The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses

• DOI: 10.1111/ajt.13872
• Publication Date: 2016-05-17T05:07:35Z
• Authors: C. Schwarz; L. Unger; B. Mahr; K. Aumayr; H. Regele; A.M. Farkas; K. Hock; N. Pilat; T. Wekerle
• Keywords: Immunosuppression; Regimen

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) of concern. We investigated the effects CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). was injected chronically (on days 0, 4, 14, and 28 every 4 weeks thereafter) dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high (HD), 1.25 (≈50 very (VHD), 6.25 (≈250 weight). Chronic therapy showed dose-dependent efficacy, with LD regimen prolonging graft survival HD VHD leading to >95% long-term preserved histology. CTLA4-Ig's effect immunosuppressive rather than tolerogenic because treatment cessation ≈3 mo led rejection. FoxP3-positive Tregs were reduced naïve mice similar degree, independent dose, recovered normal values recipients under chronic therapy. Treg depletion (anti-CD25) resulted an impaired outcome had no detectable Consequently, partially effective when are removed, whereas at higher doses effectively maintains Tregs.