Cytokines, Complement, and Immune Drugs Flashcards
What do Th1 cells secrete?
IFN-gamma (macrophage activator), Il-2 (T cell growth factor and CD8 T cell activator), Lymphotoxin B
What do Th2 cells secrete?
Il-4, Il-5, Il-10, Il-13
What do classically activated macrophages secrete?
Il-1, TNF-alpha
CD markers for Tregs
CD3, CD4, CD25
What do Tregs secrete?
Anti-inflammatory - Il-1/TGF-B
Fever (major)
Il-1, TNF
PGE2 mediates fever in hypothalamus
T cell “growth factor”
Il-2 (especially T-regs)
Stimulates bone marrow, acts like GM-CSF
Il-3 (secreted by T cells)
Stimulates IgE/IgG production
Il-4
Stimulates IgA class switching
Il-5
Associated with acute phase proteins
Il-1, Il-6
Major chemotactic factors for neutrophils
Il-8
LTB4
C5A
Bacterial products
CD on macrophages that recognizes LPS
CD14 (marker of monocyte-macrophage lineage)
What cleaves pre-kallikrein to kallikrein?
Hageman’s factor (12a)
What cleaves HMWK to bradykinin?
Kallikrein
Bradykinin
Histamine (vasodilation, increased permeability) + pain
What inhibits bradykinin?
ACE (ACEi cause increase in bradykinin –> cough, edema)
Prostacyclin (PGI2)
Endothelial cells
Vasodilator
Inhibits platelet aggregation
LTC4, D4, E4
Slow-reacting substances of anaphylaxis All contract SM: 1) Vasoconstriction (arteriole) 2) Bronchoconstriction (SM) 3) Increased vascular permeability (pericytes)
How are mast cells activated?
1) Trauma
2) C3a, C5a “anaphylotoxins”
3) Cross-linking of surface antigen
Histamine
Vasodilation of arterioles
Increased permeability at post-capillary venule
Mediates anaphylaxis
Pain
Bradykinin and PGE2 sensitize nerve endings
What mediates P selection release from W-P bodies in endothelium?
Histamine
What mediates E-selection on endothelium?
TNF-alpha, Il-1
What molecule do selectins bind on leukocytes?
Sialyl Lewis X
What upregulates cellular adhesion molecules ICAM and VCAM on endothelium?
TNF, Il-1
What upregulates integrins on leukocytes?
C5a, LTB4
TCR Complex
TCR, CD3, associated ITAMs on Zeta
Endogenous pyrogen
Il-6, also secreted by TH2
Induces differentiation of T cells into TH1 cells
IL-12 (INF-gamma)
Activates NK Cells
IL-12 (IL-2, IFN-beta, IFN-alpha)
Decreased MHC I expression
Mediates septic shock
TNF-alpha
Has antiviral and antitumor properties
IFN-gamma
Stimulates growth and differentiation of eos
Il-5
Promotes B cell growth
Il-4
Il-10
Anti-inflammatory
Inhibits TH1
Similar to TGF-B
Interferons alpha and beta
Inhibit viral protein synthesis in neighboring cells - the neighboring cells will translate proteins when there is the presence of viral RNA (dsDNA)
Suppresses TH2 cells
IFN-gamma
Increases MHC I and II expression and antigen expression in all cells
IFN-gamma
Binds B7 on APCs, B cells, or Macrophages
CD28 on T cell
Cell surface proteins of helper T cell
CD4, CD40 ligand
C3b
opsonization (macrophages have C3b receptor)
C5b-9
cytolysis by MAC - without it, susceptible to neisseria
Inhibitors of complement activation
Decay accelerating factor (DAF), inhibits c3 convertase
C1 esterase inhibitor
Prevent complement activation on self-cells (RBCs)
C1 esterase inhibitor deficiency
Hereditary angioedema, ACEi contraindicated
C3 deficiency
Recurrent pyogenic sinus and respiratory tract infections
Increased susceptibility to type III hypersensitivity rxns
DAF (GPI anchored enzyme) deficiency
PNH, RBC lysis
Receptor for EBV on B Cells
CD21
B Cell CD markers
CD19, CD20, CD21, CD40
Macrophage CD markers
CD14, CD40
Fc and C3b receptors
