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Deep-phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment

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Shahram Kordasti ; Benedetta Costantini ; Thomas Seidl ; Pilar Perez Abellan ; Marc Martinez Llordella ; Donal Mclornan ; Kirsten E. Diggins ; Austin Kulasekararaj ; Cinzia Benfatto ; Xingmin Feng ; Alexander Smith ; Syed A. Mian ; Rossella Melchiotti ; Emanuele de De Rinaldis ; Richard Ellis ; Nedyalko Petrov ; Giovanni A.M. Povoleri ; Sun Sook Chung ; N. Shaun B. Thomas ; Farzin Farzaneh ; Jonathan M. Irish ; Susanne Heck ; Neal S. Young ; Judith C.W. Marsh ; Ghulam J. Mufti

Original languageEnglish
Pages (from-to)1193-1205
Number of pages13
JournalBlood
Volume128
Issue number9
Early online date8 Jun 2016
DOIs
StatePublished - 1 Sep 2016

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Abstract

Idiopathic aplastic anemia (AA) is an immune-mediated and serious form of bone marrow failure. Akin to other autoimmune diseases, we have previously shown that in AA regulatory T-cells (Tregs) are reduced in number and function. The aim of this study was to further characterize Treg subpopulations in AA and investigate the potential correlation between specific Treg subsets and response to immunosuppressive therapy (IST) as well as their in-vitro expandability for potential clinical use. Using mass cytometry (CyTOF) and an unbiased multidimensional analytical approach, we identified two specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene-expression, expandability and function. Treg subpopulation B, predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4 and CD45RO within FOXP3hi, CD127lo Tregs), expresses the IL- 2/STAT5 pathway and cell-cycle commitment genes. Furthermore, in-vitro expanded Tregs become functional and with the characteristics of Treg subpopulation B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2 sensitive and expandable in-vitro, suggesting novel therapeutic approaches such as low dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration.

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