Chronic heart allograft rejection in rats demonstrates a dynamic interplay between IFN-γ and IL-10 producing T cells

Abstract

The relative roles of different types of T cells and their modes of alloantigen recognition and cytokine production in chronic rejection have been controversial. This may be due to the use of models involving various immune interventions. We recently reported a rat heart allograft model (PVG.1U-to-PVG.R8) that consistently develops chronic rejection without any immune manipulations. Using this model, we investigated the frequency of indirectly activated alloreactive CD4+ T cells and directly/indirectly induced CD8+ T cells and characterized their cytokine profiles at various times posttransplantation. In vitro quantitative–proliferative and intracellular cytokine assays were performed using recipient lymphocytes as responders against donor and third party stimulator cells. Intragraft transcript levels for IFN-γ were measured using competitive RT-PCR. We observed a steady increase in the frequency of donor reactive CD4+ T cells, peaking on day 18–22 posttransplantation, followed by a decline to background levels on day 60. These cells produced high levels of IL-10 that steadily increased throughout the 100-day experimental period. In contrast, the frequency of donor reactive CD8+ T cells was similar to that of naı̈ve cells and remained unchanged throughout the study. CD8+ T cells produced high amounts of IFN-γ only on days 39–45 posttransplantation when chronic rejection was apparent. There was a sharp increase in intragraft IFN-γ transcripts on days 8–12 that peaked on days 39–45 followed by a steady decrease thereafter. Our results demonstrate that chronic rejection in this model involves a dynamic interplay between alloreactive CD8+IFN-γ+ and CD4+IL-10+ T cells, both of which may have differential effects on the pathogenesis of the disease.