Future Treatment Options in PBC

ABSTRACT

Because the etiopathogenesis of PBC is incompletely defined, curative therapies have not been identified, and the focus has been on prevention of disease progression. Ursodeoxycholic acid retards progression and is likely to be combined with newer therapies in future trials. Advances in our understanding of the roles of retroviral infection and autoimmune responses of T and B cells to PBC-specific autoantigens provides rationales for studies of the safety and efficacy of antiretroviral, immunosuppressive, and immunomodulatory agents in PBC. Promising options include inhibition of (1) T-cell activation and proliferation; (2) transendothelial migration and activation of effector cells; (4) cytokine and immunoglobulin effector mechanisms; and (5) inflammation and oxidation. Depletion and immunomodulation of T and B cells may provide opportunities to thwart re-emergence of effector mechanisms. Induction of tolerance in susceptible people before onset of disease or of hyporesponsiveness in established disease is increasingly feasible, as is prevention of biliary fibrosis.

KEYWORDS

Primary biliary cirrhosis - autoantibody - cholestasis - immunopathogenesis - immunosuppression

REFERENCES

• 1 Vierling J M, Braun M, Wang H-M. Immunopathogenesis of vanishing bile duct syndromes. In: Alpini G, LeSage GD, LaRusso NF Pathophysiology of the Biliary Epithelia Georgetown, TX; Landes Bioscience/Eurekah.com 2003: 349-375
• 2 Mato T K, Davis P A, Odin J A, Coppel R L, Gershwin M E. Sidechain biology and the immunogenicity of PDC-E2, the major autoantigen of primary biliary cirrhosis.  Hepatology. 2004;  40 1241-1248
• 3 Selmi C, Gershwin M E. Bacteria and human autoimmunity: the case of primary biliary cirrhosis.  Curr Opin Rheumatol. 2004;  16 406-410
• 4 Xu L, Shen Z, Guo L et al.. Does a betaretrovirus infection trigger primary biliary cirrhosis?.  Proc Natl Acad Sci USA. 2003;  100 8454-8459
• 5 Selmi C, Ross S R, Ansari A A et al.. Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis.  Gastroenterology. 2004;  127 493-501
• 6 Ichiki Y, Shimoda S, Ishibashi H, Gershwin M E. Is primary biliary cirrhosis a model autoimmune disease?.  Autoimmun Rev. 2004;  3 331-336
• 7 Kita H, Nalbandian G, Keeffe E B, Coppel R L, Gershwin M E. Pathogenesis of primary biliary cirrhosis.  Clin Liver Dis. 2003;  7 821-839
• 8 Olafsson S, Gudjonsson H, Selmi C et al.. Antimitochondrial antibodies and reactivity to N. aromaticivorans proteins in Icelandic patients with primary biliary cirrhosis and their relatives.  Am J Gastroenterol. 2004;  99 2143-2146
• 9 Long S A, Van De W J, Gershwin M E. Antimitochondrial antibodies in primary biliary cirrhosis: the role of xenobiotics.  Autoimmun Rev. 2002;  1 37-42
• 10 Prince M I, Chetwynd A, Craig W L, Metcalf J V, James O F. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort.  Gut. 2004;  53 865-870
• 11 Gottlieb A B. Alefacept is well tolerated in patients with chronic plaque psoriasis.  J Cutan Med Surg. 2004;  8(suppl 2) 14-19
• 12 Zhao S P, Wu J. Fenofibrate reduces tumor necrosis factor-alpha serum concentration and adipocyte secretion of hypercholesterolemic rabbits.  Clin Chim Acta. 2004;  347 145-150
• 13 Crisby M. Modulation of the inflammatory process by statins.  Drugs Today (Barc). 2003;  39 137-143
• 14 Vierling J M. Primary biliary cirrhosis and autoimmune cholangiopathy.  Clin Liver Dis. 2004;  8 177-194
• 15 Muratori P, Muratori L, Gershwin M E et al.. ‘True’ antimitochondrial antibody-negative primary biliary cirrhosis, low sensitivity of the routine assays, or both?.  Clin Exp Immunol. 2004;  135 154-158
• 16 Shigematsu H, Shimoda S, Nakamura M et al.. Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: implications for molecular mimicry and cross-recognition among mitochondrial autoantigens.  Hepatology. 2000;  32 901-909
• 17 Matsumura S, Kita H, He X S et al.. Comprehensive mapping of HLA-A0201-restricted CD8 T-cell epitopes on PDC-E2 in primary biliary cirrhosis.  Hepatology. 2002;  36 1125-1134
• 18 Albanis E, Safadi R, Friedman S L. Treatment of hepatic fibrosis: almost there.  Curr Gastroenterol Rep. 2003;  5 48-56
