title: Loss of direct and maintenance of indirect alloresponses in renal allograft recipients: implications for the pathogenesis of chronic allograft nephropathy.
abstract: Chronic allograft nephropathy (CAN) is the principal cause of late renal allograft failure. This complex process is multifactorial in origin, and there is good evidence for immune-mediated effects. The immune contribution to this process is directed by CD4(+) T cells, which can be activated by either direct or indirect pathways of allorecognition. For the first time, these pathways have been simultaneously compared in a cohort of 22 longstanding renal allograft recipients (13 with good function and nine with CAN). CD4(+) T cells from all patients reveal donor-specific hyporesponsiveness by the direct pathway according to proliferation or the secretion of the cytokines IL-2, IL-5, and IFN-gamma. Donor-specific cytotoxic T cell responses were also attenuated. In contrast, the frequencies of indirectly alloreactive cells were maintained, patients with CAN having significantly higher frequencies of CD4(+) T cells indirectly activated by allogeneic peptides when compared with controls with good allograft function. An extensive search for alloantibodies has revealed significant titers in only a minority of patients, both with and without CAN. In summary, this study demonstrates widespread donor-specific hyporesponsiveness in directly activated CD4(+) T cells derived from longstanding recipients of renal allografts, whether they have CAN or not. However, patients with CAN have significantly higher frequencies of CD4(+) T cells activated by donor Ags in an indirect manner, a phenomenon resembling split tolerance. These findings provide an insight into the pathogenesis of CAN and also have implications for the development of a clinical tolerance assay.
authors.affiliation: Department of Immunology, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom.
authors.forename: R J
authors.initials: RJ
authors.lastname: Baker
authors.forename: M P
authors.initials: MP
authors.lastname: Hernandez-Fuentes
authors.forename: P A
authors.initials: PA
authors.lastname: Brookes
authors.forename: A N
authors.initials: AN
authors.lastname: Chaudhry
authors.forename: H T
authors.initials: HT
authors.lastname: Cook
authors.forename: R I
authors.initials: RI
authors.lastname: Lechler
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002908:Chronic Disease; D015331:Cohort Studies; D016207:Cytokines / Q000096:biosynthesis; D003601:Cytotoxicity Tests, Immunologic; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology*; D007674:Kidney Diseases / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014019:Tissue Donors; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D007136:Immunoglobulins; D007519:Isoantigens