title: 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 (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.
authors.affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, USA. tzhang@smail.umaryland.edu
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Fresnay
authors.forename: E
authors.initials: E
authors.lastname: Welty
authors.forename: N
authors.initials: N
authors.lastname: Sangrampurkar
authors.forename: E
authors.initials: E
authors.lastname: Rybak
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: X-F
authors.initials: XF
authors.lastname: Cheng
authors.forename: Q
authors.initials: Q
authors.lastname: Feng
authors.forename: C
authors.initials: C
authors.lastname: Avon
authors.forename: A
authors.initials: A
authors.lastname: Laaris
authors.forename: M
authors.initials: M
authors.lastname: Whitters
authors.forename: A M
authors.initials: AM
authors.lastname: Nagelin
authors.forename: R M
authors.initials: RM
authors.lastname: O'Hara
authors.forename: A M
authors.initials: AM
authors.lastname: Azimzadeh
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000037:antagonists & inhibitors*; D060908:CTLA-4 Antigen / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016027:Heart Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen