title: Key role for CD4 T cells during mixed antibody-mediated rejection of renal allografts.
abstract: We utilized mouse models to elucidate the immunologic mechanisms of functional graft loss during mixed antibody-mediated rejection of renal allografts (mixed AMR), in which humoral and cellular responses to the graft occur concomitantly. Although the majority of T cells in the graft at the time of rejection were CD8 T cells with only a minor population of CD4 T cells, depletion of CD4 but not CD8 cells prevented acute graft loss during mixed AMR. CD4 depletion eliminated antidonor alloantibodies and conferred protection from destruction of renal allografts. ELISPOT revealed that CD4 T effectors responded to donor alloantigens by both the direct and indirect pathways of allorecognition. In transfer studies, CD4 T effectors primed to donor alloantigens were highly effective at promoting acute graft dysfunction, and exhibited the attributes of effector T cells. Laser capture microdissection and confirmatory immunostaining studies revealed that CD4 T cells infiltrating the graft produced effector molecules with graft destructive potential. Bioluminescent imaging confirmed that CD4 T effectors traffic to the graft site in immune replete hosts. These data document that host CD4 T cells can promote acute dysfunction of renal allografts by directly mediating graft injury in addition to facilitating antidonor alloantibody responses.
authors.affiliation: Department of Surgery, Ohio State University Wexner Medical Center, Columbus, OH.
authors.forename: A
authors.initials: A
authors.lastname: Gaughan
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: R P
authors.initials: RP
authors.lastname: Pelletier
authors.forename: T
authors.initials: T
authors.lastname: Nadasdy
authors.forename: S
authors.initials: S
authors.lastname: Brodsky
authors.forename: S
authors.initials: S
authors.lastname: Roy
authors.forename: M
authors.initials: M
authors.lastname: Lodder
authors.forename: D
authors.initials: D
authors.lastname: Bobek
authors.forename: S
authors.initials: S
authors.lastname: Mofatt-Bruce
authors.forename: R L
authors.initials: RL
authors.lastname: Fairchild
authors.forename: M L
authors.initials: ML
authors.lastname: Henry
authors.forename: G A
authors.initials: GA
authors.lastname: Hadley
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D006084:Graft Rejection / Q000209:etiology*; D007518:Isoantibodies / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D007674:Kidney Diseases / Q000150:complications / Q000276:immunology* / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects*; D061346:Laser Capture Microdissection; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014184:Transplantation, Homologous
chemical_list: D007518:Isoantibodies; D007519:Isoantigens
keywords: Adoptive transfer; ELISPOT; T cell-mediated rejection; antibody-mediated rejection; graft infiltrating lymphocytes