Delayed-type hypersensitivity-like mechanisms dominate late acute rejection episodes in renal allograft recipients.
Episodes of acute rejection (aRx) may occur in functional renal allografts even at a very late stage post-Tx. Histopathology in early and late aRx looks quite similar--however, there is a slower deterioration of graft function in late aRx, suggesting that pathogenetic immune mechanisms are different. In order to investigate this phenomenon we studied the gene expression pattern (IL-1beta, 2, 4, 8, 10, IFNgamma, TNFalpha, GrnA, IL-2R p55/p75) in PBMC and core biopsies from long-term renal allograft recipients with histologically proven late aRx and compared it with transplant and non-transplant controls using a semiquantitative RT-PCR technique. PBMC and graft-infiltrating cells of patients with late aRx showed an upregulation, especially of IFN-gamma, IL-4, IL-10, and TNFalpha transcripts. While IL-2 mRNA was only detected in PBMC of two patients with late aRx who were not on cyclosporine, upregulation of intragraft IL-2 mRNA allowed the best discrimination between aRx and the other groups (sensitivity: 83%, specificity: 93%). In contrast to several reports on early Rx we did not notice an elevation of granzyme A transcripts in comparison with the controls, suggesting that cell-mediated inflammatory processes (CD4+ T cell-mediated DTH) dominate the late aRx, while early aRx is characterized by the additional involvement of cytotoxic T cell response. This may explain the distinct clinical course. Additionally, in a pilot study we successfully treated late aRx in 10/12 patients with the anti-CD 4 mAb, 16H5. Our encouraging therapeutic results underline the pathogenetic role of CD4+ T cells and support our hypothesis on DTH-like mechanisms in late aRx.
Ode-Hakim
S
S
Institute of Medical Immunology, Humboldt University, Berlin, Germany.
Docke
W D
WD
Kern
F
F
Emmrich
F
F
Volk
H D
HD
Reinke
P
P
D016207:Cytokines / Q000097:blood*; D006084:Graft Rejection / Q000097:blood / Q000276:immunology*; D053804:Granzymes; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000097:blood / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D012697:Serine Endopeptidases / Q000097:blood*; D014184:Transplantation, Homologous; D015854:Up-Regulation
D016207:Cytokines; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human