• 19 Friedman S L. Liver fibrosis-from bench to bedside.  J Hepatol. 2003;  38(suppl 1) S38-S53
• 20 Elster E A, Hale D A, Mannon R B, Cendales L C, Swanson S J, Kirk A D. The road to tolerance: renal transplant tolerance induction in nonhuman primate studies and clinical trials.  Transpl Immunol. 2004;  13 87-99
• 21 Oo Y H, Neuberger J. Options for treatment of primary biliary cirrhosis.  Drugs. 2004;  64 2261-2271
• 22 Lazaridis K N, Gores G J, Lindor K D. Ursodeoxycholic acid mechanisms of action and clinical use in hepatobiliary disorders.  J Hepatol. 2001;  35 134-146
• 23 Gluud C, Christensen E. Ursodeoxycholic acid for primary biliary cirrhosis.  Cochrane Database Syst Rev. 2002;  1 CD000551
• 24 Corpechot C, Carrat F, Bahr A, Chretien Y, Poupon R E, Poupon R. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis.  Gastroenterology. 2005;  128 297-303
• 25 Corpechot C, Poujol-Robert A, Wendum D et al.. Biochemical markers of liver fibrosis and lymphocytic piecemeal necrosis in UDCA-treated patients with primary biliary cirrhosis.  Liver Int. 2004;  24 187-193
• 26 Bogdanos D P, Pares A, Baum H et al.. Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epitope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrhosis.  J Autoimmun. 2004;  22 353-362
• 27 Abdulkarim A S, Petrovic L M, Kim W R, Angulo P, Lloyd R V, Lindor K D. Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae?.  J Hepatol. 2004;  40 380-384
• 28 Durazzo M, Rosina F, Premoli A et al.. Lack of association between seroprevalence of Helicobacter pylori infection and primary biliary cirrhosis.  World J Gastroenterol. 2004;  10 3179-3181
• 29 Mason A, Xu L, Neuberger J. Proof of principal studies to assess the role of the human betaretrovirus in patients with primary biliary cirrhosis.  Am J Gastroenterol. 2004;  99 2499-2500
• 30 Mason A L, Farr G H, Xu L, Hubscher S G, Neuberger J M. Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis.  Am J Gastroenterol. 2004;  99 2348-2355
• 31 Hung C C, Chang S C. Impact of highly active antiretroviral therapy on incidence and management of human immunodeficiency virus-related opportunistic infections.  J Antimicrob Chemother. 2004;  54 849-853
• 32 Vierling J M, Flores P A. Evolving new therapies of autoimmune hepatitis.  Clin Liver Dis. 2002;  6 825-850
• 33 Wiseman H, Duffy R. New advances in the understanding of the role of steroids and steroid receptors in disease.  Biochem Soc Trans. 2001;  29(pt 2) 205-209
• 34 Mitchison H C, Palmer J M, Bassendine M F, Watson A J, Record C O, James O F. A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results.  J Hepatol. 1992;  15 336-344
• 35 Okamoto R, Yamamoto K, Yabushita K et al.. T cell repertoire in primary biliary cirrhosis: a common T cell clone and repertoire change after treatment.  J Clin Immunol. 2001;  21 278-285
• 36 Mazzella G, Fusaroli P, Pezzoli A et al.. Methylprednisolone administration in primary biliary cirrhosis increases cholic acid turnover, synthesis, and deoxycholate concentration in bile.  Dig Dis Sci. 1999;  44 2478-2483
• 37 Leuschner M, Guldutuna S, You T, Hubner K, Bhatti S, Leuschner U. Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis.  J Hepatol. 1996;  25 49-57
• 38 O'Connell E J. Review of the unique properties of budesonide.  Clin Ther. 2003;  25(suppl C) C42-C60
• 39 Hempfling W, Grunhage F, Dilger K, Reichel C, Beuers U, Sauerbruch T. Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis.  Hepatology. 2003;  38 196-202
• 40 Leuschner M, Maier K P, Schlichting J et al.. Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial.  Gastroenterology. 1999;  117 918-925
• 41 Rautiainen H, Karkkainen P, Karvonen A L et al.. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial.  Hepatology. 2005;  41 747-752
• 42 Angulo P, Jorgensen R A, Keach J C, Dickson E R, Smith C, Lindor K D. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.  Hepatology. 2000;  31 318-323
• 43 Jorgensen K A, Koefoed-Nielsen P B, Karamperis N. Calcineurin phosphatase activity and immunosuppression. A review on the role of calcineurin phosphatase activity and the immunosuppressive effect of cyclosporin A and tacrolimus.  Scand J Immunol. 2003;  57 93-98
