Immunomodulatory Drugs and Monoclonal Antibodies

  • Howard A. Liebman


Autoimmune disorders result for either congenital or acquired defects in central or peripheral immune tolerance. A genetic propensity may underlie the development of most such disorders, but an external trigger may be required for the eventual development of the autoimmune disease. The development of pharmacologic agents to treat such disorders by inducing self-tolerance has progressed over the last 60 years. Historically termed immunosuppressive agents, it is now understood that they may modulate the immune system varied and unexpected ways. While many of the original immune-modulatory agents were cytotoxic drugs developed to treat lymphoid and myeloid malignancies, newer agents target specific immune cell populations, immune signaling pathways, immune cellular trafficking, and signaling molecules such as chemokines and cytokines. In particular, monoclonal antibodies that inhibit cytokine or cytokine receptors have become important immune-modulating agents in autoimmune disease.


Autoimmunity Immune modulation Immunosuppression 


  1. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003;3:745–56.CrossRefPubMedGoogle Scholar
  2. Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transpl. 1996;10:77–84.Google Scholar
  3. Alunno A, Bistoni O, Bartoloni E, Catebi S, Bigerna B, et al. Il-17 producing CD4CD8 cells are expanded in peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patients with primary Sjogren’s syndrome. Ann Rheum Dis. 2013;72:2865–292.CrossRefGoogle Scholar
  4. Barcellini W, Fattizzo B, Zaninoni A, Radice T, Nichele I, et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood. 2014;124:2930–6.CrossRefPubMedGoogle Scholar
  5. Blasczyk R, Westhoff U, Grosse-Wilde H. Soluble CD4, Cd8, and HLA molecules in commercial immunoglobulin preparations. Lancet. 1993;341:789–90.CrossRefPubMedGoogle Scholar
  6. Blumberg N, Spinelli SL, Francis CW, Taubman MB, Phipps RP. The platelet as an immune cell. CD40 ligand and transfusion immunomodulation. Immunol Res. 2009;45:251–60.CrossRefPubMedGoogle Scholar
  7. Boruchov DM, Gururangan S, Dirscoll MC, Bussel JB. Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP). Blood. 2007;110:3526–31.CrossRefPubMedGoogle Scholar
  8. Bussel JB, Pharm LC, Aledort L, Nachman R. Maintenance treatment of adults with chronic refractory immune thrombocytopenic purpura using repeated intravenous infusions of gammaglobulin. Blood. 1988;72:121–7.PubMedGoogle Scholar
  9. Bussel JB, Lee CS, Seery C, Lmahiyerobo AA, Thompson MV, et al. Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women with immune thrombocytopenia of less than two years. Haematologica. 2014;99:1264–71.CrossRefPubMedCentralPubMedGoogle Scholar
  10. Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D. Cryoglobulinemia Vasculitis. Am J Med. 2012;128:950–5.CrossRefGoogle Scholar
  11. Calasan MB, Vastert SJ, Scholman RC, Verweij F, Klein M, et al. Methrotrexate treatment affects effector but not regulatory T cells in juvenile idiopathic arthritis. Rheumatology. 2015;54:1724–34.CrossRefGoogle Scholar
  12. Canaud G, Bienaime F, Tabarin F, Bataillon G, Seilhean D, Noel LH, et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014;371:303–12.CrossRefPubMedGoogle Scholar
  13. Chandramouli NB, Rodgers GM. Prolonged immunoglobulin and platelet infusion for treatment of immune thrombocytopenia. Am J Hematol. 2000;65:85–6.CrossRefPubMedGoogle Scholar
