Unknown

Dataset Information

0

Selective CD28 blockade attenuates acute and chronic rejection of murine cardiac allografts in a CTLA-4-dependent manner.


ABSTRACT: Selective blockade of CD28 is a promising therapy to inhibit pathogenic alloimmunity. However, evaluation of this approach in transplantation has been very limited. Using a novel nonactivating single-chain Fv-based reagent (?28scFv), we have investigated the role of CD28 and cytotoxic T lymphocyte antigen 4 (CTLA-4) in a murine cardiac transplant model. Blockade of CD28 for 2 weeks after engraftment promoted allograft survival, and significantly attenuated chronic rejection when combined with transient CD154-blockade or calcineurin inhibition. Graft acceptance was associated with decreased alloantibody production, increased proportion of early graft infiltration by regulatory T cells and increased expression of regulatory dendritic cell genes. Blockade of CTLA-4 during ?28scFv-based treatments led to prompt rejection in all animals and inhibited expression of forkhead box P3 (Foxp3), programmed death (PD)-1 and 2,3-indoleamine dioxygenase (IDO) in the graft. These results show that CD28 signaling during the first weeks after transplant is a pivotal mediator of pathogenic alloimmunity, and that selective CD28 blockade prolongs graft acceptance by at least two immunomodulatory mechanisms. Selective CD28 inhibition while sparing CTLA-4 is thus a promising approach to inhibit pathogenic alloimmunity.

PROVIDER: S-EPMC3158027 | BioStudies |

REPOSITORIES: biostudies

Similar Datasets

2013-01-01 | S-EPMC3733932 | BioStudies
| S-EPMC4124942 | BioStudies
2010-01-01 | S-EPMC2860737 | BioStudies
2017-01-01 | S-EPMC5590720 | BioStudies
2015-01-01 | S-EPMC4628789 | BioStudies
2019-01-01 | S-EPMC6658342 | BioStudies
2016-01-01 | S-EPMC5118475 | BioStudies
| S-EPMC4071624 | BioStudies
2016-01-01 | S-EPMC4922695 | BioStudies
2014-01-01 | S-EPMC3973119 | BioStudies