• 44 Jiang S, Herrera O, Lechler R I. New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance.  Curr Opin Immunol. 2004;  16 550-557
• 45 Wu H Y, Weiner H L. Oral tolerance.  Immunol Res. 2003;  28 265-284
• 46 Beukers R, de Rave S, van den Berg J W, Schalm S W. Oral pharmacokinetics of cyclosporin in patients with primary biliary cirrhosis and patients with skin diseases.  Aliment Pharmacol Ther. 1992;  6 459-468
• 47 Wiesner R H, Ludwig J, Lindor K D et al.. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis.  N Engl J Med. 1990;  322 1419-1424
• 48 Lombard M, Portmann B, Neuberger J et al.. Cyclosporin A treatment in primary biliary cirrhosis: results of a long-term placebo controlled trial.  Gastroenterology. 1993;  104 519-526
• 49 Guanabens N, Pares A, Navasa M et al.. Cyclosporin A increases the biochemical markers of bone remodeling in primary biliary cirrhosis.  J Hepatol. 1994;  21 24-28
• 50 Hanley D A, Ayer L M, Gundberg C M, Minuk G Y. Parameters of calcium metabolism during a pilot study of cyclosporin A in patients with symptomatic primary biliary cirrhosis.  Clin Invest Med. 1991;  14 282-287
• 51 Parsons H G, Thirsk J E, Frohlich J, Dias V, Minuk G Y. Effect of cyclosporin A on serum lipids in primary biliary cirrhosis patients.  Clin Invest Med. 1989;  12 386-391
• 52 Robson S C, Neuberger J M, Williams R. The influence of cyclosporine A therapy on sex hormone levels in pre- and post-menopausal women with primary biliary cirrhosis.  J Hepatol. 1994;  21 412-416
• 53 McMichael J, Lieberman R, McCauley J, Irish W, Marino I, Doyle H. Computer-guided randomized concentration-controlled trials of tacrolimus in autoimmunity: multiple sclerosis and primary biliary cirrhosis.  Ther Drug Monit. 1996;  18 435-437
• 54 Thomson A W, Bonham C A, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms.  Ther Drug Monit. 1995;  17 584-591
• 55 Lunz III J G, Contrucci S, Ruppert K et al.. Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs.  Am J Pathol. 2001;  158 1379-1390
• 56 Neuberger J, Gunson B, Hubscher S, Nightingale P. Immunosuppression affects the rate of recurrent primary biliary cirrhosis after liver transplantation.  Liver Transpl. 2004;  10 488-491
• 57 Simon H U, Spath P J. IVIG-mechanisms of action.  Allergy. 2003;  58 543-552
• 58 Sherer Y, Levy Y, Langevitz P, Rauova L, Fabrizzi F, Shoenfeld Y. Adverse effects of intravenous immunoglobulin therapy in 56 patients with autoimmune diseases.  Pharmacology. 2001;  62 133-137
• 59 Skov L, Kragballe K, Zachariae C et al.. HuMax-CD4: a fully human monoclonal anti-CD4 antibody for the treatment of psoriasis vulgaris.  Arch Dermatol. 2003;  139 1433-1439
• 60 Winsor-Hines D, Merrill C, O’Mahony M et al.. Induction of immunological tolerance/hyporesponsiveness in baboons with a nondepleting CD4 antibody.  J Immunol. 2004;  173 4715-4723
• 61 Mileski W J, Burkhart D, Hunt J L et al.. Clinical effects of inhibiting leukocyte adhesion with monoclonal antibody to intercellular adhesion molecule-1 (enlimomab) in the treatment of partial-thickness burn injury.  J Trauma. 2003;  54 950-958
• 62 Becker K J. Anti-leukocyte antibodies: LeukArrest (Hu23F2G) and Enlimomab (R6.5) in acute stroke.  Curr Med Res Opin. 2002;  18(suppl 2) s18-s22
• 63 Dedrick R L, Walicke P, Garovoy M. Anti-adhesion antibodies efalizumab, a humanized anti-CD11a monoclonal antibody.  Transpl Immunol. 2002;  9 181-186
• 64 Leonardi C L, Papp K A, Gordon K B et al.. Extended efalizumab therapy improves chronic plaque psoriasis: results from a randomized phase III trial.  J Am Acad Dermatol. 2005;  52(3 pt 1) 425-433
• 65 Menter A, Gordon K, Carey W et al.. Efficacy and safety observed during 24 weeks of efalizumab therapy in patients with moderate to severe plaque psoriasis.  Arch Dermatol. 2005;  141 31-38
• 66 Najafian N, Sayegh M H. CTLA4-Ig: a novel immunosuppressive agent.  Expert Opin Investig Drugs. 2000;  9 2147-2157
