Proteasome inhibition with bortezomib depletes plasma cells and specific autoantibody production in primary thymic cell cultures from early-onset myasthenia gravis patients

Journal of Immunology

Volumn 193, Issue 3, 2014, Pages 1055-1063

  Gomez, Alejandro M ^a   Willcox, Nick ^b   Vrolix, Kathleen ^a   Hummel, Jonas ^a   Nogales Gadea, Gisela ^a,c   Saxena, Abhishek ^a   Duimel, Hans ^a   Verheyen, Fons ^a   Molenaar, Peter C ^a   Buurman, Wim A ^a   De Baets, Marc H ^a   Martinez Martinez, Pilar ^a,d   Losen, Mario ^a,d  

^a MAASTRICHT UNIVERSITY   (Netherlands)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^d JOHN RADCLIFFE HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOANTIBODY; BORTEZOMIB; CHOLINERGIC RECEPTOR; D4902; DEXAMETHASONE; IMMUNOGLOBULIN G; LENALIDOMIDE; PROTEASOME; UNCLASSIFIED DRUG;

ANTIBODY PRODUCTION; APOPTOSIS; ARTICLE; CELL COUNT; CELL SURVIVAL; CELL ULTRASTRUCTURE; CELL VIABILITY; CONCENTRATION RESPONSE; DRUG CYTOTOXICITY; DRUG EFFICACY; DRUG MECHANISM; ENDOPLASMIC RETICULUM STRESS; ENZYME INHIBITION; HUMAN; HUMAN CELL; IC 50; LYMPHOCYTE PROLIFERATION; MYASTHENIA GRAVIS; PLASMA CELL; PRIORITY JOURNAL; THYMOCYTE;

ADOLESCENT; ADULT; AGE OF ONSET; ANTINEOPLASTIC AGENTS; AUTOANTIBODIES; BORONIC ACIDS; CELLS, CULTURED; ENDOPLASMIC RETICULUM STRESS; FEMALE; HUMANS; MALE; PLASMA CELLS; PRIMARY CELL CULTURE; PROTEASOME ENDOPEPTIDASE COMPLEX; PYRAZINES; THYMUS GLAND; YOUNG ADULT;

EID: 84906097547     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1301555     Document Type: Article

References (68)

