bma statins and transplantation

HMG-CoA Reductase Inhibitors as Immunomodulators

Potential Use in Transplant Rejection

Liza J. Raggatt and Nicola C. PartridgeDrugs 2002; 62 (15): 2185-2191

PowerPoint presentation done by Nabil Zeidan

Use of Statins after organ transplantation

• Most transplants are allografts

• Today immunosuppressive agents (e.g., cyclosporin A) can prevent acuteacute rejection, however, may induce hyperlipidimia

• Observation: Hyperlipidimia may promote chronic rejection [1]

• Statins initially given to blood lipids in transplant recipients and improve long term graft survival.

• In heart transplants recipients, one study found that statins improved one year survival [2].

• However, another study found no effect on acute rejection episodes or episode severity following fluvastatin fluvastatin treatment [3].

• In one report it was observed that pravastatinpravastatin could improve chronic rejection outcome when given in combination with other immunosuppressive agents [4].

Use of Statins after organ transplantation

Biological actions of Statins

• Statins lower blood cholesterol by competitively inhibiting HMG-CoA reductase, which catalyzes the rate limiting step in biosynthesis of cholesterol, and by up-regulating LDL receptors on cells.

• Reduced production of cholesterol also is accompanied by a decrease in the levels of cholesterol pathway intermediates, including isoprenoids.

• Isoprenoids are added to crucial proteins (e.g., Ras, Rho Rac) as part of post-translational events. Inhibition of isoprenoid production prevents function of these proteins.

• Statins can bind Leukocyte Function-Associated Antigen-1 (LFA-1) in cholesterol and mevalonate independent way and prevent it from interacting with other receptors [24]

Biological actions of Statins

Some observed immunomodulatory and anti-inflammatory effects

• Statins affect cytokine activity (in a study heart cytokine activity inhibited [11]).

• Statins have antiprolerative activity on mesangial and endothelial cells by cholesterol-independent ways [12,13]

• They lower intracellular isoprenoid intermediates [12]• They up-regulate Bone Morphogenic Protein-2 (BMP-

2) production (important for bone formation) [14]• They suppress T-cell response [18]• They lower chemokine response in PBMC [19]• They inhibit MHC-II induction [20]

The class II major histocompatibility complex (MHC) and T cell activation

• Engagement of MHC-II and T-cell Receptors (TCRs) is required for helper T-cell (Th cells) differentiation and proliferation.

• This interaction is crucial to produce effector Th cells.

Class II MHC and transplant rejection

• In allogeneic transplantation the tissue is attacked by the immune system of the host.

• Recognition of the MHC-II molecule as a foreign antigen (Ag), not the loaded peptide, induces the attack [25].

Molecular mechanisms behind statins’ immunomodulatory effects

• Statin treatment to IFN-γ-stimulated primary macrophages and endothelial cells has been shown to lower inducible MHC-II transcription + translation [20]

However, is it in a

cholesterol-dependent manner ?

• Statins prevent LFA-1 & ICAM-1 binding which is crucial for T-cell activation [24]

• Synthetic statin analogues that can bind to LFA-1 but not HMG-CoA was observed to inhibit T-cell activation [24]. However, some of the inhibitory effect was suppressed by mevalonate addition.


• Vascular endothelial cells act like Antigen Presenting Cells (APCs) during the process of transplant rejection [45] and promote rejection.

• By lowering MHC-II expression on vaslcular endothelial cells and by preventing LFA-1/ICAM-1 interaction, statins may prevent rejection. [20, 24].


• The authors in this article conclude by saying that manipulation of the immune system may harmful. They gave the example of the Altered Peptide Ligands (ALPs).

• However, they also say that although statins may possess immunomodulatory properties, no convincing reports show that statins make the host more susceptible to infections at the clinically given dose [47].

• A better understanding of cholesterol synthesis in relation to HMG-CoA inhibition and LFA-1 mediated Th1 response inhibition is needed.


References• Article numbering was used1 - Isoniemi H. Hyperlipidemia after renal transplantation-facts and potential

implications. Nephrol Dial Transplant 1995; 10: 457-9

2 - Keogh A, Macdonald P, Kaan M, et al. Efficacy and safety of pravastatin vs simvastatin after cardiac transplantation. J Heart Lung Transplant 2000; 19: 529-37

3 - Holdaas H, Jardine AG, Wheeler DC, et al. Effect of fluvastatin on acute renal allograft rejection: a randomized multicenter trial. Kidney Int 2001; 60: 1990-7

4 - Katznelson S,WilkinsonAH, Kobashigawa JA, et al. The effect of pravastatin on acute rejection after kidney transplantation: a pilot study. Transplantation 1996; 61: 1469-74

10 - Egashira K, Hirooka Y, Kai H, et al. Reduction in serum cholesterol with pravastatin improves endothelium-dependentcoronary vasomotion in patients with hypercholesterolemia. Circulation 1994; 89: 2519-24

References11 -Weis M, Pehlivanli S, Bruno M, et al. . Simvastatin treatment is associated with improvement in coronary endothelial function and decreased cytokine activation in patients after heart transplantation. J Am Coll Cardiol 2001; 38: 814-8

12 - Corsini A, Mazzotti M, Raiteri M, et al. Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis 1993; 101: 117-25

13 - Massy ZA, Guijarro C, O’Donnell MP, et al. Regulation of mesangial cell proliferation by the mevalonate pathway. Contrib Nephrol 1997; 120: 191-6

14 - Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science 1999; 286: 1825-6

References18 -Kurakata S, Kada M, Shimada Y, et al. Effect of different inhibitors of

3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. Immunopharmocology 1996; 34: 51-61

19 - RomanoM, Diomede L, Sironi M, et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest 2000; 80: 1095-100

20 - Kwak B, Mulhaupt F, Myit S, et al. Statins as a newly recognized type of immunomodulator. NatMed 2000; 6: 1299-402

24 - Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 2001; 7: 687-92

25 - Meyer D, Thompson G. How selection shapes variation of the human major histocompatibility complex: a review. Ann Hum Genet 2001; 65: 1-26

45 - Yun S, Rose ML, Fabre JW. The induction of major histocompatibility complex class II expression is sufficient for the direct activation of human CD4+ T cells by porcine vascular endothelial cells. Transplantation 2000; 69: 940-4

47 - Genain CP, Zamvil SS. Specific immunotherapy: one size does not fit all. Nat Med 2000; 6: 1098-100

References

bma statins and transplantation

Technology