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1、Pathogenesis-oriented approaches for the management of immune thrombocytopenia,Qilu hospital,Shandong University No competing financial interests to declare,Ming Hou,MD,PhD,ITPBackground,Immune thrombocytopenia(ITP)is the most common autoimmune hemorrhagic disorder,Incidence:3 new cases x 100,000 pe
2、rson-yearsPrevalence:20 cases x 100,000 person-years,12,10,8,6,4,2,0,18,1824,2534,3544,4554,5559,5964,6574,7584,85100,Total,Age(Year),Average annual incidence(/100,000 person-years),Female,Male,Schoonen,et al.Br J Haematol 2009;92:116571,Average annual ITP incidence by age group and gender(n=1145),E
3、vents per patient-year,Fatal,0.4%,1.2%,13%,0.35,0.30,0.25,0.20,0.15,0.10,0.05,0.00,40,Age(years),4060,60,Non-fatal,2.5%,7.3%,1.75,1.50,1.25,1.00,0.75,0.50,0.25,0.00,40,Age(years),4060,60,72%,Cohen,et al.Arch Intern Med 2000;160:163038,Estimated annual rate of bleeding according to age group,Life Qua
4、lity in Chronic ITP Patients,American Journal of Hematology DOI 10.1002/ajh 2008,Healthy,General Population,Cancer,Hypertension,Arthritis,ITP,Diabetes,CHF,Limo,ITP,Part I Pathogenesis of ITP,Pathogenesis,Increased platelet destruction,2,Decreased platelet production,3,1.Lost of tolerance,Oligoclonal
5、 GP-specific T-lymphocytes Fogarty PF,et al.Clin Adv Hematol Oncol 2003;1:365-71Disturbed apoptosis of GP-specific T-lymphocytes Olsson,et al.Thromb Haemost 2005;93:139-44Lost of T-cell tolerance to self antigen in ITP Peng，et al.Blood 2003；101：2721-26 Zhang，et al.J Thrombosis Haemostasis 2007；6:158
6、65,1.Lost of tolerance,T cell activation in ITP Semple et al.Blood 1991;78:2619-25 Semple et al.Blood 1996;87:4245-54,Mapping T-cell epitopes in ITPKuwana et al.J Clin Invest 1998;1002:1393-402 Sukati et al.Blood 2007;109:4528-38,Pathogenesis,Increased platelet destruction,2,Decreased platelet produ
7、ction,3,2.Increased platelet destruction,Autoantibody-mediated platelet clearance;Zucker-Franklin，et al.N Engl J Med 1977;297:517-23CTL-mediated platelet lysis Olsson，et al.Nat Med 2003;9:1123-27,2.Increased platelet destruction,Zhao CH,et al.Haematologica 2008;93:1428-30,Zhang F,et al.Eur J Haemato
8、l 2006;76:427-31,Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura,Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies,2.Increased platelet destruction,Chow,et
9、 al.Blood 2010;115:1247-53,GPIIIa knockout miceImmunized with platelets,CD19(+)Splenocytes,CD8(+)Splenocytes,SCID mice,Thrombo-cytopenia,Thrombo-cytopenia,Mouse model of ITP,Pathogenesis,Increased platelet destruction,2,Decreased platelet production,3,Platelet production is suboptimal in ITP patient
10、s,Autologous 111In-platelet studies show platelet production normal in 2/3 patientsTPO levels normal in 75%of ITP patients(relative TPO deficiency)Autoantibodies inhibit both Mk growth and Mk apoptosisTrail-mediated megakaryocyte para-apoptosis leading to in vitro dysmegakaryocytopoiesis and impaire
11、d platelet production,Hou et al.Br J Haematol 1998;101:420-4,Thrombopoietin levels in ITP patients,3.Decreased platelet production,Autoantibody-mediated dysmegakaryocytopoiesis,Chang,et al.Blood 2003;102:887-95,McMillan,et al.Blood 2004;103:1364-69,Immune thrombocytopenic purpura(ITP)plasma and puri
12、fied ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro,Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP,3.Decreased platelet production,CTL-mediated Impaired megakaryocyte apoptosis,Li,et al.Br J Haematol 2007;139:
13、605-11,3.Decreased platelet production,Trail-mediated megakaryocyte para-apoptosis leading to in vitro dysmegakaryocytopoiesis,plasma,antibody,Removal of antibody,The number of megakaryocytes,Megakaryocyte apoptosis,Antibodies inhibit the Generation of megakaryocytes,Yang,et al.Blood 2010;116:4307-1
