Pravastatin prolongs graft survival in an allogeneic rat model of orthotopic single lung transplantation.
OBJECTIVE
MHC class II molecules play central roles in immune recognition and rejection. As statins have been shown to inhibit the production of these molecules, we analyzed the possible immunosuppressive effect of pravastatin, using our rat model of orthotopic lung transplantation.


METHODS
Single orthotopic lung transplantation was performed in a Fischer 344-to-Wistar Kyoto strain combination. One group received pravastatin i.p. after transplantation, controls NaCl. Statin serum levels were analyzed by high performance liquid chromatography (HPLC). Animals were sacrificed on postoperative day (POD) 14 and 21. At sacrifice, samples were obtained for histology, immunhistochemistry, flow cytometry and real-time RT-PCR analysis of CD25, TNF-alpha, and MHC class II expression. Rejection was graded via histochemistry, using a system based on the working formulation of The International Society of Heart and Lung Transplantation. Immunohistochemistry was performed for expression of MHC class II, T-cell receptor, CD25, CD4/8 cell, NK cells, granulocytes and monocytes in naïve lungs and grafts from donor and recipient animals. Flow cytometric analysis of recipient peripheral blood mononuclear cells (PBMC) was used to analyze expression of CD3, CD4, CD8, and RT1B in both groups. In vitro analyses of MHC class II expression were performed in parallel.


RESULTS
HPLC confirmed effective delivery of pravastatin. Recipients treated with pravastatin showed significantly less rejection on POD 14 and on POD 21, when compared to controls. Immunohistochemistry showed specific differences, suggesting a delay in rejection in the pravastatin group. Flow cytometric analyses showed a higher expression of CD4 in the control group on POD 21. Results of real-time RT-PCR analyses for MHC class II expression showed a significant decrease in expression in the statin-treated group. Flow cytometric analysis of gamma-IFN stimulated rat PBMC showed an inhibition of upregulation of MHC class II expression by pravastatin in vitro.


CONCLUSIONS
Pravastatin prolongs graft survival in our allogeneic rat model of orthotopic lung transplantation. We assume that the underlying mechanism for this effect is the inhibition of upregulation of MHC class II molecule synthesis, thus blocking downstream effector mechanisms of the immune system.
Li
Yijiang
Y
Hannover Thoracic Transplant Program, Division of Thoracic- and Cardiovascular Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Köster
Thorsten
T
Mörike
Christiane
C
v Hörsten
Stephan
S
Martin
Ullrich
U
Bader
Michael
M
Haverich
Axel
A
Simon
Andre R
AR
D000818:Animals; D001991:Bronchitis / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D005434:Flow Cytometry / Q000379:methods; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D007150:Immunohistochemistry / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000276:immunology; D016040:Lung Transplantation / Q000379:methods*; D008297:Male; D023421:Models, Animal; D017035:Pravastatin / Q000097:blood / Q000276:immunology*; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D015704:CD4 Antigens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D017035:Pravastatin