Immunomodulation at Cardiac Surgery. William T McBride MD

Transcription

1

2 Immunomodulation at Cardiac Surgery William T McBride MD March 2005

3 Basic Structure of Immune System Immune response Adaptive specific memory Innate non-specific no memory

4 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins Should we immunomodulate? How should we immunomodulate?

5 Innate Immune Response Humoral and Cellular

6 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

7 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

8

9 Intrinsic system (XIIa) (HMWK +XIa) Extrinsic system Prothrombin Thrombin Fibrinogen Fibrin X Xa Prothrombin Thrombin Fibrinogen Fibrin TF TF TF TF VII VII VII VII Barrier to spread of infection

10 Intrinsic system (XIIa) Extrinsic system Prothrombin Thrombin Fibrinogen Fibrin Prothrombin Thrombin Fibrinogen Fibrin TF TF TF TF

11 PROCOAGULANT Intrinsic system (XIIa) Extrinsic system Prothrombin Thrombin Fibrinogen Fibrin Prothrombin Thrombin Fibrinogen Fibrin TF TF TF TF

12

13 Gp 1b vwf

14 thrombin IIb IIIa IIb IIIa IIb IIIa Gp 1b Gp 1b vwf Gp 1a IIa Gp 1b

15 PROCOAGULANT Intrinsic system (XIIa) Extrinsic system Prothrombin Thrombin Fibrinogen Fibrin Prothrombin Thrombin Fibrinogen Fibrin TF TF TF TF ANTICOAGULANT

16 PROCOAGULANT Intrinsic system (XIIa) Extrinsic system Prothrombin Thrombin Fibrinogen Fibrin Prothrombin Thrombin Fibrinogen Fibrin TF TF TF TF ANTICOAGULANT

17 Prothrombin Thrombin Fibrinogen Fibrin Thrombomodulin S TF Thrombin Protein C

18 Prothrombin Thrombin Fibrinogen Fibrin Thrombomodulin S APCR TF Thrombin Protein C

19 Prothrombin Thrombin Fibrinogen Fibrin Thrombomodulin Thrombin S APCR Protein C TF VIIa TFPI ANTICOAGULATION V & VIII

20 Fibrinolytic system tpa + upa(endothelially produced) Plasminogen Plasmin

21 Fibrinolytic system Anti Fibrinolysis tpa + PA inhibitor 1 (PAI1) upa(endothelially produced) (PA1-tPA cleared in liver) Plasminogen Plasmin α2-antiplasmin (PAP complex) Platelet damage (gp1b)

22 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

23 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

24 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

25 3. XIIa Pre-kallikrein kallikrein Bradykininogen bradykinin 1. Vasodilation

26 3. XIIa Pre-kallikrein kallikrein Bradykininogen bradykinin 1. Vasodilation 2. Capillary leak

27 4. Complement system Classical Alternative Lectin Pathways Lysis Opsonisation Immune complexes

28 Coagulation system Fibrinolytic system Bradykinin Complement Neutrophil activation Oedema

29 Coagulation affects the rest of the immune response! ADAPTIVE (specific) b INNATE (non-specific) a CELLULAR lymphocytes ADCC HUMORAL antibodies APC < monocyte/macrophages >phagocytosis CELLULAR NK cells cytokines a granulocytes HUMORAL clotting cascade classical pathway< complement >alternate pathway kallikrein-kinins

30 Procoagulant APC T H Prevention of clot propagation anticoagulation X APC T H Fibrinolysis APC T H Antifibrinolysis APC T H

31 3. XIIa Pre-kallikrein kallikrein Bradykininogen bradykinin 1. Vasodilation 2. Capillary leak

32 Intrinsic system (XIIa) Extrinsic system Prothrombin Thrombin Fibrinogen Fibrin IL-8 Prothrombin Thrombin Fibrinogen Fibrin Prothrombin + Xa IL-1 in macrophages (Jones A. Immunology 1990;71:236) Thrombin TF IL-8 in TFmonocyte TFcell line (Suk K Immunol VII VIILett VII1999;67:223) Thrombin, Xa, fibrin IL-8 in endothelial cell lines (Senden et al J Immunol 1998;161: 4318) Barrier to spread of infection

