title: Imatinib impairs the proliferation and function of CD4+CD25+ regulatory T cells in a dose-dependent manner.
abstract: The tyrosine kinase inhibitor imatinib has been reported to inhibit CD8+ T lymphocytes. Little is known about its effects on CD4+CD25+ regulatory T cells (T(reg) cells) which might regulate the graft-vs.-leukemia (GVL) reaction after allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion (DLI). This is of particular interest in patients with relapse of chronic myeloid leukemia (CML) after allo-SCT, as the two therapeutical options DLI and imatinib might interact reversely. Here, we demonstrate that the proliferation of CD4+CD25+ T(reg) cells and their production of IL-10, TGF-beta1 and granzyme B as markers of activation were significantly down-regulated by imatinib in a dose-dependent manner. In addition, the expression of surface CD69, both surface and intracellular GITR, FoxP3, CD152 (CTLA) of activated CD4+CD25+ T(reg) cells were inhibited by imatinib in a dose-dependent manner. In light of these findings, clinical administration of imatinib might not result in a reduction of the GVL effect on CML patients receiving imatinib after allo-SCT and/or DLI or other CD8+ T lymphocyte based immunotherapies as the function of CD8+ cytotoxic T lymphocytes and CD4+CD25(hi) Treg cells is hampered in a similar way by imatinib.
authors.affiliation: Department of Internal Medicine III, University Clinic, Robert-Koch-Strasse 8, D-89081 Ulm, Germany.
authors.forename: Jinfei
authors.initials: J
authors.lastname: Chen
authors.forename: Anita
authors.initials: A
authors.lastname: Schmitt
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Giannopoulos
authors.forename: Baoan
authors.initials: B
authors.lastname: Chen
authors.forename: Markus
authors.initials: M
authors.lastname: Rojewski
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Donald
authors.initials: D
authors.lastname: Bunjes
authors.forename: Michael
authors.initials: M
authors.lastname: Schmitt
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D000068877:Imatinib Mesylate; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D001549:Benzamides; D060908:CTLA-4 Antigen; D016207:Cytokines; D051858:Forkhead Transcription Factors; D000068877:Imatinib Mesylate; D037181:Lectins, C-Type; D010879:Piperazines; D011743:Pyrimidines; D000099192:CD69 Antigens; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human