  14. Chatrath H, Allen L, Boyer TD. Use of sirolimus in the treatment of refractory autoimmune hepatitis. Am J Med. 2014;127:1128–31.CrossRefPubMedGoogle Scholar
  15. Choi PY, Roncolato F, Badoux X, Ramanathan S, Ho SJ, Chong BH. A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4). Blood. 2015;126:500–3.CrossRefPubMedCentralPubMedGoogle Scholar
  16. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: a diverse set of disorders with different immune mechanisms. Blood. 2009;113:6511–21.CrossRefPubMedCentralPubMedGoogle Scholar
  17. Clatworthy MR, Wallin EF, Jayne DR. Antiglomerular basement membrane disease after alemtuzumab. N Engl J Med. 2008;359:768–9.CrossRefPubMedGoogle Scholar
  18. Coca A, Sanz I. Updates on B-cell immunotherapies for systemic lupus erythematosus and Sjogren’s syndrome. Curr Opin Rheumtol. 2012;24:451–6.Google Scholar
  19. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380:1819–28.CrossRefPubMedGoogle Scholar
  20. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132:52–65.CrossRefPubMedGoogle Scholar
  21. Cuker A, Coles AJ, Sullivan H, Fox E, Goldberg M, et al. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood. 2011;118:6299–305.CrossRefPubMedGoogle Scholar
  22. Daniels GH, Vladic A, Brinar V, Zavalishin I, Valente W, et al. Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. J Clin Endocrinol Metab. 2014;99:80–9.CrossRefPubMedGoogle Scholar
  23. de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150:670–80.CrossRefPubMedGoogle Scholar
  24. Del Prete G. The concept of type-1 and type-2 helper T cells and their cytokines in humans. Int Rev Immunol. 1998;16:427–55.CrossRefPubMedGoogle Scholar
  25. Dierickx D, Kentos A, Delannoy A. The role of rituximab in adults with warm antibody autoimmune hemolytic anemia. Blood. 2015;125:3223–9.CrossRefPubMedGoogle Scholar
  26. Dissanayake D, Hall H, Brown NB, Elford AR, Hamilton SR, Murakami K, et al. Nuclear factor-κB1 controls the functional maturation of dendritic cells and prevents the activation of autoreactive T cells. Nat Med. 2011;17:1663–7.CrossRefPubMedGoogle Scholar
  27. Fong W, Holroyd C, Davidson B, Armstrong R, Harvey N, et al. The effectiveness of a real life dose reduction strategy for tumour necrosis factor inhibitors in ankylosing spondylitis and psoriatic arthritis. Rheumatology. 2016;55:1837–42.CrossRefPubMedGoogle Scholar
  28. Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood. 2008;112:250–5.CrossRefPubMedGoogle Scholar
  29. Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity. 2013;39:1003–18.CrossRefPubMedCentralPubMedGoogle Scholar
  30. Gattorno M, Obici L, Cattalini M, Tormey V, Abrams K, et al. Canakinumab reverses overexpression of inflammatory response genes in tumour necrosis factor receptor-associated periodic syndrome. Ann Rheum Dis. 2017;76:303–9.CrossRefPubMedGoogle Scholar
  31. Genestier L, Paillot R, Bonnefoy-Bernard N, Meffre G, Flacher M, et al. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest. 1998;102:322–8.CrossRefPubMedCentralPubMedGoogle Scholar
  32. Gesundheit B, Cividalli G, Freeman A, Yatziv S, Koren G, Baruchel S. Cyclosporin A in the treatment of refractory immune thrombocytopenia purpura in children. Eur J Haematol. 2001;66:347–51.CrossRefPubMedGoogle Scholar
  33. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56:641–8.CrossRefPubMedGoogle Scholar
  34. Gomez-Almaguer D, Solano-Genesta M, Tarin-Arzaga L, Herrera-Garza JL, Cantu-Rodriguez OG, et al. Low dose rituximab and alemtuzumab combination therapy for patient with steroid-refractory autoimmune cytopenias. Blood. 2010;116:4783–5.CrossRefPubMedGoogle Scholar