33 Procoagulant APC T H Prevention of clot propagation anticoagulation X APC T H Fibrinolysis APC T H Antifibrinolysis APC T H

34 Prothrombin Thrombin Fibrinogen Fibrin Thrombomodulin Thrombin S APCR Protein C TF VIIa TFPI ANTICOAGULATION TFPI reduces IL-6 and IL-8 in baboons (Biemond BJ. Thromb Haemostas 1995;73:223) APC inhibits leukocyte activation in in rats V & VIII (Taoka Y. J Neuroscience 1998;18:1393) rhapc reduce mortality from 31% to 25% after 28 days (Esmon CT. Crit Care Medicine 2001;29:S48-51)

35 Procoagulant APC T H Prevention of clot propagation anticoagulation X APC T H Fibrinolysis APC T H Antifibrinolysis APC T H

36 Fibrinolytic system tpa + upa Plasminogen Plasmin chemotaxis

37 Fibrinolytic system Anti Fibrinolysis tpa + upa PA inhibitor 1 (PAI1) Plasminogen Plasmin α2-antiplasmin (PAP complex) PAI inhibits LPS induced TNF Production by monocytes in vitro (Robson SC. J Clin Lab Immunol 1990;33:83)

38 Should we immunomodulate the coagulation system? Yes! We want to reduce tissue oedema and systemic neutrophil activation Yes we want to reduce effects on the rest of the immune response How should we immunomodulate? Reduce blood contact with foreign surfaces eg Biocompatible technologies eg heparin coating Off-Pump cardiac surgery Reduce platelet activation eg using aprotinin

39 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

40 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

41 Cellular natural response P-selectin E-selectin VCAM ICAM TNF

42 Cellular natural response L-selectin integrins P-selectin E-selectin VCAM ICAM TNF

43 Cellular natural response P-selectin E-selectin VCAM ICAM Lactoferrin Myeloperoxidase Free Oxygen radicals TISSUE DAMAGE

44 Cellular natural response P-selectin E-selectin VCAM ICAM Lactoferrin Myeloperoxidase Free Oxygen radicals APOPTOSIS TISSUE DAMAGE

45 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

46 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

47 Tissue antigen presenting cells

48

49

50 P-selectin E-selectin VCAM ICAM TNF

51 The story of the dendritic cell (simplified!!!)

52 CD14+ CD16+

53 GM-CSF IL-4 CD14+ CD16+

54 GM-CSF IL-4 CD14- CD16+ CD1a+

55 GM-CSF Local Tissue IL-4 Damage CD14- CD16+ CD1a+

56 GM-CSF Local Tissue IL-4 Damage CD14- CD16+ CD1a+ Heparan danger signals

57 GM-CSF Local Tissue IL-4 Damage CD14- CD83+ Heparan danger signals

58 Tissue antigen presenting cell

59 Tissue antigen presenting cell

60

61 Lymph node Cortex B-cell area Cortex T-Cell area Medulla

62 Monocytes Double Stained for CD14 CD16 (Placebo) Monocytes Double Stained for CD14 CD16 (MP) Cellular Positivity (%) *** ** Cellular Positivity (%) # *** * 0 T0 T1 T2 T3 T4 Sample Times 0 T0 T1 T2 T3 T4 Sample Times

63 Should we modulate innate cellular responses ie dendritic cells, macrophages and neutrophils? Yes and No! Yes! A systemic neutrophil actvation secondary to excessive TNF production can lead to a damaging response How to modulate? Biocompatible technologies Steroids reduce inflammatory mediators and neutrophil activation No! DC function is important in controlling anti-viral and antibacterial immunity. We do not want to risk infection

