title: Disruption of Transplant Tolerance by an "Incognito" Form of CD8 T Cell-Dependent Memory.
abstract: Several approaches successfully achieve allograft tolerance in preclinical models but are challenging to translate into clinical practice. Many clinically relevant factors can attenuate allograft tolerance induction, including intrinsic genetic resistance, peritransplant infection, inflammation, and preexisting antidonor immunity. The prevailing view for immune memory as a tolerance barrier is that the host harbors memory cells that spontaneously cross-react to donor MHC antigens. Such preexisting "heterologous" memory cells have direct reactivity to donor cells and resist most tolerance regimens. In this study, we developed a model system to determine if an alternative form of immune memory could also block tolerance. We posited that host memory T cells could potentially respond to donor-derived non-MHC antigens, such as latent viral antigens or autoantigens, to which the host is immune. Results show that immunity to a model nonself antigen, ovalbumin (OVA), can dramatically disrupt tolerance despite undetectable initial reactivity to donor MHC antigens. Importantly, this blockade of tolerance was CD8+T cell-dependent and required linked antigen presentation of alloantigens with the test OVA antigen. As such, this pathway represents an unapparent, or "incognito," form of immunity that is sufficient to prevent tolerance and that can be an unforeseen additional immune barrier to clinical transplant tolerance.
authors.affiliation: Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO.
authors.forename: M K
authors.initials: MK
authors.lastname: Nelsen
authors.affiliation: Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO.
authors.forename: K S
authors.initials: KS
authors.lastname: Beard
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
authors.forename: R J
authors.initials: RJ
authors.lastname: Plenter
authors.affiliation: Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO.
authors.forename: R M
authors.initials: RM
authors.lastname: Kedl
authors.affiliation: Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO.
authors.forename: E T
authors.initials: ET
authors.lastname: Clambey
authors.affiliation: Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO.
authors.forename: R G
authors.initials: RG
authors.lastname: Gill
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D010047:Ovalbumin
keywords: T cell biology; basic (laboratory) research/science; immune regulation; immunobiology; islet transplantation; tolerance; tolerance: costimulation blockade