Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 16, Issue 12, Pages 3404-3415Publisher
WILEY
DOI: 10.1111/ajt.13872
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Funding
- Bristol-Myers Squibb Pharmaceuticals
- Medical Scientific Fund of the Mayor of the City of Vienna [13042]
- Hochschuljubilaumsstiftung of Vienna
- Austrian Science Fund (FWF) [W1212] Funding Source: Austrian Science Fund (FWF)
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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 (approximate to 10 mg/kg body weight); high dose (HD), 1.25 mg (approximate to 50 mg/kg body weight); and very high dose (VHD), 6.25 mg (approximate to 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 approximate to 3 mo led to rejection. FoxP3-positive Tregs were reduced in naive 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.
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