Adoptive transfer of primed CD4+ T-lymphocytes induces pattern of chronic allograft nephropathy in a nude rat model

BACKGROUND: Chronic allograft nephropathy (CAN) remains the most common cause of late graft loss in renal transplantation. Presensitized patients have a specifically increased risk to lose their graft. To analyze the immunological factors involved, a new experimental rat model was created with nude athymic LEW.RNU rats as recipients of F344 renal allografts. METHODS: Adoptive transfer of CD4+ T-lymphocytes (2x, 3.5x, or 5 x 10(7) cells) primed against donor skin grafts was performed one week after transplantation. The animals were monitored for renal function, graft infiltrating cells, and the development of donor specific alloantibodies for 20 weeks or until graft loss. RESULTS: Survival of the animals was dose dependent; rats suffered from renal failure with severe albuminuria and developed various lesions typical for CAN including interstitial fibrosis and tubular atrophy. The cell infiltrate in the graft increased with the amount of CD4+ T-cells transferred and consists predominantly of CD4+ T-cells and macrophages/monocytes. More than half of the grafts showed histological signs of glomerulopathy consistent with CAN. 9/12 rats with CAN had antibodies against the donor major histocompatibility complex (MHC)-I and in all rats donor specific anti-glomerular basement membrane (GBM) antibodies were detected. CONCLUSION: Adoptive transfer of primed CD4+ T-cells results in a severe infiltrate of CD4+ cells in the graft and production of anti-MHC and GBM antibodies in this nude rat model. Histological changes are consistent with CAN with frequent glomerular changes. In conclusion, the induction of donor specific alloantibodies by primed CD4+ T-lymphocytes may play an important role in the pathogenesis of CAN.