title: Immunotoxin Against a Donor MHC Class II Molecule Induces Indefinite Survival of Murine Kidney Allografts.
abstract: Rejection of donor organs depends on the trafficking of donor passenger leukocytes to the secondary lymphoid organs of the recipient to elicit an immune response via the direct antigen presentation pathway. Therefore, the depletion of passenger leukocytes may be clinically applicable as a strategy to improve graft survival. Because major histocompatibility complex (MHC) class II(+) cells are most efficient at inducing immune responses, selective depletion of this population from donor grafts may dampen the alloimmune response and prolong graft survival. In a fully MHC mismatched mouse kidney allograft model, we describe the synthesis of an immunotoxin, consisting of the F(ab')2 fragment of a monoclonal antibody against the donor MHC class II molecule I-A(k) conjugated with the plant-derived ribosomal inactivating protein gelonin. This anti-I-A(k) gelonin immunotoxin depletes I-A(k) expressing cells specifically in vitro and in vivo. When given to recipients of kidney allografts, it resulted in indefinite graft survival with normal graft function, presence of Foxp3(+) cells within donor grafts, diminished donor-specific antibody formation, and delayed rejection of subsequent donor-type skin grafts. Strategies aimed at the donor arm of the immune system using agents such as immunotoxins may be a useful adjuvant to existing recipient-orientated immunosuppression.
authors.affiliation: Medical Research Council (MRC) Centre for Transplantation, School of Medicine at Guy's, King's, and St. Thomas' Hospitals, King's College London, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Brown
authors.affiliation: Medical Research Council (MRC) Centre for Transplantation, School of Medicine at Guy's, King's, and St. Thomas' Hospitals, King's College London, London, UK.
authors.forename: A K
authors.initials: AK
authors.lastname: Nowocin
authors.forename: L
authors.initials: L
authors.lastname: Meader
authors.affiliation: Medical Research Council (MRC) Centre for Transplantation, School of Medicine at Guy's, King's, and St. Thomas' Hospitals, King's College London, London, UK.
authors.forename: L A
authors.initials: LA
authors.lastname: Edwards
authors.affiliation: Medical Research Council (MRC) Centre for Transplantation, School of Medicine at Guy's, King's, and St. Thomas' Hospitals, King's College London, London, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Smith
authors.affiliation: Medical Research Council (MRC) Centre for Transplantation, School of Medicine at Guy's, King's, and St. Thomas' Hospitals, King's College London, London, UK.
authors.forename: W
authors.initials: W
authors.lastname: Wong
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D000922:Immunotoxins / Q000494:pharmacology*; D016030:Kidney Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D054789:Ribosome Inactivating Proteins, Type 1 / Q000737:chemistry; D014019:Tissue Donors
chemical_list: D000911:Antibodies, Monoclonal; D000949:Histocompatibility Antigens Class II; D000922:Immunotoxins; D054789:Ribosome Inactivating Proteins, Type 1; C025674:GEL protein, Gelonium multiflorum
keywords: animal models; basic (laboratory) research, science; dendritic cell; fusion proteins and monoclonal antibodies; immunobiology, kidney transplantation; immunosuppressant; major histocompatibility complex (MHC); murine, antigen presentation; nephrology; recognition