Immune thrombocytopenic purpura (ITP) is a bleeding autoimmune disease with accelerated platelet destruction as a result of breakdown of immune tolerance. Clinical trials using thrombopoietic agents to stimulate platelet production have shown favorable outcomes with respect to safety, tolerability and efficacy in increasing platelet counts in patients with ITP. Indeed two such agent romiplostim (Nplate) and eltrombopag were recently licensed. Although some of these thrombopoietic agents are predicted to lack immunomodulatory activity, the immune status of patients who have improved platelet counts is unknown. We and others have recently showed that regulatory CD4+CD25hi T cells (Treg) that normally control autoimmunity and inflammation have an overall impaired function in patients with chronic refractory ITP. Damage to megakaryocytes resulting in an inflammatory marrow environment and elevated circulatory pro-inflammatory cytokines have been reported in ITP patients. The goal of the proposed time-sensitive ancillary study to ongoing clinical trials of ITP is to analyze the immune responses following treatment with thrombopoietic agents with a special emphasis on regulatory T-cell-associated effects. Our preliminary data indicates that Treg function is improved in ITP patients on treatment with thrombopoietic agents. Our hypothesis is that patients with chronic ITP have an inherent defect in their Treg suppressive activities, and that treatment with thrombopoietic agents results in the induction of Tregs with improved function. We also predict that patients with durable normalized Treg activity will have better prognosis and response to treatment. We will test our hypothesis with the following specific aims: 1) to characterize Treg function, and correlate its activity with immune effector (T and B) cell activity in longitudinal analysis of patients before, during and after treatment, 2) to characterize the Treg defect in patients with ITP, and 3) to identify the mechanisms leading to improved Treg activity in treated patients, specifically their origin and induction mechanism(s). We believe that the proposed studies will provide important insights into the underlying autoimmune pathology in ITP and may identify a role for Tregs on prognosis and response to treatment with thrombopoietic agents, leading to better patient care and possible new treatment strategies.
Patients with immune thrombocytopenic purpura (ITP) have fewer platelets than the average healthy human being, because their immune system attacks and destroys some of their platelets. ITP patients do not produce enough platelets to compensate for those destroyed. Because platelets help people stop bleeding, and ITP patients have fewer platelets, they can sometimes die from internal bleeding. Our goal is to understand why the immune cells of ITP patients attack their own platelets. It is our belief that the patient's immune cells are defective, sending signals for the platelets to be attacked. There are new types of drugs that increase platelet numbers and are used to treat ITP patients. However, it is unclear if the drugs are fixing the defective immune cells, or just increasing the low platelet count. Our studies will focus on patients'recovery after they stop taking these new drugs. We will try to determine whether they will have a normal immune system, or if the lack of drugs will allow the faulty immune cells to once again start attacking platelets. We believe that understanding how the immune cells are affected by the drugs will provide the breakthrough knowledge that helps us cure all ITP patients.
|Bussel, James B; Lee, Christina S; Seery, Caroline et al. (2014) Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration. Haematologica 99:1264-71|
|Zhong, Hui; Bao, Weili; Friedman, David et al. (2014) Hemin controls T cell polarization in sickle cell alloimmunization. J Immunol 193:102-10|
|Zhong, Hui; Yazdanbakhsh, Karina (2013) Differential control of Helios(+/-) Treg development by monocyte subsets through disparate inflammatory cytokines. Blood 121:2494-502|
|Yazdanbakhsh, Karina; Zhong, Hui; Bao, Weili (2013) Immune dysregulation in immune thrombocytopenia. Semin Hematol 50 Suppl 1:S63-7|
|Bao, Weili; Bussel, James B; Heck, Susanne et al. (2010) Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood 116:4639-45|
|Bussel, James B (2009) Traditional and new approaches to the management of immune thrombocytopenia: issues of when and who to treat. Hematol Oncol Clin North Am 23:1329-41|