  35. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–64.CrossRefPubMedGoogle Scholar
  36. Gregersen PK, Behrens TW. Genetics of autoimmune diseases-disorders of immune homeostasis. Nat Rev Genet. 2006;7:917–28.CrossRefPubMedGoogle Scholar
  37. Gupta N, Kavuru S, Patel D, Janson D, Driscoll N, et al. Rituximab-based chemotherapy for steroid-refractory autoimmune hemolytic anemia of chronic lymphocytic leukemia. Leukemia. 2002;16:2092–5.CrossRefPubMedGoogle Scholar
  38. Hamrock DJ. Adverse events associated with intravenous immunoglobulin therapy. Int Immunopharamacol. 2006;6:535–42.CrossRefGoogle Scholar
  39. Hench PS, Kendall EC, Slocumb CH, Polley HF. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorterone compound E) and pituitary adrenocorticotropic hormone on rheumatoid arthritis. Mayo Clin Proc. 1949;24:181–97.Google Scholar
  40. Hibi T, Imai Y, Senoo A, Ohta K, Ukyo Y. Efficacy and safety of golimumab 52-week maintenance therapy in Japanese patients with moderate to severely active ulcerative colitis: a phase 3, double-blind, randomized, placebo-controlled study-(PURSUIT-J study). J Gastroenterol. 2017;03:21.Google Scholar
  41. Imbach P, Barandun S, d’Apuzzo V, Baumgartner C, Hirt A, et al. High-dose intravenous immunoglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet. 1981;1:1228–31.CrossRefPubMedGoogle Scholar
  42. Imbach P, Lazarus AH, Kuhne T. Intravenous immunoglobulins induce potentially synergistic immunomodulations in autoimmune disorders. Vox Sang. 2010;98:385–94.CrossRefPubMedGoogle Scholar
  43. Jones JL, Thompson SAJ, Loh P, Davies JL, Tuohy OC, et al. Human autoimmunity after lymphocyte depletion is causes by homeostatic T-cell proliferation. PNAS. 2013;110:20200–5.CrossRefPubMedCentralPubMedGoogle Scholar
  44. Kanakry DG, Ganguly S, Zhurak M, Bolanos-Meade J, Thoburn C, et al. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med. 2013;5:211ra157.CrossRefPubMedCentralPubMedGoogle Scholar
  45. Kappers-Klunne MC, van't Veer MB. Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy. Br J Haematol. 2001;114:121–5.CrossRefPubMedGoogle Scholar
  46. Kavanaugh A, Puig L, Gottlieb AB, Ritchlin C, You Y, et al. Efficacy and safety of ustekinumab in psoriatic arthritis patients with peripheral arthritis and physician-reported spondylitis: post-hoc analyses from two phase III, multicentre, double-blind, placebo-controlled studies (PSUMMIT-1/PSUMMIT-2). Ann Rheum Dis. 2016;75:1984–8.CrossRefPubMedGoogle Scholar
  47. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34:637–50.CrossRefPubMedGoogle Scholar
  48. Kosiewicz MM, Dryden GW, Chhabra A, Alard P. Relationship between gut microbiota and development of T cell associated disease. FEBS Lett. 2014;588:4195–206.CrossRefPubMedGoogle Scholar
  49. Kuchroo V, Ohashi PS, Sartor RB, Vinuesa CG. Dysregulation of immune homeostasis in autoimmune disease. Nat Med. 2012;18:42–7.CrossRefPubMedGoogle Scholar
  50. Kucuksahin O, Yildizgoren MT, Ilgen U, Ates A, Kinikli G, et al. Anti-interleukin-1 treatment in 26 patients with refractory familial mediterranean fever. Mod Rheumatol. 2017;27:350–5.CrossRefPubMedGoogle Scholar
  51. Kuemmerle-Deschner JB, Hofer F, Endres T, Kortus-Goetze B, Blank N, Weisbarth-Riedel E, et al. Real-life effectiveness of canakinumab in cryopyrin-associated periodic syndrome. Rheumatology. 2016;55:689–96.CrossRefPubMedGoogle Scholar
