EFFECTS OF IRON ON THE IMMUNE SYSTEM

Transcription

1 EFFECTS OF IRON ON THE IMMUNE SYSTEM Gert Mayer Department of Internal Medicine IV (Nephrology and Hypertension) Medical University Innsbruck Austria

2 Conflicts of interest Research Support: Amgen, Roche, Takeda, Ratiopharm Honoraria: Amgen, Roche, Takeda, Medice, Astro Pharma, Ratiopharm

3 INTERACTION BETWEEN INFECTION / INFLAMMATION AND IRON METABOLISM EFFECTS OF IRON SUPPLEMENTATION DURING INFECTION / INFLAMMATION EFFECTS OF IRON SUPPLEMENTATION ON THE IMMUNE SYSTEM IN THE ABSENCE OF INFECTION / INFLAMMATION

4 INTERACTION BETWEEN INFECTION / INFLAMMATION AND IRON METABOLISM EFFECTS OF IRON SUPPLEMENTATION DURING INFECTION / INFLAMMATION EFFECTS OF IRON SUPPLEMENTATION ON THE IMMUNE SYSTEM IN THE ABSENCE OF INFECTION / INFLAMMATION

5 Drakesmith H et al. Science 2012

6 INVESTIGATION OF A RESEARCHERS DEATH DUE TO SEPTICEMIC PLAGUE BY ATTENUATED YERSINIA PESTIS Frank KM et al. N Engl J Med 2011

7 Drakesmith H et al. Science 2012

8 IRON CHAPERON PROTEINS ARE ACUTE PHASE REACTION PROTEINS Innere Medizin IV Lactoferrin, Transferrin, Ferritin chaperon proteins for iron Haptoglobin chaperon protein for hemoglobin Hemopexin chaperon protein for heme

9 Ward RJ et al. J Neural Transm 2011

10 HEPCIDIN REGULATION BY IRON AVAILABILITY AND INFLAMMATION Babitt JL et al. Am J Kidney Dis 2010

11 MONOCYTE/MACROPHAGE A KEY ROLE IN IRON METABOLISM AND INFLAMMATION Ward RJ et al. J Neural Transm 2011

12 NUTRITIONAL IMMUNITY (I) Innere Medizin IV Microorganism (auto) immune dysregulation LPS IFN γ Il-6 Il-1 Hepcidin erythrophagozytosis Ferroportin M1 macrophage Hepcidin Recalcati S et al. Autoimm Rev 2012 DMT 1 TNF- α, IL-1, -6, -10, -12,-18 NO, O 2-,OH -, H 2 O 2

13 NUTRITIONAL IMMUNITY (II) Innere Medizin IV LPS IFN γ Il-6 Il-1 IL-4 IL-10 Il-13 Iron uptake, storage and release macrophage

14 Anemia of chronic disease (ACD) most frequent anaemia among hospitalised patients mild to moderate, normochromic, normocytic develops in patients with cellular immune activation degree of anaemia correlated to immune activation

15 INTERACTION BETWEEN INFECTION / INFLAMMATION AND IRON METABOLISM EFFECTS OF IRON SUPPLEMENTATION DURING INFECTION / INFLAMMATION EFFECTS OF IRON SUPPLEMENTATION ON THE IMMUNE SYSTEM IN THE ABSENCE OF INFECTION / INFLAMMATION

16 MONOCYTE INTRACELLULAR IRON RETENTION AFTER IV IRON IS DETERMINED BY HEPCIDIN LEVELS intracellular ferritin concentration (ng/ml) p = 0.72 p = 0.02 day 0 48 hours prior iron therapy after iron therapy high serum hepcidin (>12 pmol/ml) low serum hepcidin (<12 pmol/ml) Sonnweber T et al. Nephrol Dial Transplant 2011

17 An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice Sindrilaru A et al. J Clin Invest 2011

18 INTERACTION BETWEEN INFECTION / INFLAMMATION AND IRON METABOLISM EFFECTS OF IRON SUPPLEMENTATION DURING INFECTION / INFLAMMATION EFFECTS OF IRON SUPPLEMENTATION ON THE IMMUNE SYSTEM IN THE ABSENCE OF INFECTION / INFLAMMATION

19 THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM 31 stable patients on hemodialysis no clinical or routine laboratory signs of infections or inflammation all on ESA therapy, serum ferritin µg/l, hemoglobin g/dl, one week after iron withdrawal the subjects were randomized to Group 1: IU/kg BW ESA / week Group 2: IU ESA/kg BW plus 100 mg iron saccharate / week Kidney Int 2003

