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Application of Immunology (Immunopharmacology (Calcineurin inhibitors…

- - - - Stages of Type I hypersensitivity
        
        Activation of mast cells + secretion of mediators
        
        Repeat exposure to antigen
        
        Activation of mast cells: Degranulation
        
        Releases cytokines + vasoactive amines
        
        Cytokine: late stage reaction (6-24 hours after exposure)
        TNFalpha :pen: Activate endothelial cells
        IL-4 and IL-13 :pen: Th2 response
        IL-5 :pen: Eosinophil
        
        Protease: Tryptase :pen: cleaves fibrinogen and activates collagenase Chymase :pen: causes mucus secretion
        
        Vasoactive amine: Vascular dilation, smooth muscle contraction etc HISTAMINE :pen:
        
        Lipid mediators: Prostaglandin :pen: vascular dilation, chemotaxis, neutrophil recruitment Leukotrienes :pen: smooth muscle contraction Platelet activating factor :pen: bronchoconstriction
        
        Recruitment of leukocyte inflammation
        
        Sensitisation
        
        First exposure to antigen
        
        Antigen activation of Tfh and Th2 cells --> Isotype switching to IgE
        
        Production of IgE --> Binding of IgE onto FccRI receptors on mast cells
      - Symptoms
        
        GIT: Increased fluid secretion, peristalsis
        
        Diarrhoea Vomitting
        
        Airways: bronchoconstriction, increased mucus secretion
        
        Wheezing, phlegm
        
        Blood vessels: Increased blood flow, permeability
        
        Increased flow to lymph nodes, blood pressure, edema
      - Clinical symptoms
        
        Systemic anaphylaxis
        
        Normally due to drug allergens like Penicillin :pen: or insect venom
        
        Stage I: Itching
        Stage II: Swelling
        Stage III: Difficulty breathing
        Stage IV: Fall in BP, loss of consciousness
        
        Allergic rhinitis
        
        Allergic conjunctivitis
        
        Asthma
        
        Lead to chronic inflammation: Remodelling, becomes permanently narrow
        
        Development of hyperreactivity to non-immunological stimuli
      - Treatment
        
        Epinephrine :fire:
        
        smooth muscle contraction, increase cardiac output, bronchodilation
        
        Corticosteroids :fire:
        
        Reduce inflammation
        
        Leukotriene antangonist :fire:
        
        Anti-IgE Ab :fire:
        
        Antihistamine :fire:
        
        Cromolyn :fire:
        
        Inhibit mast cell degranulation
  - - - Mechanisms are similar but normally cause tissue damage
        
        Release complement by-products and recruit neutrophils
        
        Opsonisation and phagocytosis
        
        Abnormal physiological response
        
        Treatment
        
        Corticosteroids
        
        Plasmapheresis :fire:
        
        To remove antibodies
        
        Intravenous IgG
        
        To compete binding of Fc receptors
        
        Anti CD40 and Anti CD20 :fire:
        
        To deplete the B cells
  - - - Mechanism are similar but normally cause vasculitis
  - - - Th1 Cells
        
        Macrophage activation
      - Th2 cells
        
        IgE production, eosinophil activation
      - CTL cells
        
        Cytotoxicity
    - - Corticosteroids
      - TNF antagonist :fire:
      - cytokine antagonist against Th1, Th2 and CTL
- - - - Tumour-infiltrating lymphocytes (TIL) contains CTL with the capacity to kill the tumours
      - Requires cross presentation :warning:
      - Role of CD4 cells:
        
        Play role in differentiating naive CD8 T cells into effector and memory CTLs
        
        Provide cytokine to increase MHC I expression by tumour cells
        
        Activate macrophages
      - Role of antibodies
        
        Little evidence for humeral immune response against tumours
        
        Can be used in antibody treatment, induce ADCC for NK cells to kill (provided host NK cells are functional)
      - M1 macrophages promote killing of tumour cells
        M2 macrophages promote growth of tumour cells
  - - - Antibody + toxin
        
        Release toxin to kill cell
      - Antibody + radioisotope
        
        Release radioisotope and kill surrounding cell
      - Tumour specific antibody
        
        Bind to CD16 :pen: to activate ADCC
        
        CD40L or Ab CD40 binds to CD40 on APC, activates APC to trigger CTL :warning:
      - Bispecific T cell engage (BiTE) :warning: (Catumaxomab and Blinatumomab)
        
        Arm 1: Binds to CD3 on T cells
        
        Arm 2: Tumour specific
        
        Arm 3: Bind to accessory: NK cells/Dendritic cell
        
        If NK --> ADCC, If Dendritic --> costimulate T cell
      - Anti PD 1 and Anti CTLA4 blockade
    - - Generate a large number of potent cells that are functional in vivo within a short time
        
        Either take from peripheral blood creating activated and expanded NK cells
        
        Or take from stem cells resulting in differentiated NK cells
      - Tumour specific without damaging normal cells
      - Tumour infiltrating lymphocytes :red_flag::
        
        Take out those lymphocytes that are attacking tumour cells, expand them and put it back into the patients
      - T cell receptor therapy :red_flag::
        
