Volume 5 Supplement 1

New development in Hematology and Oncology in 2011

Open Access

Restoration of T cell tolerance in primary ITP

  • Xin-guang Liu1,
  • Jun Peng1 and
  • Ming Hou1
Journal of Hematology & Oncology20125(Suppl 1):A5

DOI: 10.1186/1756-8722-5-S1-A5

Published: 25 April 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 [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 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 [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.

Authors’ Affiliations

(1)
Department of Hematology, Qilu Hospital, Shandong University

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Copyright

© Liu et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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