1. Irani, S., and B. Lang. 2008. Autoantibody-mediated disorders of the central nervous system. Autoimmunity 41: 55-65.
2. Sahashi, K., A. G. Engel, E. H. Lambert, and F. M. Howard, Jr. 1980. Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis. J. Neuropathol. Exp. Neurol. 39: 160-172.
3. Heinemann, S., J. Merlie, and J. Lindstrom. 1978. Modulation of acetylcholine receptor in rat diaphragm by anti-receptor sera. Nature 274: 65-68.
4. Gregersen, P. K., R. Kosoy, A. T. Lee, J. Lamb, J. Sussman, D. McKee, K. R. Simpfendorfer, R. Pirskanen-Matell, F. Piehl, Q. Pan-Hammarstrom, et al. 2012. Risk for myasthenia gravis maps to a (151) Pro? Ala change in TNIP1 and to human leukocyte antigen-B 08. Ann. Neurol. 72: 927-935.
5. Le Panse, R., J. Bismuth, G. Cizeron-Clairac, J. M. Weiss, P. Cufi, P. Dartevelle, N. K. De Rosbo, and S. Berrih-Aknin. 2010. Thymic remodeling associated with hyperplasia in myasthenia gravis. Autoimmunity 43: 401-412.
6. Castleman, B., and E. H. Norris. 1949. The pathology of the thymus in myasthenia gravis; a study of 35 cases. Medicine (Baltimore) 28: 27-58.
7. Willcox, H. N., J. Newsom-Davis, and L. R. Calder. 1984. Cell types required for anti-acetylcholine receptor antibody synthesis by cultured thymocytes and blood lymphocytes in myasthenia gravis. Clin. Exp. Immunol. 58: 97-106.
8. Gold, R., R. Hohlfeld, and K. V. Toyka. 2008. Progress in the treatment of myasthenia gravis. Ther. Adv. Neurol. Disord. 1: 36-51.
9. Hehir, M. K., T. M. Burns, J. Alpers, M. R. Conaway, M. Sawa, and D. B. Sanders. 2010. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis: outcomes in 102 patients. Muscle Nerve 41: 593-598.
10. Díaz-Manera, J., E. Martínez-Hernández, L. Querol, R. Klooster, R. Rojas-García, X. Suárez-Calvet, J. L. Muñoz-Blanco, C. Mazia, K. R. Straasheijm, E. Gallardo, et al. 2012. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology 78: 189-193.
11. Cupps, T. R., T. L. Gerrard, R. J. Falkoff, G. Whalen, and A. S. Fauci. 1985. Effects of in vitro corticosteroids on B cell activation, proliferation, and differentiation. J. Clin. Invest. 75: 754-761.
12. Ashwell, J. D., F. W. Lu, and M. S. Vacchio. 2000. Glucocorticoids in T cell development and function. Annu. Rev. Immunol. 18: 309-345.
13. Brown, T. E., A. Ahmed, R. S. Filo, R. C. Knudsen, and K. W. Sell. 1976. The immunosuppressive mechanism of azathioprine. I. In vitro effect on lymphocyte function in the baboon. Transplantation 21: 27-35.
14. Helmreich, E., M. Kern, and H. N. Eisen. 1961. The secretion of antibody by isolated lymph node cells. J. Biol. Chem. 236: 464-473.
15. Hibi, T., and H. M. Dosch. 1986. Limiting dilution analysis of the B cell compartment in human bone marrow. Eur. J. Immunol. 16: 139-145.
16. Amanna, I. J., N. E. Carlson, and M. K. Slifka. 2007. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357: 1903-1915.
17. Manz, R. A., A. E. Hauser, F. Hiepe, and A. Radbruch. 2005. Maintenance of serum antibody levels. Annu. Rev. Immunol. 23: 367-386.
18. Hiepe, F., T. Dörner, A. E. Hauser, B. F. Hoyer, H. Mei, and A. Radbruch. 2011. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat. Rev. Rheumatol. 7: 170-178.
19. Obeng, E. A., L. M. Carlson, D. M. Gutman, W. J. Harrington, Jr., K. P. Lee, and L. H. Boise. 2006. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107: 4907-4916.
20. Meister, S., U. Schubert, K. Neubert, K. Herrmann, R. Burger, M. Gramatzki, S. Hahn, S. Schreiber, S. Wilhelm, M. Herrmann, et al. 2007. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res. 67: 1783-1792.