        Generate own receptor and put it back into he body
      - Chimeric Antigen Receptor (CAR) :red_flag:
        
        Antigen binding domain: CD19 and MAGE-A3
        
        :warning: BINDS TO CO-RECEPTOR CD3 instead of MHC receptor
        
        New generation has co-stimulator CD28 too
        
        Types of gene transfer platform:
        
        Lentiviral
        
        DNA plasmid
        
        Transposon
    - - Dendritic cell vaccines
        
        :tornado: How does DC vaccine works :tornado:
        
        Extract dendritic cells (Langerhan cells, Dermal CD14 DC)
        
        DC cells are polarised that decreases generation of Treg functions, Strong CD4 T cell help, High affinity CTL, block suppressive mechanism
- - - - Mechanism of Acute antibody mediated rejection :red_flag:
        
        Antibody binding --> Complement activation --> Makes holes in cell --> recruitment of neutrophils and monocytes + necrosis + coagulation
      - When there is an recipient antibody that is already directed agains the donor HLA
    - - T cell enters the tissues via rolling-adhesion-diapedesis
  - - - Direct allorecognition
        
        Allo-MHC class II recognised by recipient CD4
      - Indirect allorecognition
        
        Antigens from graft enter circulation and reach recipient DC in secondary lymphoid tissue
        
        Donor cells migrate to secondary lymphoid tissue and engulfed by recipient DC
        
        Recipient APC migrate to graft, pick up antigen, then re enter secondary lymphoid tissue
        
        Antigen presentation in MHC groove, involves ubiquitin proteosome TAP-1
      - :tornado: The allo-immune response: Antigen signal transduction :tornado:
        Triggering the T cell receptor activate target proteins, calcium is released from ER regulates Calcineurin, activate NFAT by dephosphorylating it, dephosphorylated NFAT enter the nucleus and move to binding site in the regulatory region of IL2 , activating transcription
        
        IL-2 trigger another cascade involving mTOR result in proliferation of lymphocytes
        
        Clonal expansion
        
        CD8
        
        CD4 T cells produce cytokines to generate cytotoxic T lymphocytes, causes apoptosis via 2 ways. 1. lytic granules containing performs or granzyme, polymerise target cells to form pores 2. FasL-Fas mechanism
        
        Does not conform to self-MHC restriction, as long as there is some similarity, it will trigger T cell to carry out apoptosis
        
        CD4
        
        Delayed type hypersensitivity
        
        Macrophages releases NO and radicals to destroy
        
        Recruit leukocytes and monocytes
        
        Release IL-2 to recruit other lymphocytes
        
        Activate CTLs
        
        Activate B cells via CD40-CD40L
        
        B cells
        
        Activated between Ig and alloantigen
        
        Receive costimulation from CD4
        
        Produces antibodies
- - - - Macrolide
      - Block T cell and B cell
      - Has other functions: Anti-proliferative and Anti-angiogenesis :warning: ANTI CANCER
        
        Coated on coronary stent to prevent hyperplasia which may lead to arterial renal stenosis
      - side effect same as calcineurin inhibitor
  - - - Side effect: Gum hyperplasia :warning: kidney, hyperglycaemia, neurotoxicity, hypertension, thromcytopenia, hyperlipidemia
    - - It is a macrolide antibiotics
      - More potent than cyclosporine
      - side effect similar to cyclosporine without gum
  - - - Impede DNA synthesis
        
        Inhibit purine synthesis
        
        Side effect: Bone marrow depression, leukopenia, anaemia, thrombocytopenia, GI toxicity
    - - Created because azathioprine has too many side effects
        
        Inhibit purine synthesis, very specific to IMPDH type II, very specific thus less bone marrow depression, less toxicity
        
        Additional effects such as suppresses antibody formation by B cell and inhibit recruitment of leukocyte to graft site
  - - - Non-selective purified IgG
        
        Opsonisation + complement activation
        
        ADCC
        
        T cell anergy induction
        
        First dose effect: cytokine storm (fever, chill, hypotension), thrombocytopenia, leukaemia, serum sickness
    - - Muromonab-CD3 :fire:
        
        Directed against CD3-TCR complex, highly specific to T lymphocytes Human-antimouse antibody
        
        Cytokine storm
  - - - Decreases circulating lymphocyte thus accumulate at lymph nodes and may swell
        
        Side effect: first dose may have drop in heart rate
- - - - Starts off with somatic recombination
        
        Negative selection :red_flag:
        
        If TCR interacts with MHC too strongly, downstream signalling is too strong
        
        If TCR interacts with MHC weakly, downstream signalling is too weak
        
        Positive selection :red_flag:
        
        T cells that bind low to moderate affinity to self-MHC will survive
  - - - Ignorance :red_flag:
        
        Interaction between TCR and self-peptide MHC too weak in the periphery
      - Anergy :red_flag:
        
        Immature DC unable to produce sufficient costimulation :warning:
        
        Active transcription of "anergy genes"
        
        Remains forever unresponsive even with proper costimulation and cytokine signals next time
      - Regulation :red_flag:
        
        Treg cells :warning: are T cells that are specific to self-antigen, they will express Foxp3
        