• 67 Li S, Thanikachalam M, Pang M, Kawaharada N, Aitouche A, Pham S M. A clinically relevant CTLA4-Ig-based regimen induces chimerism and tolerance to heart grafts.  Ann Thorac Surg. 2001;  72 1306-1310
• 68 Hodak E, David M. Alefacept: a review of the literature and practical guidelines for management.  Dermatol Ther. 2004;  17 383-392
• 69 Liu C M, McKenna J K, Krueger G G. Alefacept: a novel biologic in the treatment of psoriasis.  Drugs Today (Barc). 2004;  40 961-974
• 70 Gordon K B, Valentine J. The efficacy of alefacept in the treatment of chronic plaque psoriasis.  J Cutan Med Surg. 2004;  8(suppl 2) 3-9
• 71 Grewal I S, Flavell R A. The role of CD40 ligand in costimulation and T-cell activation.  Immunol Rev. 1996;  153 85-106
• 72 Elster E A, Xu H, Tadaki D K et al.. Treatment with the humanized CD154-specific monoclonal antibody, hu5C8, prevents acute rejection of primary skin allografts in nonhuman primates.  Transplantation. 2001;  72 1473-1478
• 73 Xu H, Tadaki D K, Elster E A et al.. Humanized anti-CD154 antibody therapy for the treatment of allograft rejection in nonhuman primates.  Transplantation. 2002;  74 940-943
• 74 Starck L, Scholz C, Dorken B, Daniel P T. Costimulation by CD137/4-1BB inhibits T cell apoptosis and induces Bcl-x(L) and c-FLIP(short) via phosphatidylinositol 3-kinase and AKT/protein kinase B.  Eur J Immunol. 2005;  35 1257-1266
• 75 Shao H, Fu Y, Liao T et al.. Anti-CD137 mAb treatment inhibits experimental autoimmune uveitis by limiting expansion and increasing apoptotic death of uveitogenic T cells.  Invest Ophthalmol Vis Sci. 2005;  46 596-603
• 76 Rowinsky E K. Targeting the molecular target of rapamycin (mTOR).  Curr Opin Oncol. 2004;  16 564-575
• 77 Nashan B. Review of the proliferation inhibitor everolimus.  Expert Opin Investig Drugs. 2002;  11 1845-1857
• 78 Kahan B D. Sirolimus-based immunosuppression: present state of the art.  J Nephrol. 2004;  17(suppl 8) S32-S39
• 79 Niemeyer G, Koch M, Light S, Kuse E R, Nashan B. Long-term safety, tolerability and efficacy of daclizumab (Zenapax) in a two-dose regimen in liver transplant recipients.  Am J Transplant. 2002;  2 454-460
• 80 Kapic E, Becic F, Kusturica J. Basiliximab, mechanism of action and pharmacological properties.  Med Arh. 2004;  58 373-376
• 81 Baudouin V, Crusiaux A, Haddad E et al.. Anaphylactic shock caused by immunoglobulin E sensitization after retreatment with the chimeric anti-interleukin-2 receptor monoclonal antibody basiliximab.  Transplantation. 2003;  76 459-463
• 82 Bielekova B, Richert N, Howard T et al.. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta.  Proc Natl Acad Sci USA. 2004;  101 8705-8708
• 83 Van Assche G, Dalle I, Noman M et al.. A pilot study on the use of the humanized anti-interleukin-2 receptor antibody daclizumab in active ulcerative colitis.  Am J Gastroenterol. 2003;  98 369-376
• 84 Lee S J, Zahrieh D, Agura E et al.. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial.  Blood. 2004;  104 1559-1564
• 85 Massenkeil G, Rackwitz S, Genvresse I, Rosen O, Dorken B, Arnold R. Basiliximab is well tolerated and effective in the treatment of steroid-refractory acute graft-versus-host disease after allogeneic stem cell transplantation.  Bone Marrow Transplant. 2002;  30 899-903
• 86 Heathcote E J. Evidence-based therapy of primary biliary cirrhosis.  Eur J Gastroenterol Hepatol. 1999;  11 607-615
• 87 Moder K G. Mycophenolate mofetil: new applications for this immunosuppressant.  Ann Allergy Asthma Immunol. 2003;  90 15-19
• 88 Jones E A. Rationale for trials of long-term mycophenolate mofetil therapy for primary biliary cirrhosis.  Hepatology. 2002;  35 258-262
• 89 Talwalkar J A, Angulo P, Keach J C, Petz J L, Jorgensen R A, Lindor K D. Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid.  J Clin Gastroenterol. 2005;  39 168-171
• 90 Maddison P, Kiely P, Kirkham B et al.. Leflunomide in rheumatoid arthritis: recommendations through a process of consensus.  Rheumatology (Oxford). 2005;  44 280-286
• 91 Grisar J, Aringer M, Koller M D et al.. Leflunomide inhibits transendothelial migration of peripheral blood mononuclear cells.  Ann Rheum Dis. 2004;  63 1632-1637
