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Restoration of T cell tolerance in primary ITP
Journal of Hematology & Oncology volume 5, Article number: A5 (2012)
Primary immune thrombocytopenia (ITP) has been traditionally thought as an antibody-mediated autoimmune disease involving platelet destruction by macrophages in the reticuloendothelia system. More recently it has become obvious that ITP is a more complex disorder in which T cell mediated immunity plays important roles in platelet destruction. Antiplatelet autoantibody production is under the control of platelet-specific helper T-cells, and loss of tolerance to self antigen by T cells is the critical step of the immune dysregulation in ITP. Dendritic cells (DCs) from ITP patients showed enhanced capacity in stimulating autologous T-cell proliferation in the presence of autologous/allogeneic platelets , and ITP patients’ T cells had elevated IL-2 secretion ability compared with controls [2, 3], suggesting increased antiplaltelet T-cell reactivity in ITP. The epitopes that recognize platelet glycoprotein (GP) IIIa on T helper (Th) cells has been determined and mapped by several groups [4, 5], thus sheding new lights on the “therapeutic vaccination” approach to reinstate tolerance in ITP. Autoreactive T-cell reactivity against platelet antigen in active ITP patients has been observed at polyclonal as well as oligoclonal levels [6, 7]. Our group has demonstrated that blocking the B7-CD28 interaction with CTLA4-Ig/CsA could induce platelet GP-specific T-cell anergy, which could exert suppressive effect on GP-reactive T cells via inducing tolerogenic dendritic cells (DCs) [8, 9]. It has been well established that apoptotic genes, such as Fas, A20, Bax, Calpastatin, IL2RB, were expressed aberrantly in patients with active ITP [10, 11], leading to autoreactive T cells resistant to activation induced cell death (AICD), which could in turn support the expansion of self-reactive T-cell clones. A loss of resistant to AICD might be an important mechanism for the achievement of remission in ITP. Previous studies have revealed that dexamethasone could suppress T-cell proliferation and induce apoptosis of T-cells in ITP [11, 12]. In addition, our group has demonstrated that a novel BAFF blocking reagent, BR3-Fc, could restore the apoptosis of both B and T cells . Th polarization in ITP has been attributed to increased Th1 [2, 14], and Th17 cells  or reduced number or function of CD4+CD25+Foxp3+ T-regulatory cells (Tregs) [16, 17]. A parallel body of aberrant cytokine patterns, such as the elevated ratio of interleukin (IL) -18/IL-18 binding protein (BP) [18, 19], the increased expression of B cell activating factor (BAFF) has been reported in active ITP patients [20, 21]. High-dose dexamthasone (HD-DXM) could not only restore Th1/Th2  or IL-18/IL-18BP balance , but also increase the number of Tregs , and inhibit the expression of BAFF . Besides HD-DXM, multiple agents, such as rituximab , intravenous immunoglobulin (IVIg) , romiplostim, eltrombopag  as well as indirubin , could increase the number or restore the function of Tregs in ITP. Our recently study showed that GP-specific induced Tregs could be successfully generated de novo from nonregulatory CD4+CD25-CD45RA+ cells and could mediate both antigen-specific and linked suppression of proliferating antiplatelet CD4+ Th cells in vitro, and further research revealed that the de novo expanded Tregs mediated their suppressive effects on T cells via actually modulating the T-cell stimulatory capacity of DCs , thus providing a clue to the potential of producing antigen-specific Tregs from the patients in vitro for the purpose of antigen-targeted cellular immunotherapy. In conclusion, induction of T-cell tolerance may provide a useful strategy for the management of ITP.
Catani L, Fagioli ME, Tazzari PL, Ricci F, Curti A, Rovito M, Preda P, Chirumbolo G, Amabile M, Lemoli RM, Tura S, Conte R, Baccarani M, Vianelli N: Dendritic cells of immune thrombocytopenic purpura (ITP) show increased capacity to present apoptotic platelets to T lymphocytes. Exp Hematol. 2006, 34: 879-887. 10.1016/j.exphem.2006.03.009.
Semple JW, Milev Y, Cosgrave D, Mody M, Hornstein A, Blanchette V, Freedman J: Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood. 1996, 87: 4245-4254.
Semple JW, Freedman J: Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia. Blood. 1991, 78: 2619-2625.
Kuwana M, Kaburaki J, Kitasato H, Kato M, Kawai S, Kawakami Y, Ikeda Y: Immunodominant epitopes on glycoprotein IIb-IIIa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura. Blood. 2001, 98: 130-139. 10.1182/blood.V98.1.130.
Sukati H, Watson HG, Urbaniak SJ, Barker RN: Mapping helper T-cell epitopes on platelet membrane glycoprotein IIIa in chronic autoimmune thrombocytopenic purpura. Blood. 2007, 109: 4528-4538. 10.1182/blood-2006-09-044388.
Ware RE, Howard TA: Phenotypic and clonal analysis of T lymphocytes in childhood immune thrombocytopenic purpura. Blood. 1993, 82: 2137-2142.
Shimomura T, Fujimura K, Takafuta T, Fujii T, Katsutani S, Noda M, Fujimoto T, Kuramoto A: Oligoclonal accumulation of T cells in peripheral blood from patients with idiopathic thrombocytopenic purpura. Br J Haematol. 1996, 95: 732-7. 10.1046/j.1365-2141.1996.d01-1967.x.
Peng J, Liu C, Liu D, Ren C, Li W, Wang Z, Xing N, Xu C, Chen X, Ji C, Zhang M, Hou M: Effects of B7-blocking agent and/or CsA on induction of platelet-specific T-cell anergy in chronic autoimmune thrombocytopenic purpura. Blood. 2003, 101: 2721-2726. 10.1182/blood-2002-06-1666.
