Premium
The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses
Author(s) -
Schwarz C.,
Unger L.,
Mahr B.,
Aumayr K.,
Regele H.,
Farkas A. M.,
Hock K.,
Pilat N.,
Wekerle T.
Publication year - 2016
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.13872
Subject(s) - medicine , immunosuppression , foxp3 , antibody , regimen , il 2 receptor , transplantation , immunology , blockade , t cell , immune system , receptor
B7.1/2‐targeted costimulation blockade ( CTLA 4 immunoglobulin [ CTLA 4‐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 CTLA 4‐Ig monotherapy in a fully mismatched heart transplant model ( BALB /c onto C57 BL /6). CTLA 4‐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 CTLA 4‐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. CTLA 4‐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 CTLA 4‐Ig dose, but recovered to normal values in heart recipients under chronic CTLA 4‐Ig therapy. Treg depletion (anti‐ CD 25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA 4‐Ig therapy is impaired when Tregs are removed, whereas CTLA 4‐Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.