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