        Releases IL-10 and TGF-beta to suppress other self-reactive T cells
        
        Expresses CTLA4
      - Maturation of naive T cells requires
        
        MHC binds to CD4/CD8
        
        Co-stimulation
        
        Etc. CD28 (T cell) binds to B7 (APC) resulting in increase in IL-2
        
        Cytokines
        
        Regulate the differentiation of CD4 T cells
  - - - PD1 expressed after activation, strongly expressed in chronically activated T cells
      - Important in chronic antigen stimulation, limits T cell mediated damage during infection
      - Tumour cells :warning: take advantage of PD1, releases PD1 to suppress tumour immunity
  - - - Genetic alteration: AIRE, Foxp3
      - Oestrogen, incidence highest during reproductive years, declines around menopause, may relapse during pregnancy, improve after that
      - Infection
        
        Group A streptococcal :warning: --> Rheumatoid fever
        
        Campylobacter jejuni :warning: --> Guillain-Barre syndrome
        
        Cossackie B :warning: --> DM
    - - Examples:
        
        Graves disease
        
        Myasthenia gravis
        
        Haemolytic disease of the new born
        
        Type 1 Dm
      - These conditions can be passed on to the newborn because maternal IgG can pass through the placenta, but it is short term because the babies will break it down afterwards
- - - - Normally manifestation occurs 3-4 months after birth :warning: due to the presence of transplacental transfer of maternal IgG
        
        Adaptive immune defects
        
        X-linked hyper-IgM syndrome :pen:
        
        Unable to undergo isotope switching because B cells requires help of CD4 to undergo switching
        
        High levels of IgM
        
        IgM is also short-lived and low affinity because they do not go through affinity maturation
        
        Macrophages also affected because it requires help from CD4 T cells
        
        Mutation of CD40L :fire: on the CD4 T cells
        
        Selective IgA deficiency :pen:
        
        IgA is needed as they provide immunity in the mucosal areas etc stomach
        
        Normally asymptomatic, symptomatic normally presented with infection caused by pyogenic organism that affect mucosal site
        
        Treatment normally with antibiotics
        
        Cannot treat with IgA infusion because
        
        Common Variable Immunodeficiency (CVID) :pen:
        
        Low serum IgG, but normal B cell levels
        
        Most common symptomatic antibody deficiency
        
        Severe combined immunodeficiency (SCID) :pen:
        
        Impaired T, NK and B cell
        
        Present early in life
        
        Innate Immune defects
        
        Neutrophil defects :pen:
        
        Dysfunction
        
        Decreased production or increased destruction
        
        Neutrophils are short-lived and have a rapid turnover rate
        
        Less than 1000/microlitre + develop fever in people with cancer
        
        Life threatning
        
        Must start treatment immediately
        
        Macrophages defect :pen:
        
        Most of the time defect in IL-12 receptor or IFN receptor :warning:
        
        Inability to mount immune response against intracellular bacteria etc. mycobacteria
  - - - Will never be able to clear all the virus due to presence of error prone replication of HIV genome generating a large number of mutants that escape
      - Continual viral replication
      - Progressive depletion of CD4 T cell
      - Results in damage in CTL cells, B cells, marcophages
    - - Corticosteroids, monoclonal antibodies
      - Increased skin cancer in organ transplant recipient
    - - Granulomatous infections (TB)
    - - Elderly
        
        Thymic involution
        
        Can no longer defend new pathogen
        
        Only focused on frequently-acquired disease
        
        Memory cells will slowly die off too due to cell scenescne
- - - - Utilise haematopoietic stem cells to restore myeloid and lymphoid cells in patients
        
        To eradicate residual tumour cells and replace HSCs
        
        Replace dysfucnctional lineage cells in aplastic anaemia, primary immunodeficiencies
    - - Some people's HLA can be seen as foreign to other's immune system, the antigen of allografts serve as a principal determinants of immune rejection are encoded in MHC, therefore the more closely donor HLA is to recipient HLA, less T cell alloreactivity
      - Infection
      - Failure to graft take
      - Graft Vs Host
  - - - Recipient cell reject graft
    - - Occurs when:
        
        Administration of immunocompetent cells
        
        Histo-incompatibility
        
        Inability of recipient to destroy or inactivate transfused cell
      - Consist of CD4 HSC from donor + some T cells from donor
        
        The ones that will give the problem is the mature T cells
        
        Priming of naive donor T cells
        
        Recognise "foreign" host MHC tissue
      - Graft versus Leukemia :fire:
        
        Alloresponse benefits by killing tumour cell
      - Treatment: Balance in maintaining the number of mature T cells
        
        3 different scenarios
        
        HSC prep contains less than optimal CD4 :pen:
        
        Give alot of T cells to increase chance that donor t cells kill all of recipient T cell so that new CD4 can go in bone marrow to propagate
        
        SCID :pen:
        
        Give zero T cells to minimise GvHD, since patient has no T cells to fight, no need for additional donor T cells to create unnecessary symptoms
        
        Leukemia :pen:
        
        Give ALOT of T cells with not perfect HLA match, so that donor T cell kill all the recipient leukaemia cells