title: Evidence for a gene controlling the induction of transplantation tolerance.
abstract: Class I mismatched kidney transplantation in Massachusetts General Hospital MHC-defined miniature swine has been studied extensively as a model for induction of systemic allograft tolerance. In a large series of juvenile swine, long-term graft acceptance has been observed consistently following a 12-day course of cyclosporine. It was therefore surprising when three of five recipients in one of our studies rejected their grafts. Examination of the origins of the rejecting animals revealed that they were derived from a subline of the SLA(dd) miniature swine herd that was intentionally being inbred toward full homozygosity and had been inbred for eight generations prior to these experiments. A blinded study of additional class I mismatched renal transplants into animals from this subline confirmed the genetic basis of this rejection. We present here preliminary evidence suggesting that a likely explanation for this phenomenon is that the rejectors in this subline are homozygous for a recessive mutant allele of a gene normally involved in the induction of tolerance. Subsequent studies will be directed toward identification and characterization of the gene(s) involved, since existence of a similar genetic locus in humans might have implications for assessing an individual's likelihood of graft rejection versus tolerance induction prior to organ transplantation.
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: P W
authors.initials: PW
authors.lastname: Lee
authors.forename: J S
authors.initials: JS
authors.lastname: Hanekamp
authors.forename: V
authors.initials: V
authors.lastname: Villani
authors.forename: P A
authors.initials: PA
authors.lastname: Vagefi
authors.forename: R A
authors.initials: RA
authors.lastname: Cina
authors.forename: C
authors.initials: C
authors.lastname: Kamano
authors.forename: P E
authors.initials: PE
authors.lastname: O'Malley
authors.forename: S
authors.initials: S
authors.lastname: Arn
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D016572:Cyclosporine / Q000627:therapeutic use*; D006084:Graft Rejection / Q000175:diagnosis* / Q000209:etiology; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007674:Kidney Diseases / Q000150:complications* / Q000188:drug therapy / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects*; D013552:Swine; D013556:Swine, Miniature; D023001:Transplantation Tolerance / Q000187:drug effects / Q000235:genetics*
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; C438668:swine leukocyte antigen; D016572:Cyclosporine
keywords: MGH miniature swine; MHC; thymus; tolerance/suppression/anergy; transplantation