title: Spontaneous acceptance of mouse kidney allografts is associated with increased Foxp3 expression and differences in the B and T cell compartments.
abstract: Spontaneous acceptance of organ allografts can identify novel mechanisms of drug-free transplantation tolerance. Spontaneous acceptance occurs in both mouse kidney transplants and rat liver transplants however the early immune processes of mouse kidney acceptance have not been studied. Acceptance of C57BL/6 strain kidney allografts in fully MHC-incompatible B10.BR recipients was compared with rejection (REJ) of heart allografts in the same strain combination. Graft infiltrate and antibody deposition were examined by immunohistochemical staining. Expression of mRNA was measured by quantitative real-time PCR. Apoptosis was examined by TUNEL staining. The majority of kidney allografts were accepted long-term and induced tolerance (TOL) of donor-strain skin grafts, showing that acceptance was not due to immune ignorance. There was an extensive infiltrate of T cells in the TOL kidney that exceeded the level in REJ hearts but subsequently declined. The main differences were deposition of IgG2a antibody in REJ that was absent in TOL, more B cells infiltrating TOL kidneys and a progressive increase in the ratio of CD8:CD4 cells during rejection. There was also significantly greater Foxp3 mRNA expression in TOL. Kidneys from RAG-/- donors were accepted, showing that donor lymphocytes were not necessary for acceptance. Neutralising antibodies to TGF-β administered from day 0 to day 6 did not prevent TOL. On the basis of cytokine expression and apoptosis there was no evidence for immune deviation or deletion as mechanisms of acceptance. In accord with the findings of spontaneous acceptance of liver allografts in rats, the main difference between mouse kidney TOL and heart REJ was in the B cell compartment. The major difference to rat liver allograft acceptance was that apoptosis of infiltrate did not appear to play a role. Instead, increased Foxp3 expression in TOL kidneys implies that regulatory T cells might be important.
authors.affiliation: A.W. Morrow Liver Laboratory, Centenary Institute, Royal Prince Alfred Hospital, and Collaborative Transplant Laboratory, Sydney University, Sydney, Australia.
authors.forename: Chuanmin
authors.initials: C
authors.lastname: Wang
authors.forename: Shaun
authors.initials: S
authors.lastname: Cordoba
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Patrick
authors.initials: P
authors.lastname: Bertolino
authors.forename: David G
authors.initials: DG
authors.lastname: Bowen
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Sharland
authors.forename: Richard D M
authors.initials: RD
authors.lastname: Allen
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: McCaughan
authors.forename: G Alex
authors.initials: GA
authors.lastname: Bishop
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000737:chemistry / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007136:Immunoglobulins / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology*; D008099:Liver / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D016031:Liver Transplantation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D016038:Skin Transplantation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007136:Immunoglobulins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta