Effects of B7-blocking agent and/or CsA on induction of platelet-specific T-cell anergy in chronic autoimmune thrombocytopenic purpura

Abstract

Chronic autoimmune thrombocytopenic purpura (AITP) is characterized by platelet-specific autoantibody production that is influenced by enhanced antiplatelet T-helper cell reactivity. Costimulatory signals are absolutely required for T-cell activation and play key roles in the decision between tolerance and immunity. In this study we cultured T cells isolated from patients with chronic AITP to investigate the effects of the B7-blocking agent cytologic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig), and cyclosporin A (CsA), alone or in combination, on induction of platelet-specific Tcell anergy. The data showed that in most cases CTLA4-Ig and/or CsA could induce tolerance toward platelet antigens based on anergy. It could be overcome by stimulation with unrelated antigens, demonstrating its platelet specificity. The anergy is associated with lack of interleukin 2 (IL-2) and withheld by exogenous IL-2, emphasizing the pivotal role of IL-2 suppression in the induction of plateletspecific anergy. We also prospectively evaluated the efficacy of CsA therapy in patients with refractory AITP and observed that the response to CsA treatment in vivo was associated with the IntroductionChronic autoimmune thrombocytopenic purpura (AITP) is an autoimmune disorder characterized by antiplatelet autoantibody-mediated platelet destruction. Autoantibody production in AITP is associated with both T-cell activation and T-B cognate interaction. [1][2][3][4] Patients with AITP have enhanced T-cell reactivity against platelets that is measurable at both the bulk polyclonal T-cell level 5,6 and at the clonal level. 7,8 Optimal T-cell activation requires 2 signals. The first signal is based on T-cell receptor (TCR) recognition of peptide/major histocompatibility complex (MHC) complexes. The second signal is provided by interaction of CD28, CD2, and leukocyte factor antigen-1 (LFA-1) on T cells with their costimulatory ligands B7 (CD80 and CD86), LFA-3, and intercellular adhesion molecule-1 (ICAM-1), respectively, on antigenpresenting cells (APCs). Because the CD28 costimulatory pathway does not depend on intracellular calcium, the B7-CD28/CTLA-4 (cytologic T-lymphocyte-associated antigen 4) interaction is considered to provide the main signal that confers cyclosporin A (CsA)-resistant interleukin 2 (IL-2) production, whereas costimulation through other accessory molecules such as CD2 is calcium dependent and thus could be blocked by CsA. [9][10][11] B7 costimulation is involved not only in the induction stage of autoimmune response but also in the effector activation of autoreactive T cells for propagating autoimmune disease. 12-16 Semple et al 6 has observed an enhanced expression of CD80 on platelets from patients with AITP, implicating a role of B7/CD28 costimulation in the pathogenesis of AITP. 6 T-cell response(s) could be inhibited by administration of the cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig), a fusion protein comprising the extracellular domain of CTLA-4 and the Fc portion of human IgG...

High-dose dexamethasone regulates interleukin-18 and interleukin-18 binding protein in idiopathic thrombocytopenic purpura

“…GC may directly inhibit Th1 cytokine production in T cells and potentially enhance Th2 cytokine synthesis by inhibiting IL-12 production in antigen-presenting cells. [17][18][19] The present observation that IL-18 and IFN-γ plasma and mRNA levels were reduced after HD-DXM treatment is in agreement with these data. The HD-DXM-mediated Th1/Th2 cytokine profile alterations observed in this study might be the results of a downregulation of IL-18 and other Th1 cytokines by induction of IL-18BP while permitting the production of Th2 cytokines.…”

Human Platelet Antigens

“…The MHC and TCR were recognized as major receptors for many years, but it is now understood that there are accessory molecules that facilitate or modulate the response and that these are potential therapeutic targets in treating ITP. 119,125,129 Antigen-presenting cells, which include B cells as well as macrophages, require specific recognition and signaling through the receptors B7, LFA-3, and ICAM-1, whereas the T cell employs the receptors CD28, LFA-1, and CD2. 125,130 Increased expression of CD40L on platelets may be a normal response of platelets activated by infection or other inflammatory mediators.…”

Chronic idiopathic thrombocytopenic purpura (ITP): molecular mechanisms and implications for therapy

“…Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), which is expressed on the surface of T cells shortly after they become activated, is the high-avidity receptor for both CD80 and CD86, binding up to 2500 times as avidly as CD28 (Refs 120, 121). 126). CTLA-4-Ig binds both CD80 and CD86 on APCs, thus preventing its necessary costimulatory signals with CD28 on T cells.…”