Down-regulation of TGF-beta and VCAM-1 is associated with successful treatment of chronic rejection in rats.

We measured the expression levels of transforming growth factor-beta (TGF-beta) and vascular cell adhesion molecule (VCAM-1) in rat kidney grafts undergoing chronic rejection and treated the rats with six different regimens in order to determine correlation between their expression levels and severity of chronic rejection. F344 or Lewis kidneys were transplanted into Lewis recipients to generate allograft or isograft groups, respectively. Graft recipients were treated with one of the following regimens: (1) untreated isograft, (2) untreated allograft, (3) tacrolimus (FK506), 1 mg/kg/d for 10 days, (4) triptolide (PG490-88), 0.5 mg/kg/d for 10 days, and (5) leflunomide analogue (FK778), 10 mg/kg/d for 10 days. Kidneys were harvested on day 90 after transplantation and subjected to histological analysis and gene expression analysis by real-time reverse transcriptase polymerase chain reaction (RT-PCR) for TGF-beta and VCAM-1. Gene expression values were compared to measurements of chronic rejection by linear regression analysis. Modified Banff score for transplant pathology show that chronic rejection was mild in the FK778 group, moderate in the PG490-88 group, and severe in the FK506 and allograft control groups. Overall, the expression levels of TGF-beta and VCAM-1 show high correlations with histological changes of chronic rejection. Suppression of the expression levels of TGF-beta and VCAM-1 is associated with the amelioration of chronic rejection by various drugs, suggesting that these molecules are important key molecules in chronic rejection.

Protective effects of PG490-88 on chronic allograft rejection by changing intragraft gene expression profiles.

Our previous study showed that PG490-88 effectively ameliorated both functional and histological changes of chronic rejection in the rat. In this experiment, we investigated the intragraft gene expression profiles of PG490-88 under successful prevention of chronic rejection in rat kidney allografts. Kidneys of F344 rats were transplanted into bilaterally nephrectomized LEW recipients. Recipients with a brief course of low-dose FK506 (1 mg/kg per day for 10 days) were dosed with PG490-88 0.5 mg/kg per day, which was predetermined and defined as the effective dose of preventing chronic allograft rejection in this model, for 90 days after grafting. Kidney grafts were harvested on day 90 after transplantation and subjected to gene expression analysis by real-time RT-PCR. Overall, the expression levels of all genes tested were upregulated in the brief course of low-dose FK506 control. PG490-88 treatment exhibited significant inhibition of intragraft m RNA levels of iNOS, IL-6, and perforin and marginal downregulation of IL-2, IFNgamma, IRF-1, TNFalpha, and TGFbeta. There was no change in IL-10, granzyme B, and PDGFalpha, when compared to the brief course of low-dose FK506 control. These results suggested that downregulation of multiple intragraft gene expression by mainly suppression of iNOS, IL-6, and perforin might be responsible for successful prevention of chronic kidney allograft nephropathy by PG490-88 in rats.

PG490-88, a new immunosuppressant, effectively prevents acute and chronic rejection in rat renal allografts.

PG490-88 is a semisynthetic derivative of the novel compound PG490 (triptolide) purified from a Chinese herb. It has been shown to prolong acute allograft survival in multiple experimental organ transplant models. However, the effect of PG490-88 on prevention of acute and chronic renal allograft rejection has not been determined. Kidneys of ACI or F344 rats were transplanted into bilaterally nephrectomized LEW recipients as the acute or chronic allograft rejection models, respectively. Treatment of LEW recipients with PG490-88 significantly prolonged ACI kidney graft survival in a dose-dependent manner when compared with the untreated allograft controls. LEW recipients of F344 kidney grafts who received PG490-88 for 90 days with a brief course of low-dose FK506 showed normal serum creatinine levels and markedly reduced histological changes of chronic rejection at day 90 after transplantation. These results suggest that PG490-88 significantly prolongs kidney allograft survival in an acute rejection model and prevents chronic allograft rejection in rats.

Using augmentative communication with infants and young children with Down syndrome.

This paper reports the use of two forms of augmentative and alternative communication (AAC) with young children with Down syndrome: a program using signing (Makaton), and the COMPIC system of computerised pictographs. Children with Down syndrome are frequently reported to have difficulties in the area of language and communication, with relative strengths in visual and perceptual areas. This suggests possible benefits from the use of AAC systems to enhance language development. The paper discusses the use of AAC systems to assist young children with Down syndrome, and reports an experimental study of the use of such systems with an object naming task.