  52. Liebman HA, Saleh MN, Bussel JB, Negrea OG, Horne H, Wegener WA, Goldenberg DM. Low-dose anti-CD20 veltuzumab given intravenously or subcutaneously is active in relapsed immune thrombocytopenia: a phase I study. Br J Haematol. 2013;162:693–701.CrossRefPubMedGoogle Scholar
  53. Lina C, Conghua W, Nan L, Ping Z. Combined treatment of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in patients with rheumatoid arthritis. J Clin Immunol. 2011;31:596–605.CrossRefPubMedGoogle Scholar
  54. Loof TG, Morgelin M, Johansson L, Oehmcke S, Olin AI, Dickneite G, et al. Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense. Blood. 2011;118:2589–98.CrossRefPubMedGoogle Scholar
  55. Loscher WN, Woertz A, Wallnofer M, Wanschitz JV, Luef G. Successful treatment of CANOMAD with IVIg and rituximab. J Neurol. 2013;260:1168–70.CrossRefPubMedGoogle Scholar
  56. Lutalo PM, D'Cruz DP. Update on belimumab for the management of systemic lupus erythematosus. Expert Opin Biol Ther. 2014;14:1701–8.CrossRefPubMedGoogle Scholar
  57. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet. 1999;354:1932–9.CrossRefPubMedGoogle Scholar
  58. Maltzman JS, Koretzky GA. Azathioprine: old drug, new actions. J Clin Invest. 2003;111:1122–4.CrossRefPubMedCentralPubMedGoogle Scholar
  59. Mantovani A, Bussolino M, Introna M. Cytokine regulation of endothelial function: from molecular level to the bedside. Immunol Today. 1997;18:231–40.CrossRefPubMedGoogle Scholar
  60. Mariette X, Seror R, Quartuccio L, Baron G, Salvin S, et al. Efficacy and safety of belimumab in primary Sjogren’s syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis. 2015;74:526–31.CrossRefPubMedGoogle Scholar
  61. Mease PJ. Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis. Curr Opin Rheumatol. 2015;27:127–33.CrossRefPubMedGoogle Scholar
  62. Mease PJ, Genovese MC, Mutebi A, Viswanathan HN, Chau D, et al. Improvement in psoriasis signs and symptoms assessed by the psoriasis symptom inventory with brodalumab treatment in patients with psoriatic arthritis. J Rheumatol. 2016;43:343–9.CrossRefPubMedGoogle Scholar
  63. Mease PJ, van der Heijde D, Ritchlin CT, Okada M, Cuchacovich RS, et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naïve patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76:79–87.CrossRefPubMedGoogle Scholar
  64. Meijsing SH, Pufall MA, So AY, Bates DL, Chen L, Yamamoto KR. DNA binding site sequence directs glucocorticoid receptor structure and activity. Science. 2009;324:407–10.CrossRefPubMedCentralPubMedGoogle Scholar
  65. Merion RM, Henry ML, Melzer JS, Sollinger H, et al. Randomized, prospective trial of mycophenolate mofetil versus azathioprine for prevention of acute renal allograft rejection after simultaneous kidney-pancreas transplantation. Transplantation. 2000;70:105–11.PubMedGoogle Scholar
  66. Miano M, Calvillo M, Palmisani E, Fioredda F, Micalizzi C, Svahn J, et al. Sirolimus for the treatment of multi-resistant autoimmune haemolytic anaemia in children. Br J Haematol. 2014;167:571–4.CrossRefPubMedGoogle Scholar
  67. Minchinton RM, Waters AH. Autoimmune thrombocytopenia and neutropenia after bone marrow transplantation. Blood. 1985;66:752–3.PubMedGoogle Scholar
  68. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376:209–20.CrossRefPubMedGoogle Scholar
  69. Newland AC, Trealeaven JG, Minchinton RM, Waters AH. High-dose intravenous IgG in adults with autoimmune thrombocytopenia. Lancet. 1983;1:84–7.CrossRefPubMedGoogle Scholar
  70. Olson SR, Chu C, Shatzel JJ, Deloughery TG. The platelet “boilermaker”: a treatment protocol to rapidly increase platelets in patients with immune thrombocytopenia. Am J Hematol. 2016.
