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
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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.
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