• 92 Cannon G W, Holden W L, Juhaeri J, Dai W, Scarazzini L, Stang P. Adverse events with disease modifying antirheumatic drugs (DMARD): a cohort study of leflunomide compared with other DMARD.  J Rheumatol. 2004;  31 1906-1911
• 93 Laborde F, Loeuille D, Chary-Valckenaere I. Life-threatening hypertriglyceridemia during leflunomide therapy in a patient with rheumatoid arthritis.  Arthritis Rheum. 2004;  50 3398
• 94 Macdonald J, Zhong T, Lazarescu A, Gan B S, Harth M. Vasculitis associated with the use of leflunomide.  J Rheumatol. 2004;  31 2076-2078
• 95 Sevilla-Mantilla C, Ortega L, Agundez J A, Fernandez-Gutierrez B, Ladero J M, Diaz-Rubio M. Leflunomide-induced acute hepatitis.  Dig Liver Dis. 2004;  36 82-84
• 96 Kremer J M, Cannon G W. Benefit/risk of leflunomide in rheumatoid arthritis.  Clin Exp Rheumatol. 2004;  22(5 suppl 35) S95-100
• 97 Korn T, Magnus T, Toyka K, Jung S. Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide-mechanisms independent of pyrimidine depletion.  J Leukoc Biol. 2004;  76 950-960
• 98 Yao H W, Li J, Chen J Q, Xu S Y. Leflunomide attenuates hepatocyte injury by inhibiting Kupffer cells.  World J Gastroenterol. 2004;  10 1608-1611
• 99 Schrepfer S, Deuse T, Schafer H, Reichenspurner H. FK778, a novel immunosuppressive agent, reduces early adhesion molecule up-regulation and prolongs cardiac allograft survival.  Transpl Int. 2005;  18 215-220
• 100 Vanrenterghem Y, van Hooff J P, Klinger M et al.. The effects of FK778 in combination with tacrolimus and steroids: a phase II multicenter study in renal transplant patients.  Transplantation. 2004;  78 9-14
• 101 Xu D, Alegre M L, Varga S S et al.. In vitro characterization of five humanized OKT3 effector function variant antibodies.  Cell Immunol. 2000;  200 16-26
• 102 Popma S H, Griswold D E, Li L. Anti-CD3 antibodies OKT3 and hOKT3gamma1(Ala-Ala) induce proliferation of T cells but impair expansion of alloreactive T cells; a specific T cell proliferation induced by anti-CD3 antibodies correlates with impaired expansion of alloreactive T cells.  Int Immunopharmacol. 2005;  5 155-162
• 103 Kjer-Nielsen L, Dunstone M A, Kostenko L et al.. Crystal structure of the human T cell receptor CD3 epsilon gamma heterodimer complexed to the therapeutic mAb OKT3.  Proc Natl Acad Sci USA. 2004;  101 7675-7680
• 104 Carpenter P A, Tso J Y, Press O W, Yu X, Anasetti C. Non-FcR-binding, humanized anti-CD3 antibody Hu291 induces apoptosis of human T cells more effectively than OKT3 and is immunosuppressive in vivo.  Transplant Proc. 2000;  32 1545-1546
• 105 Ravandi F. O'Brien S. Alemtuzumab.  Expert Rev Anticancer Ther. 2005;  5 39-51
• 106 Marcos A, Eghtesad B, Fung J J et al.. Use of alemtuzumab and tacrolimus monotherapy for cadaveric liver transplantation: with particular reference to hepatitis C virus.  Transplantation. 2004;  78 966-971
• 107 Iannitto E, Minardi V, Calvaruso G et al.. Hepatitis B virus reactivation and alemtuzumab therapy.  Eur J Haematol. 2005;  74 254-258
• 108 Cannon G W, Kremer J M. Leflunomide.  Rheum Dis Clin North Am. 2004;  30 295-309
• 109 Migita K, Miyashita T, Ishibashi H et al.. Suppressive effect of leflunomide metabolite (A77 1726) on metalloproteinase production in IL-1beta stimulated rheumatoid synovial fibroblasts.  Clin Exp Immunol. 2004;  137 612-616
• 110 Brinkmann V. FTY720: mechanism of action and potential benefit in organ transplantation.  Yonsei Med J. 2004;  45 991-997
• 111 Muller H, Hofer S, Kaneider N et al.. The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells.  Eur J Immunol. 2005;  35 533-545
• 112 Lee W J, Yoo H S, Suh P G, Oh S, Lim J S, Lee Y M. Sphingosine mediates FTY720-induced apoptosis in LLC-PK1 cells.  Exp Mol Med. 2004;  36 420-427
• 113 Nagahara Y, Ikekita M, Shinomiya T. T cell selective apoptosis by a novel immunosuppressant, FTY720, is closely regulated with Bcl-2.  Br J Pharmacol. 2002;  137 953-962
• 114 Kita Y, Li X K, Nogimura H et al.. CTLA4Ig-gene transfection with FTY720 administration markedly inhibits the obliterative airway disease in heterotopically transplanted rat tracheas.  Transplant Proc. 2003;  35 458-460