  71. Orrock JE, Ilowite NT. Canakinumab for the treatment of active systemic juvenile idiopathic arthritis. Expert Rev Clin Pharmacol. 2016;9:1015–24.CrossRefPubMedGoogle Scholar
  72. Ostrowsk RA, Bussey MR, Tehrani R, Jay W. Biologic therapy for therapy for the treatment of giant cell arteritis. Neuro-Ophthalmology. 2014;38:107–12.CrossRefGoogle Scholar
  73. Palmer E. Negative selection—clearing out the bad apples from the T-cell repertoire. Nat Rev Immunol. 2003;3:383–91.CrossRefPubMedGoogle Scholar
  74. Parkin J, Cohen B. An overview of the immune system. Lancet. 2001;357:1777–89.CrossRefPubMedGoogle Scholar
  75. Patel VL, Mahevas M, Lee SY, Stasi R, Cunningham-Rundles S, Godeau B, et al. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood. 2012;119:5989–95.CrossRefPubMedCentralPubMedGoogle Scholar
  76. Psarra AMG, Sekeris CE. Glucocorticoid receptors and other nuclear transcription factors in mitochondria and possible functions. Biochim Biophys Acta. 2009;1787:431–6.CrossRefPubMedGoogle Scholar
  77. Quiquandon I, Fenaux P, Caulier MT, Pagniez D, Huart JJ, Bauters F. Re-evaluation of the role of azathioprine in the treatment of adult chronic idiopathic thrombocytopenic purpura: a report on 53 cases. Br J Haematol. 1990;74:223–8.CrossRefPubMedGoogle Scholar
  78. Rioux JC, Goyette P, Vyse TJ, Hammarström L, Fernando MMA, Green T, et al. Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proc Natl Acad Sci U S A. 2009;106:18680–5.CrossRefPubMedCentralPubMedGoogle Scholar
  79. Ru J, Liebman HA. Successful treatment of refractory pure red cell aplasia associated with lymphoproliferative disorders with the anti-CD52 monoclonal antibody alemtuzumab (CAMPATH-1H). Br J Haematol. 2003;123:278–81.CrossRefPubMedGoogle Scholar
  80. Rubenstein E, Arkfeld DG, Metyas S, Shinada S, Liebman HA. Rituximab treatment for resistant antiphospholipid syndrome. J Rheumatol. 2006;33:355–7.PubMedGoogle Scholar
  81. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.CrossRefPubMedGoogle Scholar
  82. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–62.CrossRefPubMedGoogle Scholar
  83. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, et al. Foxp3+CD25+ CD4+ natural regulatory cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8–27.CrossRefPubMedGoogle Scholar
  84. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876–85.CrossRefPubMedGoogle Scholar
  85. Sasse SK, Mailloux CM, Barczak AJ, Wang Q, Altonsy MO, Jain MK, et al. The glucocorticoid receptor and KLF15 regulate gene expression dynamics and integrate signals through feed-forward circuitry. Mol Cell Biol. 2013;33:2104–15.CrossRefPubMedCentralPubMedGoogle Scholar
  86. Schwartz R, Dameshek W. Drug-induced immune tolerance. Nature. 1959;183:1682–3.CrossRefPubMedGoogle Scholar
  87. Schwartz R, Dameshek W. The effect of 6-mercaptopurine on homograft reactions. J Clin Invest. 1960;39:952–9588.CrossRefPubMedCentralPubMedGoogle Scholar
  88. Schwartz R, Dameshek W. Treatment of autoimmune hemolytic anemia with 6-mercaptopurine and thioguanine. Blood. 1962;19:483–500.PubMedGoogle Scholar
  89. Seite JF, Shoenfeld Y, Youinou P, Hillion S. What is the content of the magic draft IVIg? Autoimmun Rev. 2008;7:432–9.CrossRefGoogle Scholar
