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The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses.
- Source :
-
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons [Am J Transplant] 2016 Dec; Vol. 16 (12), pp. 3404-3415. Date of Electronic Publication: 2016 Jul 05. - Publication Year :
- 2016
-
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.<br /> (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Subjects :
- Abatacept administration & dosage
Animals
CTLA-4 Antigen
Female
Graft Survival drug effects
Immune Tolerance
Immunosuppression Therapy
Immunosuppressive Agents administration & dosage
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
T-Lymphocytes, Regulatory drug effects
Abatacept pharmacology
Graft Survival immunology
Heart Transplantation
Immunosuppressive Agents pharmacology
T-Lymphocytes, Regulatory immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1600-6143
- Volume :
- 16
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
- Publication Type :
- Academic Journal
- Accession number :
- 27184870
- Full Text :
- https://doi.org/10.1111/ajt.13872