64 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

65 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

66 TNFα IL1β TH1 IL-2 IFNγ Delayed type hypersensitivity (DTH)

67 TNFα IL1β TH1 IL-2 IFNγ IL-2 IFNγ TCTX

68 TNFα IL1β TH1 IL-2 IFNγ IL-2 IFNγ TCTX

69 Lymph node Cortex B-cell area Cortex T-Cell area Medulla

70 If the antigen is T-independent:

71 If the antigen is T-dependent:

72 If the antigen is T-dependent:

73 IL-10 IL-4 IL-6 If the antigen is T-dependent: TH2

74 Endogenonous Modulation of Specific Immunity in Major Trauma & Surgery

75 TH0 TNFα IL1β TH1 B TH2 IL-2 IFNγ IL-10 IL-4 IL-6

76 TH0 TNFα IL1β TH1 B TH2 IL-2 IFNγ plasma IL-2 plasma IFNγ in vitro IL-2 production DTH skin response IL-10 IL-4 IL-6 INDOMETHACIN THYMOPENTIN Markewitz A et al, Eur J Cardiothorac Surg 1996;10;1:61-67

77 TH0 TNFα IL1β TH1 B TH2 IL-2 IFNγ plasma IL-2 plasma IFNγ in vitro IL-2 production DTH skin response IL-10 IL-4 IL-6 INDOMETHACIN THYMOPENTIN Markewitz A et al, Eur J Cardiothorac Surg 1996;10;1:61-67

78 Prostaglandins are selectively immunosuppressive PGE2 on TH0 inhibits TH1 promotes TH2 Gold et al Arth & Rheum;37:6: Cicaprost (prostacyclin analogue) with rolipram (type IV PDEI) monocyte TNFα Greten TF 1996 (Eur J Pharmacol;299: ) PGE2 depresses IL-2 production in vitro and MLR. Stone CD et al Ann Thor Surg; 49:

79 PGE at cardiovascular surgery PGE released following declamping Rittenhouse EA et al 1976 (Surgery 80: ) Prostacyclin in pleural space post CABG Singh HP et al 1995 (Ann Thor Surg 59: ) Prostacyclin in both CPB and non CPB paediatric surgery Greeley WJ et al 1988 (95:5: )

80 TH0 Prostaglandins Complement TNFα IL1β TH1 B TH2 IL-2 IFNγ IL-10 IL-4 IL-6 Ballas ZK, et al. Complement inhibits immune responses. Eur J Immunology 1983;13:279-

81 Should we modulate B and T lymphocyte responses? The dilemma Type 1 helper T cell function (anti-viral and anti-bacterial) is already impaired. We do not want to impair further. In fact we may want to enhance TH1 function Eg indomethacin???? Reduce prostaglandin burden?? Reduce tissue damage?? Minimally invasive surgery??? TNF and IL-1 are involved in TH1 activation. In excess these cytokines precipitate a systemic inflammatory response, Nevertheless they are needed locally in TH1 responses. We do not want to inhibit the important local action of these cytokines

82 ADAPTIVE (specific) b INNATE (non-specific) CELLULAR lymphocytes APC < monocyte/macrophages >phagocytosis CELLULAR NK cells a ADCC cytokines a granulocytes HUMORAL antibodies classical pathway< complement >alternate pathway HUMORAL clotting cascade kallikrein-kinins

83 The balance of pro and anti-inflammatory processes

84 APC T H cytokine production endothelium local binding endothelium local effects spill-over

85 CPB + complement IL-8, TNF, IL-1 _ IL-10 IL-1ra TNFsr2 Neutrophils

86 The phased plasma anti-inflammatory response (adult CPB) IL-10 *** IL-1ra IL-1ra (pgml-1) mean & SEM *** Sample times *** *** *** IL-10 (pgml-1) mean & SEM p < 0.001*** McBride WT et al. British Journal of Anaesthesia 1995;75 (6):

87 TNF soluble receptor-2 (adult CPB) 3000 ** *** TNFsr-2 (pgml -1 ) (mean and SEM) *** * p < 0.05* p < 0.01** p < 0.001*** sampling times