NK Cells CD marker
CD16 (binds Fc of IgG)
CD56 (unique marker for NK)
Does NOT expression CD4, 8, 3
Il-12
Important in granuloma formation
Macrophages present antigen to CD4 T cells that secrete Il-12 and promote conversion to TH1 phenotype that, in turn, secrete IFN-gamma to activate macrophages
Cyclosporine - Mechanism
- Binds to cyclophilins inside the cells
- Complex blocks differentiation and activation of T cells by inhibition of calcineurin, thus preventing production of Il-2 and its receptor
Cyclosporine - Clinical Use
Supresses organ rejection after transplant
Selected autoimmune disorders
Cyclosporine - Toxicity
7H’s
1=Hirsutism
2=Hyperplasia of gums
3=Harm to kidneys
4=Hypertension
5=Hyperglycemia
6=Hyperlipidemia
7=Hyper hand (tremor)
Tacrolimus (FK-506) - Mechanism
Similar to cyclosporine, binds to FK-binding protein, inhbiting calcinuerin and IL-2
Tacrolimus (FK-506) - Clinical Use
Potent immunosuppression used in organ transplant recipients
Tacrolimus (FK-506) - Toxicity
Similar to cyclosporine - no gum hyperplasia or hirsutism
Sirolimus (rapamycin) - Mechanism
Inhibits mTOR, thereby inhibiting T cell proliferation in response to Il-2
Sirolimus (rapamycin) - Clinical Use
Immunosupression after kidney transplantation in combo with cyclosporine and corticosteroids; also used with drug-eluting stents
Sirolimus (rapamycin) - Toxicity
Hyperlipidemia
Thrombocytopenia
Leukopenia
Azathioprine - mechanism
Antimetabolite precursor of 6-MP that interferes with metabolism and synthesis of nucleic acids - toxic to proliferating lymphocytes
Azathioprine - clinical use
Kidney transplant, autoimmune disorders (including glomerulonephritis and hemolytic anemia)
Azathioprine - toxicity
Bone marrow suppression
Toxic effects may be increased by allopurinol since metabolite mercaptopurine is metabolized by xanthine oxidase
Muromonab-CD3 (OKT3) - mechanism
Monoclonal Ab that binds to CD3 (epsilon chain) on the surface of T cells
Blocks cellular interaction with CD3 protein responsible for TCR signal transducion
Muromonab-CD3 (OKT3) - clinical use
Immunosuppression for kidney transplantation
Muromonab-CD3 (OKT3) - toxicity
cytokine release syndrome, hypersensitivity rxn
Aldesleukin (IL-2) - Recombinant cytokine
Renal cell carcinoma, metastatic melanoma
Epoetin alka (EPO) - Recombinant cytokine
Anemias (especially renal failure)
Filgrastim (G-CSF) - Recombinant cytokine
Recovery of bone marrow
Sagramostim (GM-CSF) - Recombinant cytokine
Recovery of bone marrow
Alpha-interferon - Recombinant cytokine
Hep B and C, Kaposi’s sarcoma, leukemias, malignant melanoma
Beta-interferon - Recombinant cytokine
MS
Gamma-interferon - Recombinant cytokine
CGD
Oprelvekin (IL-11) - Recombinant cytokine
Thrombocytopenia
Thrombopoetin - Recombinant cytokine
Thrombocytopenia
Digoxin Immune Fab
Target - Target is Digoxin
Clinical use - Antidote for digoxin intoxication
Infliximab
Target - TNF-alpha
Clinical use - Crohn’s, RA, Psoriatic arthritis, Ankylosing spondylitis
Adalimumab
Target - TNF-alpha
Clinical use - Crohn’s, RA, Psoriatic arthritis
Abciximab
Target - GPIIb/IIIa
clinical use - prevent cardiac ischemia in unstable angina and in patients treated with percutaneous coronary intervention
Trastuzumab (Herceptin)
Target - HER2
Clinical use - HER2 overexpressed BC
Rituximab
Target - CD20
Use - B cell non-Hodskin’s lymphomas
Omalizumab
Target - IgE
Use - Last resort treatment of nonsteroid responsive asthma
Induces MHC II expression
IFN-gamma