On cellular immunology in chronic idiopathic thrombocytopenic purpura (ITP)

Abstract

Chronic idiopathic thrombocytopenic purpura (ITP) is an acquired autoimmune disease characterized by a low platelet count and mucocutaneous bleedings. Chronic ITP is considered to be mediated by autoantibodies leading to premature destruction of platelets in the reticuloendothelial system. Previous findings indicate that T-helper (Th)-cells are activated by antigen-presenting cells and by subsequent secretion of different Th cytokines initiate the autoantibody production. However, the results are inconsistent. Also, a platelet specific antibody can only be detected in about 60 % of ITP patients. Furthermore, it is well known that cytotoxic T-cells play a key role in immune responses toward virus-infected and malignant cells, through their potent ability to induce apoptotic death in these cells. Even though the potential role of cellular immune response in chronic ITP is being elucidated, a cell-mediated cytotoxic component in the pathogenesis of chronic ITP has not been investigated.The aims of the present study were to investigate the T-cell immune response in chronic ITP by analysing: (i) the Th-cell cytokine profiles in serum/plasma and mononuclear cell cultures, (ii) gene expression profiles of T-cells and (iii) the hypothesis of T-cell mediated cytotoxicity towards platelets. Patients with chronic ITP were divided into different groups based on their platelet count (plc), active disease (plc <50 x 109/L), stable disease (plc 50-150 x 109/L) and in remission (plc >150 x 109/L. Patients with ITP in remission had significantly higher plasma levels of TGF-b1, a Th3 cytokine, compared to patients with active disease and controls. Further, we also found that peripheral mononuclear cells from chronic ITP patients with active disease had a significantly lower production of TGF-b1 compared to patients with stable disease, patients in remission and controls. In a DNA microarray screen several cytotoxic genes, together with genes involved in a Th1 cell response, showed increased expression in both patients with active disease and in remission compared to controls. Also, several members of the killer inhibitory receptor (KIR) family were upregulated in patients in remission compared to both patients with active disease and controls. In addition, analysis by flow cytometry showed a higher percentage of T-cells expressing KIRs in ITP patients in remission. An in vitro assay measuring the destruction of radiolabelled autologous platelets by T-cells showed positive platelet lysis in six of eight ITP patients with active disease, while no platelet lysis was detected in ITP patients in remission. Conclusions: Chronic ITP patients with active disease had low plasma levels and reduced mononuclear cell production of TGF-b1. This could indicate that ITP in active stage is associated with a down-regulated Th3 response, and remission might be induced by up-regulation of the Th3 response and a TGF-b1 mediated immune suppression. Also, our data strongly suggest that cell-mediated cytotoxicity contributes to the destruction of platelets in ITP and that this is inhibited by the up-regulation of KIRs in T-cells, resulting in remission. These findings may open possibilities for novel therapeutic strategies for management of patients with chronic ITP.