21. Hideshima, T., P. Richardson, D. Chauhan, V. J. Palombella, P. J. Elliott, J. Adams, and K. C. Anderson. 2001. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 61: 3071-3076.
22. Neubert, K., S. Meister, K. Moser, F. Weisel, D. Maseda, K. Amann, C. Wiethe, T. H. Winkler, J. R. Kalden, R. A. Manz, and R. E. Voll. 2008. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat. Med. 14: 748-755.
23. Gomez, A. M., N. Willcox, P. C. Molenaar, W. Buurman, P. Martinez-Martinez, M. H. De Baets, and M. Losen. 2012. Targeting plasma cells with proteasome inhibitors: possible roles in treating myasthenia gravis? Ann. N. Y. Acad. Sci. 1274: 48-59.
24. Woodle, E. S., R. R. Alloway, and A. Girnita. 2011. Proteasome inhibitor treatment of antibody-mediated allograft rejection. Curr. Opin. Organ Transplant. 16: 434-438.
25. Shortt, J., D. H. Oh, and S. S. Opat. 2013. ADAMTS13 antibody depletion by bortezomib in thrombotic thrombocytopenic purpura. N. Engl. J. Med. 368: 90-92.
26. Gomez, A. M., K. Vrolix, P. Martínez-Martínez, P. C. Molenaar, M. Phernambucq, E. van der Esch, H. Duimel, F. Verheyen, R. E. Voll, R. A. Manz, et al. 2011. Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis. J. Immunol. 186: 2503-2513.
27. Bontscho, J., A. Schreiber, R. A. Manz, W. Schneider, F. C. Luft, and R. Kettritz. 2011. Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis. J. Am. Soc. Nephrol. 22: 336-348.
28. Davies, F., and R. Baz. 2010. Lenalidomide mode of action: linking bench and clinical findings. Blood Rev. 24(Suppl. 1): S13-S19.
29. Shannon, E., F. Sandoval, N. Greig, and P. Stagg. 2012. Lenalidomide alone or lenalidomide plus dexamethasone significantly inhibit IgG and IgM in vitro . A possible explanation for their mechanism of action in treating multiple myeloma. Int. Immunopharmacol. 12: 441-446.
30. Shiono, H., I. Roxanis,W. Zhang, G. P. Sims, A.Meager, L.W. Jacobson, J. L. Liu, I. Matthews, Y. L. Wong, M. Bonifati, et al. 2003. Scenarios for autoimmunization of T and B cells in myasthenia gravis. Ann. N. Y. Acad. Sci. 998: 237-256.
31. Hill, M. E., H. Shiono, J. Newsom-Davis, and N. Willcox. 2008. The myasthenia gravis thymus: a rare source of human autoantibody-secreting plasma cells for testing potential therapeutics. J. Neuroimmunol. 201-202: 50-56.
32. Bai, M., M. Doukas, A. Papoudou-Bai, A. Barbouti, K. Stefanaki, V. Galani, and P. Kanavaros. 2013. Immunohistological analysis of cell cycle and apoptosis regulators in thymus. Ann. Anat. 195: 159-165.
33. Le, P. T., H. T. Maecker, and J. E. Cook. 1995. In situ detection and characterization of apoptotic thymocytes in human thymus. Expression of bcl-2 in vivo does not prevent apoptosis. J. Immunol. 154: 4371-4378.
34. Purton, J. F., R. L. Boyd, T. J. Cole, and D. I. Godfrey. 2000. Intrathymic T cell development and selection proceeds normally in the absence of glucocorticoid receptor signaling. Immunity 13: 179-186.
35. Willcox, H. N., J. Newsom-Davis, and L. R. Calder. 1983. Greatly increased autoantibody production in myasthenia gravis by thymocyte suspensions prepared with proteolytic enzymes. Clin. Exp. Immunol. 54: 378-386.
36. van der Neut Kolfschoten, M., J. Schuurman, M. Losen, W. K. Bleeker, P. Martínez-Martínez, E. Vermeulen, T. H. den Bleker, L. Wiegman, T. Vink, L. A. Aarden, et al. 2007. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 317: 1554-1557.