• 115 Kimura T, Hasegawa T, Nakai H et al.. FTY720 reduces T-cell recruitment into murine intestinal allograft and prevents activation of graft-infiltrating cells.  Transplantation. 2003;  75 1469-1474
• 116 Han S, Zhang X, Wang G et al.. FTY720 suppresses humoral immunity by inhibiting germinal center reaction.  Blood. 2004;  104 4129-4133
• 117 Koyrakh L, Roman M I, Brinkmann V, Wickman K. The heart rate decrease caused by acute FTY720 administration is mediated by the G protein-gated potassium channel I.  Am J Transplant. 2005;  5 529-536
• 118 Anonymous. Natalizumab: AN 100226, anti-4alpha integrin monoclonal antibody.  Drugs R D. 2004;  5 102-107
• 119 Miller D H, Khan O A, Sheremata W A et al.. A controlled trial of natalizumab for relapsing multiple sclerosis.  N Engl J Med. 2003;  348 15-23
• 120 Ghosh S, Goldin E, Gordon F H et al.. Natalizumab for active Crohn’s disease.  N Engl J Med. 2003;  348 24-32
• 121 In Brief. Natalizumab (Tysabri) withdrawn.  Med Lett Drugs Ther. 2005;  47 21
• 122 Fernandez E J, Lolis E. Structure, function, and inhibition of chemokines.  Annu Rev Pharmacol Toxicol. 2002;  42 469-499
• 123 Kamihira T, Shimoda S, Nakamura M et al.. Biliary epithelial cells regulate autoreactive T cells: implications for biliary-specific diseases.  Hepatology. 2005;  41 151-159
• 124 Shaw J P, Johnson Z, Borlat F et al.. The X-ray structure of RANTES: heparin-derived disaccharides allows the rational design of chemokine inhibitors.  Structure (Camb). 2004;  12 2081-2093
• 125 Matsui M, Weaver J, Proudfoot A E et al.. Treatment of experimental autoimmune encephalomyelitis with the chemokine receptor antagonist Met-RANTES.  J Neuroimmunol. 2002;  128 16-22
• 126 Sigrist S, Oberholzer J, Bohbot A et al.. Activation of human macrophages by allogeneic islets preparations: inhibition by AOP-RANTES and heparinoids.  Immunology. 2004;  111 416-421
• 127 Kawamura T, Bruse S E, Abraha A et al.. PSC-RANTES blocks R5 human immunodeficiency virus infection of Langerhans cells isolated from individuals with a variety of CCR5 diplotypes.  J Virol. 2004;  78 7602-7609
• 128 Foster-Cuevas M, Wright G J, Puklavec M J, Brown M H, Barclay A N. Human herpesvirus 8 K14 protein mimics CD200 in down-regulating macrophage activation through CD200 receptor.  J Virol. 2004;  78 7667-7676
• 129 Song E, Zou H, Yao Y et al.. Early application of Met-RANTES ameliorates chronic allograft nephropathy.  Kidney Int. 2002;  61 676-685
• 130 Bedke J, Stojanovic T, Grone H J et al.. Met-RANTES improves acute-rejection-induced microvascular injury in rat small bowel transplantation.  Transplant Proc. 2002;  34 1049
• 131 Chvatchko Y, Proudfoot A E, Buser R et al.. Inhibition of airway inflammation by amino-terminally modified RANTES/CC chemokine ligand 5 analogues is not mediated through CCR3.  J Immunol. 2003;  171 5498-5506
• 132 Heise C E, Pahuja A, Hudson S C et al.. Pharmacological Characterization of CXC Chemokine Receptor 3 (CXCR3) Ligands and a Small-Molecule Antagonist.  J Pharmacol Exp Ther. 2005;  313 1263-1271
• 133 Belperio J A, Keane M P, Burdick M D et al.. Role of CXCL9/CXCR3 chemokine biology during pathogenesis of acute lung allograft rejection.  J Immunol. 2003;  171 4844-4852
• 134 Schreiber S, Fedorak R N, Nielsen O H et al.. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn’s disease. Crohn’s Disease IL-10 Cooperative Study Group.  Gastroenterology. 2000;  119 1461-1472
• 135 Rea D, Laface D, Hutchins B et al.. Recombinant adenovirus-transduced human dendritic cells engineered to secrete interleukin-10 (IL-10) suppress Th1-type responses while selectively activating IL-10-producing CD4+ T cells.  Hum Immunol. 2004;  65 1344-1355
• 136 Shen C, Assche G V, Colpaert S et al.. Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept.  Aliment Pharmacol Ther. 2005;  21 251-258
• 137 van den Brande J, Hommes D W, Peppelenbosch M P. Infliximab induced T lymphocyte apoptosis in Crohn’s disease.  J Rheumatol. 2005;  74(suppl) 26-30
• 138 Tak P P. Effects of infliximab treatment on rheumatoid synovial tissue.  J Rheumatol Suppl. 2005;  74 31-34
