title: The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses.
abstract: B7.1/2-targeted costimulation blockade (CTLA4 immunoglobulin [CTLA4-Ig]) is available for immunosuppression after kidney transplantation, but its potentially detrimental impact on regulatory T cells (Tregs) is of concern. We investigated the effects of CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). CTLA4-Ig was injected chronically (on days 0, 4, 14, and 28 and every 4 weeks thereafter) in dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high dose (HD), 1.25 mg (≈50 mg/kg body weight); and very high dose (VHD), 6.25 mg (≈250 mg/kg body weight). Chronic CTLA4-Ig therapy showed dose-dependent efficacy, with the LD regimen prolonging graft survival and with the HD and VHD regimens leading to >95% long-term graft survival and preserved histology. CTLA4-Ig's effect was immunosuppressive rather than tolerogenic because treatment cessation after ≈3 mo led to rejection. FoxP3-positive Tregs were reduced in naïve mice to a similar degree, independent of the CTLA4-Ig dose, but recovered to normal values in heart recipients under chronic CTLA4-Ig therapy. Treg depletion (anti-CD25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA4-Ig therapy is impaired when Tregs are removed, whereas CTLA4-Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Schwarz
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Unger
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Mahr
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Aumayr
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Regele
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: A M
authors.initials: AM
authors.lastname: Farkas
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Hock
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: N
authors.identifier: 0000-0003-4071-9397
authors.initials: N
authors.lastname: Pilat
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Wekerle
mesh_terms: D000069594:Abatacept / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D060908:CTLA-4 Antigen; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007166:Immunosuppressive Agents; D000069594:Abatacept
keywords: basic (laboratory) research/science; fusion proteins and monoclonal antibodies: belatacept; immune regulation; immunosuppressant; immunosuppression/immune modulation; lymphocyte biology