Restoration of T cell tolerance in primary ITP

Journal of Hematology & Oncology, Apr 2012

Xin-guang Liu, Jun Peng, Ming Hou

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://www.jhoonline.org/content/pdf/1756-8722-5-S1-A5.pdf

Restoration of T cell tolerance in primary ITP

Liu et al. Journal of Hematology & Oncology Restoration of T cell tolerance in primary ITP Xin-guang Liu 0 1 Jun Peng 0 1 Ming Hou 0 1 0 References 1. 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. 2. Semple JW, Milev Y, Cosgrave D, Mody M, Hornstein A, Blanchette V, Freedman J: Differences in serum cytokine levels in acute and chronic 1 Department of Hematology, Qilu Hospital, Shandong University , 107 West Wenhua Road, Jinan , P. R. China - 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 [1], 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 GPreactive 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 [13]. Th polarization in ITP has been attributed to increased Th1 [2,14], and Th17 cells [15] 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 [14] or IL-18/IL-18BP balance [19], but also increase the number of Tregs [16], and inhibit the expression of BAFF [12]. Besides HD-DXM, multiple agents, such as rituximab [22], intravenous immunoglobulin (IVIg) [23], romiplostim, eltrombopag [24] as well as indirubin [25], 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 [26], 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. phenotype and antiplatelet T-cell reactivity . Blood 1996 , 87 : 4245 - 4254 . 3. Semple JW , Freedman J : Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia . Blood 1991 , 78 : 2619 - 2625 . 4. Kuwana M , Kaburaki J , Kitasato H , Kato M , Kawai S , Kawakami Y , Ikeda Y : Blood 2001 , 98 : 130 - 139 . 5. Sukati H , Watson HG , Urbaniak SJ , Barker RN : Mapping helper T-cell thrombocytopenic purpura . Blood 2007 , 109 : 4528 - 4538 . 6. Ware RE , Howard TA : Phenotypic and clonal analysis of T lymphocytes in childhood immune thro (...truncated)


This is a preview of a remote PDF: http://www.jhoonline.org/content/pdf/1756-8722-5-S1-A5.pdf

Xin-guang Liu, Jun Peng, Ming Hou. Restoration of T cell tolerance in primary ITP, Journal of Hematology & Oncology, 2012, pp. A5, 5,