  90. Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology. 2004;127:485–92.CrossRefPubMedGoogle Scholar
  91. Shan J, Feng L, Li Y, Sun G, Chen X, Chen P. The effects of rapamycin on regulatory T cells: its potential time-dependent role in inducing transplant tolerance. Immunol Lett. 2014;182:74–86.CrossRefGoogle Scholar
  92. Sollinger HW, For the U.S. Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation. 1995;60:225–35.CrossRefPubMedGoogle Scholar
  93. Stasi R, Del Poeta G, Stipa E, Evangelista ML, Trawinska MM, Cooper N, et al. Response to B-cell depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura. Blood. 2007;110:2924–30.CrossRefPubMedGoogle Scholar
  94. Stasi R, Cooper N, Del Poeta G, Stipa E, Laura Evangelista M, Abruzzese E, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood. 2008;112:1147–50.CrossRefPubMedGoogle Scholar
  95. Takahashi T, Nomura T. Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2003;212:8–27.Google Scholar
  96. Taylor RM, Bockenstedt P, Su GL, Marrero JA, Pelliter SM, et al. Immune thrombocytopenic purpura following liver transplantation: a case series and review of the literature. Liver Transpl. 2006;12:781–91.CrossRefPubMedGoogle Scholar
  97. Teitsma XM, Marijnissen AKA, Bijlsma JWJ, Lafeber FPJ, Jacobs JWG. Tocilizumab as monotherapy or combination therapy for treating active rheumatoid arthritis: a meta-analysis of efficacy and safety reported in randomized controlled trials. Arthritis Res Ther. 2016;18:211–24.CrossRefPubMedCentralPubMedGoogle Scholar
  98. Van der Goes MC, Jacobs JW, Bijlsma JW. The value of glucocorticoid co-therapy in different rheumatic diseases-positive and adverse effects. Arthritis Res Ther. 2014;16(Suppl 2):1–13.Google Scholar
  99. Von Kutzleben S, Pryce G, Giovannoni G, Baker D. Depletion of CD52-positive cells inhibits the development of central nervous system autoimmune disease, but depletes an immune-tolerance promoting CD8 T-cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis. Immunology. 2016;150:444–55.CrossRefGoogle Scholar
  100. Weetman AP. Graves’ disease following immune reconstitution or immunomodulatory treatment: should we manage it any differently? Clin Endocrinol. 2014;80:629–32.CrossRefGoogle Scholar
  101. Weinblatt ME, Bingham CO 3rd, Burmester G-R, Bykerk VP, Furst DE, et al. A phase 3 study evaluating continuation, tapering, and withdrawal of certolizumab pegol after 1 year of therapy in early rheumatoid arthritis patients. Arthritis Rheumatol. 2017. (print online).Google Scholar
  102. Wiederrecht G, Lam E, Hung S, Martin M, Sigal N. The mechanism of action of FK-506 and cyclosporin A. Ann N Y Acad Sci. 1993;696:9–19.CrossRefPubMedGoogle Scholar
  103. Yan S, Xigo-mei D, Wang Q-T, Sun X-J, Wei W. Prednisone treatment inhibits the differentiation of B lymphocytes into plasma cells in MRL/MpSlac Ipr mice. Acta Pharmacol Sin. 2015;36:1367–1376.Google Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Jane Anne Nohl Division of Hematology and Center for the Study of Blood DiseasesKeck School of Medicine of the University of Southern CaliforniaLos AngelesUSA
  2. 2.Norris Cancer CenterLos AngelesUSA

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