20 THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM Hemoglobin (g/ dl) baseline 3 months p ANOVA over 5me p difference in trend / / Ferri5n (ng/ml) Transferrin satura5on (%) / / / /- 97 < < / /- 282 < / / / / iron supplementation iron supplementation iron supplementation Kidney Int 2003

21 THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM 20 TNF-α (ng/l) 10 * iron yes no days Kidney Int 2003

22 THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM TNF-α (ng/l) r=0.56 p=0.008 IL-4 (ng/l) r=0.43 p= TfS, % TfS, % Kidney Int 2003

23 THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM IL-12 TH0 IL-4 TH1 - - TH2 IFN-γ IL-2 TNF-α IL-4, IL-5 IL-10 IL macrophage courtesy G. Weiss TNF- α, IL-1, -6, -10, -12,-18 NO, O2 -,OH -, H 2 O 2

24 THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM IL-12 TH0 IL-4 TH TH2 Iron - IFN-γ IL-2 TNF-α macrophage + IL-4, IL-5 IL-10 IL-13 courtesy G. Weiss TNF- α, IL-1, -6, -10, -12,-18 NO, O2 -,OH -, H 2 O 2

25 THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM mean IL-6 concentration in supernatant of monocytic cell culture (ng/ml) p=0.01 p=0.04 p= baseline serum ferritin level low (<170 ng/ml) high (>350 ng/ml) 0 0 Control IFN-γ LPS Sonnweber T et al. Nephrol Dial Transplant 2011

26 MAYBE NOT ONLY INCREASED IRON AVAILABILITY BUT ALSO IMPAIRED TH 1 RESPONSE? Frank KM et al. N Engl J Med 2011

27 DISTINCT IMMUNOLOGIC EFFECTS OF DIFFERENT INTRAVENOUS IRON PREPARATIONS ON MONOCYTES Fell LH et al. Nephrol Dial Transplant 2014

28 IRON SUCROSE PROMOTES APOPTOSIS IN POLYMORPHONUCLEAR LEUCOCYTES Ichii H et al. Am J Nephrol 2012

29 HIGH DOSE PARENTERAL IRON SUCROSE DEPRESSES NEUTROPHIL INTRACELLULAR KILLING CAPACITY Deicher R et al. Kidney Int 2003

30 EFFECTS OF INFECTION / INFLAMMATION ON IRON METABOLISM EFFECTS OF IRON SUPPLEMENTATION DURING INFECTION / INFLAMMATION EFFECTS OF IRON SUPPLEMENTATION ON THE IMMUNE SYSTEM IN THE ABSENCE OF INFECTION / INFLAMMATION

31 THE EFFECT OF IRON ADMINISTRATION ON THE IMMUNE SYSTEM TNF-α (ng/l r=0.394 p=0.046 TfS, % r=0.428 p= POX (µmol/l) POX (µmol/l) Kidney Int 2003

32 EFFECT OF DIFFERENT IRON PREPARATIONS ON APOPTOSIS OF MONONUCLEAR CELLS IN VIVO 50 control iron sucrose iron dextrane 40 ferric gluconate ferric carboxym % apoptotic cells T0 T1 T2 T3 Martin-Malo A et al Nephrol Dial Transplant 2012

33 SALMONELLA INDUCED INTESTINAL INFLAMMATION IS ATTENUATED IN Hfe -/- MICE Wang L et al. J Immunol 2008

34 IRON REGULATORY PROTEINS AND IMMUNE SYSTEM Innere Medizin IV Lactoferrin weak iron chelator Immunoregulator effects on Th1/Th2 cell activities Transferrin iron transporter present on monocytes, macrophages, T lymphocytes, required for early T cell differentiation Transferrin receptor 1 cellular iron uptake iron uptake by activated lymphocytes, required for DNA synthesis and cell division of T lymphocytes Ferroportin cellular iron exporter toll-like gate receptor 4 mediates downregulation in infection etc. Ward RJ et al. J Neural Transm 2011

35 IRON INHIBITS IFN γ ACTIVITY IN HUMAN MONOCYTES/MACROPHAGES Innere Medizin IV desferrioxamine GTP IFN- γ + - Fe +2 Fe +3 transferrin/fe tryptophan GTP-CH IDO neopterin TNF- α MHC class II kynurenine Weiss et al. Exp Hematol 1992, J Exp Med 1994