title: Mechanisms of tolerance to parental parathyroid tissue when combined with human allogeneic thymus transplantation.
abstract: BACKGROUND
  The induction of tolerance toward third-party solid organ grafts with allogeneic thymus tissue transplantation has not been previously demonstrated in human subjects.
  
  
  OBJECTIVE
  Infants with complete DiGeorge anomaly (having neither thymus nor parathyroid function) were studied for conditions and mechanisms required for the development of tolerance to third-party solid organ tissues.
  
  
  METHODS
  Four infants who met the criteria received parental parathyroid with allogeneic thymus transplantation and were studied.
  
  
  RESULTS
  Two of 3 survivors showed function of both grafts but subsequently lost parathyroid function. They demonstrated alloreactivity against the parathyroid donor in mixed lymphocyte cultures. For these 2 recipients, parathyroid donor HLA class II alleles were mismatched with the recipient and thymus. MHC class II tetramers confirmed the presence of recipient CD4(+) T cells with specificity toward a mismatched parathyroid donor class II allele. The third survivor has persistent graft function and lacks alloreactivity toward the parathyroid donor. All parathyroid donor class II alleles were shared with either the recipient or the thymus graft, with minor differences between the parathyroid (HLA-DRB1∗1104) and thymus (HLA-DRB1∗1101). Tetramer analyses detected recipient T cells specific for the parathyroid HLA-DRB1∗1104 allele. Alloreactivity toward the parathyroid donor was restored with low doses of IL-2.
  
  
  CONCLUSIONS
  Tolerance toward parathyroid grafts in combined parental parathyroid and allogeneic thymus transplantation requires matching of thymus tissue to parathyroid HLA class II alleles to promote negative selection and suppression of recipient T cells that have alloreactivity toward the parathyroid grafts. This matching strategy may be applied toward tolerance induction in future combined thymus and solid organ transplantation efforts.
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC 27710, USA. chinn001@mc.duke.edu
authors.forename: Ivan K
authors.initials: IK
authors.lastname: Chinn
authors.forename: John A
authors.initials: JA
authors.lastname: Olson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Skinner
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: McCarthy
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Gupton
authors.forename: Dong-Feng
authors.initials: DF
authors.lastname: Chen
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Bonilla
authors.forename: Robert L
authors.initials: RL
authors.lastname: Roberts
authors.forename: Maria G
authors.initials: MG
authors.lastname: Kanariou
authors.forename: Blythe H
authors.initials: BH
authors.lastname: Devlin
authors.forename: M Louise
authors.initials: ML
authors.lastname: Markert
mesh_terms: D000328:Adult; D004062:DiGeorge Syndrome / Q000628:therapy*; D006085:Graft Survival / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D007959:Lymphocyte Culture Test, Mixed; D010280:Parathyroid Glands / Q000276:immunology / Q000637:transplantation*; D010290:Parents; D013950:Thymus Gland / Q000276:immunology / Q000637:transplantation*; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000949:Histocompatibility Antigens Class II