88 The phased plasma anti-inflammatory cytokine response (children) TNFsr2 IL-10 (pgml -1 ) mean & SEM McBride et al. Cytokine 1996;8;9: ** ** ** ** Sample times * * IL-1ra & TNFsr-2(pgml -1 ) mean & SEM IL-10 IL-1ra p< 0.05* p < 0.01**

89 Control of the balance.. Local binding CPB complement Plasma balance + _ IL-8, TNF, IL-1 Remove pro Leave anti IL-10 IL-1ra TNFsr2 Neutrophils

90 Cytokine molecular weights TNF 17 kda IL kda IL-8 8 kda IL kda IL-1ra 22kDa TNFsr1 75 kda TNFsr2 55 kda

91 Why should we modulate systemic cytokine balance Systemic cytokine imbalance can lead to endothelial dysfunction coagulation disturbances organ dysfunction eg renal dysfunction

92 Why should we modulate systemic cytokine balance Systemic cytokine imbalance can lead to endothelial dysfunction coagulation disturbances organ dysfunction eg renal dysfunction

93 Procoagulant APC T H Prevention of clot propagation anticoagulation X APC T H Fibrinolysis APC T H Antifibrinolysis APC T H

94 Intrinsic system (XIIa) Extrinsic system Prothrombin Thrombin Fibrinogen Fibrin Prothrombin Thrombin Fibrinogen Fibrin TF TF TF TF VII VII VII VII Barrier to spread of infection

95 Intrinsic system (XIIa) Extrinsic system Prothrombin Thrombin Fibrinogen Fibrin Prothrombin Thrombin Fibrinogen Fibrin TF VII TF TF TF TF VII VII VII VII TF TF TF TF VII VII VII VII Anti inflammatory cytokines IL-10,TGFβ, IL-4,IL-13 Pro inflammatory cytokines IL-1α, IL-1β, TNFα, IL-8, IFNγ Barrier to spread of infection

96 Intrinsic system (XIIa) Extrinsic system Prothrombin Thrombin Fibrinogen Fibrin Prothrombin Thrombin Fibrinogen Fibrin TF VII TF VII TF VII TF TF TF VII VII Anti inflammatory cytokines IL-10,TGFβ, IL-4,IL-13 Pro inflammatory cytokines IL-1α, IL-1β, TNFα, IL-8, IFNγ Barrier to spread of infection

97 Intrinsic system (XIIa) Extrinsic system TF VII Prothrombin Thrombin Fibrinogen Fibrin TF VII TF VII Prothrombin Thrombin Fibrinogen Fibrin Proinflammatory cytoknes TF (Herbert JM FEBS letters 1992:310) TF TF Antiinflammatory TF cytokines TF VII VII (Herbert JM FEBS letters 1993:268) (Del Prete. Blood 1995;86: ) Anti inflammatory cytokines IL-10,TGFβ, IL-4,IL-13 Pro inflammatory cytokines IL-1α, IL-1β, TNFα, IL-8, IFNγ Barrier to spread of infection

98 Procoagulant APC T H Prevention of clot propagation anticoagulation X APC T H Fibrinolysis APC T H Antifibrinolysis APC T H

99 Prothrombin Thrombin Fibrinogen Fibrin Thrombomodulin S APCR Protein C Thrombin V & VIII ANTICOAGULATION Pro inflammatory cytokines IL-1α, IL-1β, TNFα, IL-8, IFNγ

100 Prothrombin Thrombin Fibrinogen Fibrin Thrombomodulin S APCR Protein C Thrombin V & VIII ANTICOAGULATION Pro inflammatory cytokines IL-1α, IL-1β, TNFα, IL-8, IFNγ

101 Prothrombin Thrombin Fibrinogen Fibrin Thrombomodulin S APCR Protein C Thrombin V & VIII ANTICOAGULATION Pro inflammatory cytokines IL-1α, IL-1β, TNFα, IL-8, IFNγ