This document discusses the potential immunomodulatory effects of statins in organ transplant recipients. It notes that while immunosuppressive drugs prevent acute rejection, they can cause hyperlipidemia which may promote chronic rejection. Studies have found statins improve outcomes when given to transplant recipients by lowering lipids. The document then explores the biological mechanisms of statins including inhibiting HMG-CoA reductase and isoprenoid production, which can suppress T-cell response and lower MHC expression on antigen presenting cells like endothelial cells. This may prevent rejection by inhibiting interactions between MHC, T-cell receptors, and adhesion molecules like LFA-1 and ICAM-1. Further research is still needed to better understand how cholesterol synthesis

1. HMG-CoA Reductase Inhibitors as
Immunomodulators
Potential Use in Transplant Rejection
Liza J. Raggatt and Nicola C. Partridge
Drugs 2002; 62 (15): 2185-2191
PowerPoint presentation done by
Nabil Zeidan

2. 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.

3. • 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
fluvastatinfluvastatin 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

4. 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.

5. • 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

6. 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]

7. 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.

8. 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].

9. 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]

10. However, is it in a
cholesterol-dependent manner ?

11. • 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.
Molecular mechanisms behind
statins’ immunomodulatory effects

12. • 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].
Molecular mechanisms behind
statins’ immunomodulatory effects

13. • 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.
Molecular mechanisms behind
statins’ immunomodulatory effects

14. References
• Article numbering was used
1 - 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

15. References
11 -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

16. References
18 -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

17. 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