• 139 Doty J D, Mazur J E, Judson M A. Treatment of sarcoidosis with infliximab.  Chest. 2005;  127 1064-1071
• 140 Baker D E. Adalimumab: human recombinant immunoglobulin g1 anti-tumor necrosis factor monoclonal antibody.  Rev Gastroenterol Disord. 2004;  4 196-210
• 141 Brocq O, Albert C, Roux C, Gerard D, Breuil V, Ziegler L E. Adalimumab in rheumatoid arthritis after failed infliximab and/or etanercept therapy: experience with 18 patients.  Joint Bone Spine. 2004;  71 601-603
• 142 Papadakis K A, Shaye O A, Vasiliauskas E A et al.. Safety and efficacy of adalimumab (D2E7) in Crohn’s disease patients with an attenuated response to infliximab.  Am J Gastroenterol. 2005;  100 75-79
• 143 Nanda S, Bathon J M. Etanercept: a clinical review of current and emerging indications.  Expert Opin Pharmacother. 2004;  5 1175-1186
• 144 Simonini G, Giani T, Stagi S, de Martino M, Falcini F. Bone status over 1 yr of etanercept treatment in juvenile idiopathic arthritis.  Rheumatology (Oxford). 2005;  44 777-780
• 145 Lebwohl M G. Use of etanercept in the dermatology setting. A review.  Am J Clin Dermatol. 2005;  6 49-59
• 146 Zein N N. Etanercept as an adjuvant to interferon and ribavirin in treatment-naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double-blind, placebo-controlled study.  J Hepatol. 2005;  42 315-322
• 147 Taal B G, Schalm S W, de Bruyn A M, de Rooy F W, Klein F. Serum IgM in primary biliary cirrhosis.  Clin Chim Acta. 1980;  108 457-463
• 148 Krams S M, Van De W J, Coppel R L et al.. Analysis of hepatic T lymphocyte and immunoglobulin deposits in patients with primary biliary cirrhosis.  Hepatology. 1990;  12 306-313
• 149 Kita H, Imawari M, Gershwin M E. Cellular immune response in primary biliary cirrhosis.  Hepatol Res. 2004;  28 12-17
• 150 Rastetter W, Molina A, White C A. Rituximab: expanding role in therapy for lymphomas and autoimmune diseases.  Annu Rev Med. 2004;  55 477-503
• 151 Horning S J. Optimizing rituximab in B-cell lymphoma.  J Clin Oncol. 2005;  23 1056-1058
• 152 Gordan L N, Grow W B, Pusateri A, Douglas V, Mendenhall N P, Lynch J W. Phase II trial of individualized rituximab dosing for patients with CD20-positive lymphoproliferative disorders.  J Clin Oncol. 2005;  23 1096-1102
• 153 Virgolini L, Marzocchi V. Rituximab in autoimmune diseases.  Biomed Pharmacother. 2004;  58 299-309
• 154 Looney R J, Anolik J H, Campbell D et al.. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab.  Arthritis Rheum. 2004;  50 2580-2589
• 155 Gottenberg J, Guillevin L, Lambotte O et al.. Tolerance and short-term efficacy of rituximab in 43 patients with systemic autoimmune diseases.  Ann Rheum Dis. 2004;  64 913-920
• 156 Kita H, Lian Z X, Van De W J et al.. Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells.  J Exp Med. 2002;  195 113-123
• 157 Fazio S, Linton M F. The role of fibrates in managing hyperlipidemia: mechanisms of action and clinical efficacy.  Curr Atheroscler Rep. 2004;  6 148-157
• 158 Chang P Y, Lu S C, Su T C et al.. Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation.  J Lipid Res. 2004;  45 2116-2122
• 159 Matsumoto T, Miyazaki H, Nakahashi Y et al.. Multidrug resistance3 is in situ detected in the liver of patients with primary biliary cirrhosis, and induced in human hepatoma cells by bezafibrate.  Hepatol Res. 2004;  30 125-136
• 160 Itakura J, Izumi N, Nishimura Y et al.. Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis.  Hepatol Res. 2004;  29 216-222
• 161 Hays T, Rusyn I, Burns A M et al.. Role of peroxisome proliferator-activated receptor-alpha (PPARalpha) in bezafibrate-induced hepatocarcinogenesis and cholestasis.  Carcinogenesis. 2005;  26 219-227
• 162 Dohmen K, Mizuta T, Nakamuta M, Shimohashi N, Ishibashi H, Yamamoto K. Fenofibrate for patients with asymptomatic primary biliary cirrhosis.  World J Gastroenterol. 2004;  10 894-898
• 163 Ho C Y, Kuo T H, Chen T S, Tsay S H, Chang F Y, Lee S D. Fenofibrate-induced acute cholestatic hepatitis.  J Chin Med Assoc. 2004;  67 245-247
• 164 Ahmed F, Petrovic L, Rosen E, Gonzalez R, Jacobson I M. Fenofibrate-induced cirrhosis.  Dig Dis Sci. 2005;  50 312-313
