Inhibition of transplant vasculopathy by pravastatin is associated with attenuation of host allo-antibody responses

184 Purpose: Pravastatin (Prav), an HMG-CoA reductase inhibitor, ameliorates coronary transplant (Tx) vasculopathy. This study was designed to analyze whether Prav-mediated effects are associated with a modulation of host allo-antibody (allo-Ab) responses. Methods: LEW to F-344 rat heterotopic abdominal cardiac Tx were performed. All recipients were given CsA (1.5 mg/kg/d ×10d). Experimental animals received adjunctive Prav (20 mg/kg/d ×4 mo). Host anti-donor IgM and IgG allo-Ab responses were screened serially in serum by flow cytometry. Results: Treatment with Prav decreased cardiac Tx neointimal occlusion score at 4 mo, as compared to controls (0.9±0.4 and 2.6±0.6, resp; p<0.05; n=6 rats/group). By that time, no significant difference in the serum IgM allo-Ab response could be found (Fig. 1). In contrast, IgG allo-Ab levels were markedly diminished in animals treated with Prav, as compared to controls (Fig. 2; p=0.03 at 1:8 dilution; n=3-5 rats/group). Syngeneic controls (LEW to LEW) had no appreciable IgG or IgM allo-Ab levels. Additionally, IgG levels were low in both treatment groups at 2 wks. However, unlike in control Tx recipients, IgG allo-Ab response was persistently diminished in Prav treated hosts at 2, 3 and 4 mo post-Tx. Conclusions: Prav is the only known agent to ameliorate Tx vasculopathy in the clinical setting. This is the first report, to our knowledge, which documents that Prav prevents the development of Tx vasculopathy in a well-defined rat model, by attenuating the host circulating allo-Ab responses.Fig. 1: IgM allo-Ab response (4 mo).Fig. 2: IgG allo-Ab response (4 mo)