Crespo, M. et al. Acute humoral rejection in renal allograft recipients: I. Incidence, serology and clinical characteristics. Transplantation 71, 652-658 (2001).
82. Rocha, P. N. et al. Beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection. Transplantation 75, 1490-1495 (2003).
83. Shah, A. et al. Treatment of C4d-positive acute humoral rejection with plasmapheresis and rabbit polyclonal antithymocyte globulin. Transplantation 77, 1399-1405 (2004).
84. Gloor, J. M. et al. Overcoming a positive crossmatch in living-donor kidney transplantation. Am. J. Transplant. 3, 1017-1023 (2003).
85. Jordan, S. C. et al. Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients. Transplantation 76, 631-636 (2003).
86. Montgomery, R. A. et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 70, 887-895 (2000).
87. Park, W. D. et al. Accommodation in ABO-incompatible kidney allografts, a novel mechanism of self-protection against antibody-mediated injury. Am. J. Transplant. 3, 952-960 (2003).
88. Tanabe, K. et al. Long-term results of ABO-incompatible living kidney transplantation: a single-center experience. Transplantation 65, 224-228 (1998).
89. Racusen, L. C. & Haas, M. Antibody-mediated rejection in renal allografts: lessons from pathology. Clin. J. Am. Soc. Nephrol. 1, 415-420 (2006).
90. Terasaki, P. I. Humoral theory of transplantation. Am. J. Transplant. 3, 665-673 (2003).
91. McHeyzer-Williams, M. G. & Ahmed, R. B cell memory and the long-lived plasma cell. Curr. Opin. Immunol. 11, 172-179 (1999).
92. Slifka, M. K., Antia, R., Whitmire, J. K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363-372 (1998).
93. Perry, D. K. et al. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am. J. Transplant. 9, 201-209 (2009).
94. Caamaño, J. H. et al. Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J. Exp. Med. 187, 185-196 (1998).
95. Franzoso, G. et al. Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J. Exp. Med. 187, 147-159 (1998).
96. Ranger, A. M. et al. Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc. Immunity 8, 125-134 (1998).
97. Barnes, P. J. & Karin, M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066-1071 (1997).
98. Baldwin, A. S. Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu. Rev. Immunol. 14, 649-683 (1996).
99. Thanos, D. & Maniatis, T. NF-kappa B: a lesson in family values. Cell 80, 529-532 (1995).
100. Sunwoo, J. B. et al. Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin. Cancer Res. 7, 1419-1428 (2001).
101. Ghosh, S., May, M. J. & Kopp, E. B. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16, 225-260 (1998).
102. McCarthy, P. L. Jr et al. Inhibition of interleukin-1 by an interleukin-1 receptor antagonist prevents graft-versus-host disease. Blood 78, 1915-1918 (1991).
103. Xun, C. Q., Thompson, J. S., Jennings, C. D., Brown, S. A. & Widmer, M. B. Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice. Blood 83, 2360-2367 (1994).
104. Wang, X., Luo, H., Chen, H., Duguid, W. & Wu, J. Role of proteasomes in T cell activation and proliferation. J. Immunol. 160, 788-801 (1998).
105. Finn, P. W., Stone, J. R., Boothby, M. R. & Perkins, D. L. Inhibition of NF-kappaB-dependent T cell activation abrogates acute allograft rejection. J. Immunol. 167, 5994-6001 (2001).
106. Richardson, P. G. et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N. Engl. J. Med. 348, 2609-2617 (2003).
107. Everly, M. J. et al. Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection. Transplantation 86, 1754-1761 (2008).
108. Trivedi, H. L. et al. Abrogation of anti-HLA antibodies via proteasome inhibition. Transplantation 87, 1555-1561 (2009).
109. Colvin, R. B. Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. J. Am. Soc. Nephrol. 18, 1046-1056 (2007).
110. Regele, H. et al. Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to chronic allograft rejection. J. Am. Soc. Nephrol. 13, 2371-2380 (2002).
111. Williams, J. M. et al. Acute vascular rejection and accommodation: divergent outcomes of the humoral response to organ transplantation. Transplantation 78, 1471-1478 (2004).
112. Brodsky, R. A. How I treat paroxysmal nocturnal hemoglobinuria. Blood 113, 6522-6527 (2009).
113. Rother, R. P., Rollins, S. A., Mojcik, C. F., Brodsky, R. A. & Bell, L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotechnol. 25, 1256-1264 (2007).
114. Mache, C. J. et al. Complement inhibitor eculizumab in atypical hemolytic uremic syndrome. Clin. J. Am. Soc. Nephrol. 4, 1312-1316 (2009).
115. Locke, J. E. et al. The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection. Am. J. Transplant. 9, 231-235 (2009).