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Selective CD28 Blockade Attenuates Acute and Chronic Rejection of Murine Cardiac Allografts in a CTLA‐4‐Dependent Manner
Author(s) -
Zhang T.,
Fresnay S.,
Welty E.,
Sangrampurkar N.,
Rybak E.,
Zhou H.,
Cheng X.F.,
Feng Q.,
Avon C.,
Laaris A.,
Whitters M.,
Nagelin A. M.,
O’Hara Jr R. M.,
Azimzadeh A. M.
Publication year - 2011
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/j.1600-6143.2011.03624.x
Subject(s) - alloimmunity , blockade , medicine , ctla 4 , cd28 , immunology , foxp3 , transplantation , regulatory t cell , calcineurin , cancer research , t cell , immune system , il 2 receptor , receptor
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 (α28scFv), 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 α28scFv‐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.