title: Regulatory allospecific T cell clones abrogate chronic allograft rejection.
abstract: True alloantigen-specific tolerance is the ultimate goal of solid organ transplantation, eliminating the need for long-term immunosuppression. Recent evidence suggests that Th1-derived cytokines are associated with rejection and Th2-derived cytokines with long-term allograft survival, but the roles of these subsets in rejection and tolerance are incompletely understood. Here, we analyzed the functional and regulatory capacities of T cell clones derived from tolerant and rejecting rats (Wistar rat donors, Lewis rat recipients). We generated and subcloned T cell lines from lymphocytes derived from either acutely rejecting grafts or from the grafts of CTLA4-Ig-treated tolerant rats. Pretransplantation adoptive transfer of T cell clones generated from rejected grafts (Th1 clones) accelerated acute rejection or promoted development of chronic rejection, whereas transfer of T cell clones generated from tolerized grafts (Th2 clones) protected rats from acute rejection and progressive organ dysfunction. When Th1 and Th2 clones were injected simultaneously, Th2 clones specifically regulated activation of Th1 clones. Rats that received injections of Th2 clones accepted long-term donor-specific skin grafts but acutely rejected third-party skin grafts. Tolerant rats treated with Th2 clones demonstrated an increased number of regulatory CD4+CD25+Foxp3+ cells and strong mononuclear cell staining for IL-10 but negligible IFN-gamma, IL-17, and IL-23 compared with untreated rats or those treated with Th1 clones. In summary, these results demonstrate the regulatory functions of Th2 cells in a clinically relevant allogeneic transplant model and provide new insight into the functional role of Th2 cells in preventing the process of chronic rejection.
authors.affiliation: Department of Surgery I, Molecular Oncology and Immunology, University of Würzburg, Würzburg, Germany.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Waaga-Gasser
authors.forename: Martin R
authors.initials: MR
authors.lastname: Grimm
authors.forename: Jens
authors.initials: J
authors.lastname: Lutz
authors.forename: Volkmar
authors.initials: V
authors.lastname: Lange
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Lenhard
authors.forename: Beatriz
authors.initials: B
authors.lastname: Aviles
authors.forename: Joana E
authors.initials: JE
authors.lastname: Kist-van Holthe
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lebedeva
authors.forename: Dimitry
authors.initials: D
authors.lastname: Samsonov
authors.forename: Detlef
authors.initials: D
authors.lastname: Meyer
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Uwe
authors.initials: U
authors.lastname: Heemann
authors.forename: Martin
authors.initials: M
authors.lastname: Gasser
authors.forename: Anil
authors.initials: A
authors.lastname: Chandraker
mesh_terms: D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D002908:Chronic Disease; D002999:Clone Cells / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D007371:Interferon-gamma