37. Frigyesi, I., J. Adolfsson, M. Ali, M. K. Christophersen, E. Johnsson, I. Turesson, U. Gullberg, M. Hansson, and B. Nilsson. 2014. Robust isolation of malignant plasma cells in multiple myeloma. Blood 123: 1336-1340.
38. Tokoyoda, K., A. E. Hauser, T. Nakayama, and A. Radbruch. 2010. Organization of immunological memory by bone marrow stroma. Nat. Rev. Immunol. 10: 193-200.
39. Perry, D. K., J. M. Burns, H. S. Pollinger, B. P. Amiot, J. M. Gloor, G. J. Gores, and M. D. Stegall. 2009. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am. J. Transplant. 9: 201-209.
40. Moreau, P., H. Pylypenko, S. Grosicki, I. Karamanesht, X. Leleu, M. Grishunina, G. Rekhtman, Z. Masliak, T. Robak, A. Shubina, et al. 2011. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 12: 431-440.
41. Häcker, G. 2000. The morphology of apoptosis. Cell Tissue Res. 301: 5-17.
42. Chauhan, D., A. V. Singh, B. Ciccarelli, P. G. Richardson, M. A. Palladino, and K. C. Anderson. 2010. Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood 115: 834-845.
43. Qian, Z., L. Zhang, Z. Cai, L. Sun, H. Wang, Q. Yi, and M. Wang. 2011. Lenalidomide synergizes with dexamethasone to induce growth arrest and apoptosis of mantle cell lymphoma cells in vitro and in vivo. Leuk. Res. 35: 380-386.
44. Matsuoka, A., A. Tochigi, M. Kishimoto, T. Nakahara, T. Kondo, T. Tsujioka, T. Tasaka, Y. Tohyama, and K. Tohyama. 2010. Lenalidomide induces cell death in an MDS-derived cell line with deletion of chromosome 5q by inhibition of cytokinesis. Leukemia 24: 748-755.
45. Hofmeister, C. C., X. Yang, F. Pichiorri, P. Chen, D. M. Rozewski, A. J. Johnson, S. Lee, Z. Liu, C. L. Garr, E. M. Hade, et al. 2011. Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein. J. Clin. Oncol. 29: 3427-3434.
46. De, A., H. M. Blotta, R. L. Mamoni, P. Louzada, M. B. Bertolo, N. T. Foss, A. C. Moreira, and M. Castro. 2002. Effects of dexamethasone on lymphocyte proliferation and cytokine production in rheumatoid arthritis. J. Rheumatol. 29: 46-51.
47. Hearing, S. D., M. Norman, C. Smyth, C. Foy, and C. M. Dayan. 1999. Wide variation in lymphocyte steroid sensitivity among healthy human volunteers. J. Clin. Endocrinol. Metab. 84: 4149-4154.
48. Horton, T. M., A. Gannavarapu, S. M. Blaney, D. Z. D'Argenio, S. E. Plon, and S. L. Berg. 2006. Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer Chemother. Pharmacol. 58: 13-23.
49. Cassese, G., S. Arce, A. E. Hauser, K. Lehnert, B. Moewes, M. Mostarac, G. Muehlinghaus, M. Szyska, A. Radbruch, and R. A. Manz. 2003. Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J. Immunol. 171: 1684-1690.
50. van Laar, J. M., M. Melchers, Y. K. Teng, B. van der Zouwen, R. Mohammadi, R. Fischer, L. Margolis, W. Fitzgerald, J. C. Grivel, F. C. Breedveld, et al. 2007. Sustained secretion of immunoglobulin by long-lived human tonsil plasma cells. Am. J. Pathol. 171: 917-927.
51. Mesin, L., R. Di Niro, K. M. Thompson, K. E. Lundin, and L. M. Sollid. 2011. Long-lived plasma cells from human small intestine biopsies secrete immunoglobulins for many weeks in vitro. J. Immunol. 187: 2867-2874.
52. Miller, J. J., III, and L. J. Cole. 1967. Resistance of long-lived lymphocytes and plasma cells in rat lymph nodes to treatment with prednisone, cyclophosphamide, 6-mercaptopurine, and actinomycin D. J. Exp. Med. 126: 109-125.
53. Willcox, N., M. Schluep, N. Sommer, D. Campana, G. Janossy, A. N. Brown, and J. Newsom-Davis. 1989. Variable corticosteroid sensitivity of thymic cortex and medullary peripheral-type lymphoid tissue in myasthenia gravis patients: structural and functional effects. Q. J. Med. 73: 1071-1087.
54. Dimopoulos, M. A., P. G. Richardson, N. Brandenburg, Z. Yu, D. M. Weber, R. Niesvizky, and G. J. Morgan. 2012. A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. Blood 119: 2764-2767.
55. Gandhi, A. K., J. Kang, L. Capone, A. Parton, L. Wu, L. H. Zhang, D. Mendy, A. Lopez-Girona, T. Tran, L. Sapinoso, et al. 2010. Dexamethasone synergizes with lenalidomide to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T and NK cell function. Curr. Cancer Drug Targets 10: 155-167.
56. Verhelle, D., L. G. Corral, K. Wong, J. H. Mueller, L. Moutouh-de Parseval, K. Jensen-Pergakes, P. H. Schafer, R. Chen, E. Glezer, G. D. Ferguson, et al. 2007. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res. 67: 746-755.
57. Mitsiades, N., C. S. Mitsiades, V. Poulaki, D. Chauhan, P. G. Richardson, T. Hideshima, N. C. Munshi, S. P. Treon, and K. C. Anderson. 2002. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 99: 4525-4530.
58. Görgün, G., E. Calabrese, E. Soydan, T. Hideshima, G. Perrone, M. Bandi, D. Cirstea, L. Santo, Y. Hu, Y. T. Tai, et al. 2010. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 116: 3227-3237.
59. Noonan, K., L. Rudraraju, A. Ferguson, A. Emerling, M. F. Pasetti, C. A. Huff, and I. Borrello. 2012. Lenalidomide-induced immunomodulation in multiple myeloma: impact on vaccines and antitumor responses. Clin. Cancer Res. 18: 1426-1434.
60. Heidt, S., D. L. Roelen, M. Vergunst, I. I. Doxiadis, F. H. Claas, and A. Mulder. 2009. Bortezomib affects the function of human B cells: possible implications for desensitization protocols. Clin. Transpl. 2009: 387-392.
61. Kim, J. S., J. I. Lee, J. Y. Shin, S. Y. Kim, J. S. Shin, J. H. Lim, H. S. Cho, I. H. Yoon, K. H. Kim, S. J. Kim, and C. G. Park. 2009. Bortezomib can suppress activation of rapamycin-resistant memory T cells without affecting regulatory T-cell viability in non-human primates. Transplantation 88: 1349-1359.
62. Berges, C., H. Haberstock, D. Fuchs, M. Miltz, M. Sadeghi, G. Opelz, V. Daniel, and C. Naujokat. 2008. Proteasome inhibition suppresses essential immune functions of human CD4+ T cells. Immunology 124: 234-246.
63. Heider, U., J. Rademacher, M. Kaiser, L. Kleeberg, I. von Metzler, and O. Sezer. 2010. Decrease in CD4+ T-cell counts in patients with multiple myeloma treated with bortezomib. Clin. Lymphoma Myeloma Leuk. 10: 134-137.
64. Blanco, B., J. A. Pérez-Simón, L. I. Sánchez-Abarca, T. Caballero-Velazquez, S. Gutierrez-Cossío, P. Hernández-Campo, M. Díez-Campelo, C. Herrero-Sanchez, C. Rodriguez-Serrano, C. Santamaría, et al. 2009. Treatment with bortezomib of human CD4+ T cells preserves natural regulatory T cells and allows the emergence of a distinct suppressor T-cell population. Haematologica 94: 975-983.
65. Bringhen, S., A. Larocca, D. Rossi, M. Cavalli, M. Genuardi, R. Ria, S. Gentili, F. Patriarca, C. Nozzoli, A. Levi, et al. 2010. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 116: 4745-4753.
66. Everly, M. J. 2009. A summary of bortezomib use in transplantation across 29 centers. Clin. Transpl. 2009: 323-337.
67. Diwan, T. S., S. Raghavaiah, J. M. Burns, W. K. Kremers, J. M. Gloor, and M. D. Stegall. 2011. The impact of proteasome inhibition on alloantibodyproducing plasma cells in vivo. Transplantation 91: 536-541.
68. Kirk, C. J. 2012. Discovery and development of second-generation proteasome inhibitors. Semin. Hematol. 49: 207-214.