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

Abstract

Chronic idiopathic thrombocytopenic purpura (ITP) is an immune-mediated disorder in which platelets are prematurely destroyed in the reticuloendothelial system by platelet autoantibodies. However, it is becoming clear that the pivotal process of the humoral immune response in the pathogenesis of the disorder is a complex interaction between antigen-presenting cells, T cells and B cells. Furthermore, it is increasingly evident that regulatory T cells play an important role and that T-cell-mediated cytotoxicity contributes to the destruction of platelets in ITP. Different new approaches to immunotherapy in chronic ITP have been explored, including use of anti-CD20, anti-CD154 and anti-CD52 antibodies. So far, these therapies have been antigen-nonspecific and the risk of general immunosuppression is a concern. Thus, improving our understanding of the interaction and relative contribution of humoral and cell-mediated mechanisms is essential for developing antigen-specific immunotherapies for the treatment of this disorder. This review aims to elucidate the current status of knowledge of the cellular and humoral immune components of chronic ITP, together with the implications of this knowledge for therapy.

The efficacy of rituximab in patients with splenectomized refractory chronic idiopathic thrombocythopenic purpura

“…Rituximab was proved to be effective in 82% of splenectomized refractory chronic ITP patients (overall response rate 14/17; with 2/14 CR, 8/14 PR and 4/14 MR). Three out Median time to response (weeks) 11 (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) of 17 patients (17.6%) did not respond to rituximab. Two patients, who achieved CR, have remained with a platelet count higher than 100 9 10 9 /l for over 6 months, with a mean platelet count 162 9 10 9 /l (range 109-216 9 10 9 /l).…”

“…The pivotal role of the humoral immune response in the pathogenesis of ITP is a complex interaction among antigen presenting cells (APCs), T cells and B cells [2]. The treatment regimens for ITP include corticosteroids, intravenous immunoglobulin (IVIg), intravenous anti-D immunoglobulin, splenectomy, danazol and other immunosuppressive drugs.…”

Human Platelet Antigens

“…This response must be tightly controlled with a network of regulatory cells and plasma factors, such the anti-Id antibodies found in IVIG. 115,118,119 In childhood ITP, which is seasonal and transient in nature, the regulatory network can usually restore itself to proper order within 6 months following the acute insult in a majority of patients. 57 In animal models, loss of peripheral tolerance to self-antigens is emerging as a possible mechanism for autoimmune disease, with particular focus on the regulatory CD4+25+ T-lymphocyte subset.…”

“…123,124 As summarized in the following section, the finding of inherent T-cell abnormalities and alterations in the expression of accessory molecules on autoreactive T cells provides a novel avenue for the development of immunotherapy in ITP. 119,125 …”

“…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.…”