title: Transforming growth factor beta (TGFβ) plays a crucial role in prolonging allograft survival in an allodepletion ("pruning") skin transplant model.
abstract: Adoptive cell therapies involving cell manipulation to achieve tolerance are increasingly being studied in animal models and in human trials. We have demonstrated that the specific removal of allo-stimulated dividing cells (or "pruning") promotes long-term allograft survival across a major MHC mismatch in transplant models including skin, heart and islet transplants. In this study, we examine the role of transforming growth factor beta (TGFβ), an important regulatory cytokine, on allograft survival in our allodepletion or "pruning" skin transplant model. Increased proliferation of CD4(+) T cells was observed following allo-stimulation of BALB/c spleen cells (labeled with CFSE) in the presence of the regulatory cytokines TGFβ and (interleukin-2) IL-2 in a mixed lymphocyte culture (MLC). Expression of the regulatory gene forkhead box-3 (FoxP3) was increased in both the allo-stimulated non-dividing (ND) (CFSE(high)) and dividing (D) (CFSE(low)) CD4(+) T cell populations, with the highest expression found in the D CD4(+) T cell population. Mice reconstituted with allo-stimulated ND CD4(+) T cells following TGFβ/IL-2 stimulation showed prolonged allograft survival, similar to previous data. Significantly, TGFβ/IL-2 stimulation prevented acute rejection of allografts across a major MHC mismatch in the presence of highly activated allo-stimulated D CD4(+) T cells. Blockade of TGFβ promoted rejection of allografts even following depletion of allo-stimulated D CD4(+) T cells. These studies support a crucial role for TGFβ in the survival of allografts and shows that regulatory cytokines TGFβ/IL2 can delay the rejection of allografts, even in the presence of highly activated alloreactive T cells.
authors.affiliation: Centre for Kidney Research (CKR), Kids Research Institute (KRI), The Children's Hospital at Westmead, Cnr Hawkesbury Rd and Hainsworth St, Westmead, NSW, Australia; Centre for Medical Bioscience (CMB), University of Wollongong, Northfields Avenue, Wollongong, NSW, Australia.
authors.forename: Debbie
authors.initials: D
authors.lastname: Watson
authors.affiliation: Centre for Kidney Research (CKR), Kids Research Institute (KRI), The Children's Hospital at Westmead, Cnr Hawkesbury Rd and Hainsworth St, Westmead, NSW, Australia.
authors.forename: Geoff Yu
authors.initials: GY
authors.lastname: Zhang
authors.affiliation: Centre for Kidney Research (CKR), Kids Research Institute (KRI), The Children's Hospital at Westmead, Cnr Hawkesbury Rd and Hainsworth St, Westmead, NSW, Australia.
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.affiliation: Centre for Kidney Research (CKR), Kids Research Institute (KRI), The Children's Hospital at Westmead, Cnr Hawkesbury Rd and Hainsworth St, Westmead, NSW, Australia.
authors.forename: Yuan-Min
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Centre for Kidney Research (CKR), Kids Research Institute (KRI), The Children's Hospital at Westmead, Cnr Hawkesbury Rd and Hainsworth St, Westmead, NSW, Australia.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Fletcher
authors.affiliation: Westmead Institute of Cancer Research (WICR), Westmead Hospital, Hawkesbury Road, Westmead, NSW, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Sartor
authors.affiliation: Centre for Kidney Research (CKR), Kids Research Institute (KRI), The Children's Hospital at Westmead, Cnr Hawkesbury Rd and Hainsworth St, Westmead, NSW, Australia. Electronic address: stephen.alexander@health.nsw.gov.au.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology*; D007376:Interleukin-2 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D023421:Models, Animal; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D016212:Transforming Growth Factor beta
keywords: Allograft; Cytokine; T cell; TGFβ; Transplantation