14、6,Part IIPathogenesis-oriented approaches for the management of immune thrombocytopenia,1.Restoration of tolerance,Zhang,et al.J Thromb Haemost 2007;6:15865,Effect of B7-blocking agent and/or CsA on induction of platelet-specific T-cell anergy in chronic autoimmune thrombocytopenic purpura,Peng，et a
15、l.Blood 2003;101:2721-6,Modulation of immune response with cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin-induced anergic T cells in chronic idiopathic thrombocytopenic purpura,（1）Induction of anergic T,Induction of T-cell tolerance to platelet Ags for patients with ITP,Induction of T-ce
16、ll tolerance to platelet Ags for patients with ITP,Specificity of T-cell anergy to platelet Ags induced by CTLA4-Ig and/or CsA,Peng，et al.Blood 2003;101:2721-6,（1）Induction of anergic T,1.Restore T cell tolerance,The induced anergized GP-specific T cells exerted suppressive effects on both GP-specif
17、ic T-cell proliferation and antibody production,Zhang,et al.J Thromb Haemost 2007;6:15865,（1）Induction of anergic T,（2）Increased the apoptosis of GP-specific T-cells,(1)Dexamethasone-induced apoptosisT-lymphocytes from ITP in remission displayed an increased apoptosis in the presence of dexamethason
18、e.Olsson,et al.Thromb Haemost2005;93:139-44,A,B,(2)BR3-Fc restores the apoptosis of GP-specific T cellsrhBAFF reduced the apoptosis of B and T cells in ITP patients;BAFF-R-Fc fusion protein(BR3-Fc)restores the apoptosis of B and T cells;Zhu，et al.Blood 2009；114:5362-67,（2）Increased the apoptosis of
19、GP-specific T-cells,Guo J Clin Immunol.2007;27:557-62,Shan,et al.Haematologica 2009;94:1603-7,Correction of Th1-dominant cytokine profiles by high-dose dexamethasonein patients with chronic idiopathic thrombocytopenic purpura,High dose Dexamethasone regulates interleukin-18 and interleukin-18 bindin
20、gprotein in idiopathic thrombocytopenic purpura,（3）Restore the balance of Th1/Th2,High-dose dexamethasone,Ling,et al.Eur J Haematol 2007;79:310-6,After the therapy of HD-DXM,the frequency of CD4+Foxp3+Treg cells was significantly increased,（4）Increase the number of Tregs,Circulating dendritic cells
21、subsets and CD4+Foxp3+regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasone,Rituximab,Stasi,et al.Blood 2008;15:1147-50,The number and the percentage of Tregs increased significantly after rituximab therapy,Analysis of regulatory T-cell changes
22、 in patients with idiopathic thrombocytopenicpurpura receiving B cell depleting therapy with rituximab,（4）Increase the number of Tregs,Indirubin,Indirubin could significantly enhance the percentages of functional Tregs,Zhang,et al.J Mol Med 2007;85:126370,The different effects of indirubin on effect
23、or and CD4+CD25+regulatory T cellsin mice:potential implication for the treatment of autoimmune diseases,（4）Increase the number of Tregs,（4）Increase the number of Tregs,De novo induction of Tregs,De novo induction of Tregs,before induction after induction,1、GP specific iTreg could be induced in vitr
24、o from ITP patients；2、iTreg can further induce the tolerance of other GP-reactive T cell by DC；,GP-iTreg+GP-pulsed DC+GP-reactive T cell,Zhang et al.Blood 2009;113:2568-77,（4）Increase the number of Tregs,Add TGF-/IL-17,24h？,IncreasediTregs,clinical application,Compared with drug，treatment with Treg
25、can reduce the adverse effect and toxic effect,（4）Increase the number of Tregs,TPO-R agonists,TPO-R agonists improve the activity of Tregs via enhancing release of TGF-,Bao,et al.Blood 2010;116:463945,Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with t
26、hrombopoietic agents,（4）Improve the activity of Tregs,(1)Rituximab for ITP(standard dose),Zaja,et al.Haematologica 2008;93:930-33Taube,et al.Haematologica 2005;90:281-3,2.Decrease the destruction of platelet,Rituximab for ITP（low dose）,Zaja,et al.Eur J Haematol 2010;85:329-34,low-dose is comparable
27、to standard dose in OR and CR,(2)Restore the balance of FcRs on monocytes,IVIg,the balance of the FcRIIA and inhibiting FcRIIB is important in mediating the therapeutic effects of IVIG,Salley,et al.ASH abstract 2009 683#,High-dose IgG alters the relative expression of Fc RIIA and Fc RIIB on human ma
28、crophages:a mechanism for IVIG therapy in human immune thrombocytopenia,The expression of FcRlla in ITP patiens increase,while that of Fcyllb decrease;the expression ratio FcRIIa/IIb recover to normal after therapied by dexamethasone,High-dose dexamethasone,Liu et al.Blood.2011;117:2061-9,(2)Restore
29、 the balance of FcRs on monocytes,Antibody species on response to IVIg,ITP mediated by anti-GPIb antibodies were less responsive to IVIg(mouse model),Webster ML,et al.Blood.2006;108:943-6,Overall response rate：64.5%GP Ib/IX(+)response rate：41.8%GP Ib/IX(-)response rate：79.5%(-)(-)response rate：83.7%
30、,Our unpublished data,Antibody species on response to IVIg,Antibody species on response to steroid,GPIb(+)GPIb(-),GPIIbIIIa(-)GPIIbIIIa(+)GPIIbIIIa(-)GPIIbIIIa(+)TotalR*9(26.5%)16(29.6%)36(80%)31(72.1%)92NR*25 38 9 12 84Total 34 54 45 43 176,*R=Response;*NR=No response,ITP patients with anti-GPIb an
31、tibodies are less responsive to steroid therapy,Zeng,et al.American Journal of Hematology 2011 Accepted,3.Increase platelet production,The normal process of platelet production,7.Increase platelet production,Bussel,et al.Blood 2009;113:2161-71,(1)Romiplostim,AMG 531,a Thrombopoiesis-Stimulating Prot
32、ein,for Chronic ITP,Kuter,et al.Lancet 2008;371:395-403,7.Increase platelet production,292 adult ITP patients were involved,with median administration time of 78 weeks.94.5%of the patients achieved a PC50109/L.More than 50%had PC 50109/L on 90%of all visits.,Kuter et al.ASH2010，Abstract#68,Romiplost
33、im,7.Increase platelet production,Bussel,et al.N Engl J Med.2007;357:2237-47,(2)Eltrombopag,Eltrombopag,Cheng G,et al.Lancet 2011;377:393-402,299 adult ITP patients were involved,87%of patients achieved a PC50109/L;Median PC increased to PC50109/L by week 2 and remained consistently through 164 week
34、s;The incidence of any bleeding symptoms declined from 56%at baseline to 16%and 20%at week 52 and week 104 respectively.Saleh et al.ASH2010，Abstract#67,7.Increase platelet production,Eltrombopag,STUDY DESIGN,(3)rhTPO,Wang,et al.Chin J Thromb Haemost 2010;15:149-53,The Response after the first stage,
35、Danazol+rhTPO,Danazol,N(case),Response,non-response,P value,Part IIICombined therapy for ITP,1.Dexamethasone plus rituximab,Zaja,et al.Blood 2010;115:2755-62,Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytope
36、nia,2.rhTPO plus Rituximab,Rituximab,rhTPO,Decrease platelet destruction,Increase platelet production,High response rate with a long TTR and SR,High response rate with a short TTR,and relapse soon after withdrawal,Open-label,non-randomized,non-placebo-controlled;rhTPO：300U/Kg/d，d1-14;Rituximab：375 m
37、g/m2,qw*4(d1,8,15,22);,Rituximab combined rhTPO in corticosteroid non-responsive ITP,2.rhTPO plus Rituximab,*Unpublished data*Arnold,et al.Ann of Intern Med 2007;146:25-33#Wang,et al.Chin J Thromb Haemost 2010;15:149-53,Efficacy Comparison,*OR:overall response;CR:complete response;R:response;,rhTPO
38、plus Rituximab,*Unpublished data*Arnold,et al.Ann of Intern Med 2007;146:25-33#Wang,et al.Chin J Thromb Haemost 2010;15:149-53 115:2755-62,Overview of the strategies,Restore T-cell tolerance,rhTPO,Increase platelet production,Romiplostim,Eltrombopag,Decrease platelet destruction,IVIg,Rituximab,Induc
39、tion of anergic T,Restore the number or function of Tregs,Restore the balance of Th1/Th2,HD-DXM,BR3-Fc,Increase the apoptosis of T cells,The work was supported by grants from National Natural Science Foundation of China(81270408,81070411,30570779,30770922,81070407,30971278,81070396),the National 973 Basic Research Program of China(2011CB503906),Key Clinical Research Project of Public Health Ministry of China(2010-2012),Taishan Scholar Foundation.,Thank You!,