• 165 Parnes S M. The role of leukotriene inhibitors in patients with paranasal sinus disease.  Curr Opin Otolaryngol Head Neck Surg. 2003;  11 184-191
• 166 Nakamura A, Yamazaki K, Suzuki K, Sato S. Increased portal tract infiltration of mast cells and eosinophils in primary biliary cirrhosis.  Am J Gastroenterol. 1997;  92 2245-2249
• 167 Obase Y, Shimoda T, Matsuse H et al.. The position of pranlukast, a cysteinyl leukotriene receptor antagonist, in the long-term treatment of asthma. 5-year follow-up study.  Respiration. 2004;  71 225-232
• 168 Joshi E M, Heasley B H, Chordia M D, Macdonald T L. In vitro metabolism of 2-acetylbenzothiophene: relevance to zileuton hepatotoxicity.  Chem Res Toxicol. 2004;  17 137-143
• 169 Su C W, Wu J C, Huang Y H, Huang Y S, Chang F Y, Lee S D. Zafirlukast-induced acute hepatitis.  Zhonghua Yi Xue Za Zhi (Taipei). 2002;  65 553-556
• 170 Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial.  Neurology. 2001;  57 1428-1434
• 171 Goldstein M F, Anoia J, Black M. Montelukast-induced hepatitis.  Ann Intern Med. 2004;  140 586-587
• 172 Fukushima C, Matsuse H, Hishikawa Y et al.. Pranlukast, a leukotriene receptor antagonist, inhibits interleukin-5 production via a mechanism distinct from leukotriene receptor antagonism.  Int Arch Allergy Immunol. 2005;  136 165-172
• 173 Ishinaga H, Takeuchi K, Kishioka C, Suzuki S, Basbaum C, Majima Y. Pranlukast inhibits NF-kappaB activation and MUC2 gene expression in cultured human epithelial cells.  Pharmacology. 2005;  73 89-96
• 174 Ichiyama T, Hasegawa S, Umeda M, Terai K, Matsubara T, Furukawa S. Pranlukast inhibits NF-kappa B activation in human monocytes/macrophages and T cells.  Clin Exp Allergy. 2003;  33 802-807
• 175 Liu K H, Lee Y M, Shon J H et al.. Potential of pranlukast and zafirlukast in the inhibition of human liver cytochrome P450 enzymes.  Xenobiotica. 2004;  34 429-438
• 176 Shimbo J, Onodera O, Tanaka K, Tsuji S. Churg-Strauss syndrome and the leukotriene receptor antagonist pranlukast.  Clin Rheumatol. 2004;  23 581-582
• 177 Fehr T, Sykes M. Tolerance induction in clinical transplantation.  Transpl Immunol. 2004;  13 117-130
• 178 Sayegh M H, Perico N, Remuzzi G. Transplantation tolerance. A complex scenario awaiting clinical applicability.  Contrib Nephrol. 2005;  146 95-104
• 179 Mayer L, Shao L. Therapeutic potential of oral tolerance.  Nat Rev Immunol. 2004;  4 407-419
• 180 Lu L, Thomson A W. Manipulation of dendritic cells for tolerance induction in transplantation and autoimmune disease.  Transplantation. 2002;  73(1 suppl) S19-S22
• 181 Xiao B G, Huang Y M, Link H. Dendritic cell vaccine design: strategies for eliciting peripheral tolerance as therapy of autoimmune diseases.  BioDrugs. 2003;  17 103-111
• 182 Suzuki A. Van De WJ, Gershwin ME, Jorgensen R, Angulo P, Lindor K. Oral tolerance and pyruvate dehydrogenase in patients with primary biliary cirrhosis.  Dev Immunol. 2002;  9 55-61
• 183 Amano K, Leung P S, Xu Q et al.. Xenobiotic-induced loss of tolerance in rabbits to the mitochondrial autoantigen of primary biliary cirrhosis is reversible.  J Immunol. 2004;  172 6444-6452
• 184 Timmerman J M, Czerwinski D K, Davis T A et al.. Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients.  Blood. 2002;  99 1517-1526
• 185 Wright G J, Cherwinski H, Foster-Cuevas M et al.. Characterization of the CD200 receptor family in mice and humans and their interactions with CD200.  J Immunol. 2003;  171 3034-3046
• 186 Gorczynski R, Chen Z, Kai Y, Lee L, Wong S, Marsden P A. CD200 is a ligand for all members of the CD200R family of immunoregulatory molecules.  J Immunol. 2004;  172 7744-7749
• 187 Jiang S, Lechler R I. Regulatory T cells in the control of transplantation tolerance and autoimmunity.  Am J Transplant. 2003;  3 516-524
• 188 Walsh P T, Taylor D K, Turka L A. Tregs and transplantation tolerance.  J Clin Invest. 2004;  114 1398-1403
• 189 Bataller R, Brenner D A. Liver fibrosis.  J Clin Invest. 2005;  115 209-218
• 190 Clouston A D, Powell E E, Walsh M J, Richardson M M, Demetris A J, Jonsson J R. Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis.  Hepatology. 2005;  41 809-818