Molecular and cellular events implicated in local tolerance to kidney allografts in miniature swine.
Long-term tolerance to class I-mismatched renal allografts can be induced in miniature swine by treatment with a short course of cyclosporine (CsA). Kidney recipients treated with CsA and untreated control kidney recipients both demonstrated infiltration of the transplanted kidney by mononuclear cells, which reached a maximum between postoperative days 8 and 11. Recipients that did not receive the tolerizing regimen rejected their grafts between postoperative days 8 and 12 in this model. The kinetics of cytokine gene expression, including interleukin (IL)-1alpha, IL-1beta, IL-2, IL-6, IL-10, tumor necrosis factor, and interferon-gamma (IFN-gamma), within the grafted kidney of rejector and acceptor animals, were determined using Northern blot hybridization. A strong correlation between rejection and up-regulation of the IFN-gamma gene was observed, whereas animals with long-term tolerance showed low levels of IFN-gamma, but high levels of IL-10 gene transcription. None of the other cytokine genes demonstrated a reproducible pattern of expression that correlated with acceptance/rejection of allografts. Analysis of transcription patterns of cytokine genes in mononuclear cells purified from renal grafts confirmed the initial observations made on biopsies. The phenotype of graft-infiltrating cells (GIC) showed a dominance of CD8+ cells, with an average of 66% single-positive cells and 19% CD4/CD8 double-positive cells, compared with 30% and 14%, respectively, for peripheral cells. Predominance of CD8+ GIC was dictated neither by the MHC antigen disparity nor the rejector/acceptor status. These results, therefore, suggest that GIC represent a regulated combination of mononuclear cells producing local immune mediators that, in part, control the fate of allografts in this large animal model.
Blancho
G
G
Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston 02129, USA.
Gianello
P R
PR
Lorf
T
T
Germana
S
S
Giangrande
I
I
Mourad
G
G
Colvin
R B
RB
Sachs
D H
DH
LeGuern
C
C
D000818:Animals; D016207:Cytokines / Q000235:genetics*; D005786:Gene Expression Regulation; D007108:Immune Tolerance; D007668:Kidney / Q000473:pathology*; D016030:Kidney Transplantation / Q000276:immunology*; D013552:Swine; D013556:Swine, Miniature; D014158:Transcription, Genetic; D014184:Transplantation, Homologous
D016207:Cytokines