Zhang XL, Peng J, Sun JZ, Guo CS, Yu Y, Wang ZG, Chu XX, Hou M: Modulation of immune response with cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin-induced anergic T cells in chronic idiopathic thrombocytopenic purpura. J Thromb Haemost. 2008, 6: 158-165.
Yoshimura C, Nomura S, Nagahama M, Ozaki Y, Kagawa H, Fukuhara S: Plasma-soluble Fas (APO-1, CD95) and soluble Fas ligand in immune thrombocytopenic purpura. Eur J Haematol. 2000, 64: 219-224. 10.1034/j.1600-0609.2000.9o096.x.
Olsson B, Andersson PO, Jacobsson S, Carlsson L, Wadenvik H: Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost. 2005, 93: 139-44.
Zhu XJ, Shi Y, Sun JZ, Shan NN, Peng J, Guo CS, Qin P, Hou M: High-dose dexamethasone inhibits BAFF expression in patients with immune thrombocytopenia. J Clin Immunol. 2009, 29: 603-610. 10.1007/s10875-009-9303-y.
Zhu XJ, Shi Y, Peng J, Guo CS, Shan NN, Qin P, Ji XB, Hou M: The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia. Blood. 2009, 114: 5362-5367. 10.1182/blood-2009-05-217513.
Guo C, Chu X, Shi Y, He W, Li L, Wang L, Wang Y, Peng J, Hou M: Correction of Th1-dominant cytokine profiles by high-dose dexamethasone in patients with chronic idiopathic thrombocytopenic purpura. J Clin Immunol. 2007, 27: 557-562. 10.1007/s10875-007-9111-1.
Zhang J, Ma D, Zhu X, Qu X, Ji C, Hou M: Elevated profile of Th17, Th1 and Tc1 cells in patients with immune thrombocytopenic purpura. Haematologica. 2009, 94: 1326-1329. 10.3324/haematol.2009.007823.
Ling Y, Cao X, Yu Z, Ruan C: Circulating dendritic cells subsets and CD4+Foxp3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome. Eur J Haematol. 2007, 79: 310-316. 10.1111/j.1600-0609.2007.00917.x.
Liu B, Zhao H, Poon MC, Han Z, Gu D, Xu M, Jia H, Yang R, Han ZC: Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura. Eur J Haematol. 2007, 78: 139-143.
Shan NN, Zhu XJ, Peng J, Qin P, Zhuang XW, Wang HC, Hou M: Interleukin 18 and interleukin 18 binding protein in patients with idiopathic thrombocytopenic purpura. Br J Haematol. 2009, 144: 755-761. 10.1111/j.1365-2141.2008.07520.x.
Shan NN, Zhu XJ, Wang Q, Wang CY, Qin P, Peng J, Hou M: High-dose dexamethasone regulates interleukin-18 and interleukin-18 binding protein in idiopathic thrombocytopenic purpura. Haematologica. 2009, 94: 1603-1607. 10.3324/haematol.2009.007708.
Emmerich F, Bal G, Barakat A, Milz J, Mühle C, Martinez-Gamboa L, Dörner T, Salama A: High-level serum B-cell activating factor and promoter polymorphisms in patients with idiopathic thrombocytopenic purpura. Br J Haematol. 2007, 136: 309-314. 10.1111/j.1365-2141.2006.06431.x.
Zhou Z, Chen Z, Li H, Chen X, Xu J, Gu D, Du W, Zheng C, Zhang L, Huang Y, Ren Q, Yang R: BAFF and BAFF-R of peripheral blood and spleen mononuclear cells in idiopathic thrombocytopenic purpura. Autoimmunity. 2009, 42: 112-119. 10.1080/08916930802397848.
Stasi R, Cooper N, Del Poeta G, Stipa E, Laura Evangelista M, Abruzzese E, Amadori S: Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood. 2008, 112: 1147-1150. 10.1182/blood-2007-12-129262.
De Groot AS, Moise L, McMurry JA, Wambre E, Van Overtvelt L, Moingeon P, Scott DW, Martin W: Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes". Blood. 2008, 112: 3303-3311. 10.1182/blood-2008-02-138073.
Bao W, Bussel JB, Heck S, He W, Karpoff M, Boulad N, Yazdanbakhsh K: Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010, 116: 4639-4645. 10.1182/blood-2010-04-281717.
Zhang A, Qu Y, Zhang B, Zhang L, Zeng C, Peng J, Ji X, Hou M, Zhao Y: The different effects of indirubin on effector and CD4+CD25+ regulatory T cells in mice: potential implication for the treatment of autoimmune diseases. J Mol Med. 2007, 85: 1263-1270. 10.1007/s00109-007-0235-9.
Zhang XL, Peng J, Sun JZ, Liu JJ, Guo CS, Wang ZG, Yu Y, Shi Y, Qin P, Li SG, Zhang LN, Hou M: De novo induction of platelet-specific CD4(+)CD25(+) regulatory T cells from CD4(+)CD25(-) cells in patients with idiopathic thrombocytopenic purpura. Blood. 2009, 113: 2568-2577. 10.1182/blood-2008-03-148288.
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Liu, X., Peng, J. & Hou, M. Restoration of T cell tolerance in primary ITP. J Hematol Oncol 5, A5 (2012) doi:10.1186/1756-8722-5-S1-A5
- Activation Induce Cell Death
- Platelet Destruction
- Cell Activate Factor