title: Murine bone marrow chimeras developing autoimmunity after CTLA-4-blockade show an expansion of T regulatory cells with an activated cytokine profile.
abstract: Autoimmune adverse events are a concern in patients treated with blocking anti-CTLA-4-mAb for solid and hematological tumors. Patient and mouse data on the contribution of a quantitative or qualitative defect of regulatory T cells (T(reg)) in this autoimmune phenomenon are conflicting. We have previously shown that a treatment course with blocking anti-CTLA-4-mAb in murine allogeneic bone marrow chimeras induces an antileukemic response in close association with systemic autoimmunity. Here, we used this model to investigate the effect of CTLA-4-blocking therapy on the kinetics of T(reg) frequency and function. As previously published, CTLA-4-blocking treatment, initiated on day 20 after bone marrow transplantation, led to overt autoimmunity by day 35. CD4(+)Foxp3(+) T(reg) frequency was determined (flowcytometry) on day 21, 23, 25 and 35: treated chimeras showed an expansion of CD4(+)Foxp3(+) T(reg) frequencies on day 25 and 35, without a prior frequency decrease. The T(reg) expansion occurred selectively in the recipient-derived CD4+ T-cell compartment. In vitro, purified CD4(+)CD25(+)FR4(high) T(reg) from 'day 35' autoimmune and control chimeras showed equal suppressive effects towards self-antigen-specific autoimmune T cells. Purified CD4(+)CD25(high)FR4(high) T(reg) from 'day 35' treated chimeras showed increased IL-10 and IFN-gamma mRNA-expression (RT-PCR) relative to control chimeras. In this model of CTLA-4-blockade-induced autoimmunity after allogeneic bone marrow transplantation, anti-CTLA-4-mAb gives rise to a progressive expansion - without a prior transient reduction - of T(reg) cells. T(reg) of autoimmune animals do not show a defect in in vitro suppressive function but show an in vivo activated cytokine profile, suggesting that the expansion occurs as a compensatory phenomenon to control autoimmunity.
authors.affiliation: Laboratory of Experimental Transplantation, University of Leuven, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: De Somer
authors.forename: Sabine
authors.initials: S
authors.lastname: Fevery
authors.forename: Dominique M A
authors.initials: DM
authors.lastname: Bullens
authors.forename: Omer
authors.initials: O
authors.lastname: Rutgeerts
authors.forename: Caroline
authors.initials: C
authors.lastname: Lenaerts
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Ahmad
authors.initials: A
authors.lastname: Kasran
authors.forename: Mark
authors.initials: M
authors.lastname: Waer
authors.forename: An D
authors.initials: AD
authors.lastname: Billiau
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000009:adverse effects* / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D015551:Autoimmunity / Q000187:drug effects; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000096:biosynthesis; D060908:CTLA-4 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018183:Transplantation Chimera
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D007371:Interferon-gamma