Immunology: Immune modulating therapies (1+2) Flashcards
Two types of immune modulation
-Boosting immune response -Suppression of immune response
List the 4 ways in which the immune system can be boosted
-Vaccination -Replacement of missing components -Blocking immune checkpoints -Cytokine therapy
Outline the immunological mechanisms involved in vaccines
-Vaccines utilise the adaptive immune response (Overall keypoint) -Clonal expansion following exposure to antigen within vaccine -T cells with appropriate specificity will proliferate and differentiate into effector cells (cytokine secreting, cytotoxic) -B cells with appropriate specificity will proliferate and differentiate to T cell independent (IgM) (memory) and plasma cells undergo germinal centre reaction and differentiate to T cell dependent IgG/A/E(M) memory and plasma cells -Immunological memory -Following infection, residual pool of specific cells with enhanced capacity to respond if re-infection occurs
What is an APC?
APCs (Antigen presenting cells) are cells that can present peptides to T lymphocytes to initiate an acquired immune response
3 examples of antigen presenting cells (APCs)?
-Dendritic cell -Macrophage -B lymphocyte
What Virus is associated with excess stimulation of clonal CD8+ T cells?
Epstein Barr Virus
Immunological memory is mediated by:
-B and T lymphocytes
What do we want from a vaccine?
-MEMORY - Generate protective, long-lasting immune response -No adverse reactions -Practical considerations – one shot, easy storage, inexpensive…
How is the effectiveness of the flu vaccine measured?
-Haemaglutinin inhibition assay
What is a mantoux test?
-A test to measure the immune response against TB, ie the effectiveness of the BCG vaccine. -Tuberculin is injected intradermally, the degree of swelling determines immune response
What are the types of vaccines? (Give examples)
-Live attenuated vaccines (eg MMR, yellow fever) -Inactivated/Component vaccines (eg trivalent flu vaccines, cholera)/(Hepatitis B) -Conjugates+ Adjuvants to increase immunogenicity (eg haemophilus infleunzae) -DNA vaccines (Experimental) -Dendritic cell vaccines (Experimental)
Advantages of Live vaccines?
-Establishes infection – ideally mild symptoms -Raises broad immune response to multiple antigens – more likely to protect against different strains -Activates all phases of immune system. T cells, B cells – with local IgA, humoral IgG -Often confer lifelong immunity after one dose
Problems with live vaccines
-Reversion to virulence -Spread to contacts
Advantages of Inactivated/ component vaccines?
-No mutation or reversion -Can be used with immunodeficient patients -Storage easier -Lower cost
Problems with Inactivated/ component vaccines?
-Often do not follow normal route of infection -Some components have poor immunogenicity -May need multiple injections -May require conjugate protein carrier or adjuvants to enhance immunogenicity
Risks or complication of vaccines?
-Live attenuated vaccines can cause reversion to virulence
Describe how conjugate vaccines are formed
-Polysaccharide plus protein carrier -Polysaccharide alone induces a T cell independent B cell response – transient -Addition of protein carrier promotes T cell immunity which enhances the B cell/antibody response
How are adjuvants used in vaccines?
-Adjuvant increases the immune response without altering its specificity (eg aluminium salts, lipids)
DNA vaccines: Advantages and disadvantages?
-Advantages -Mimics a virally infected cell -Potential for developing cancer vaccines against tumour associated antigens or mutational antigens -Disadvantages -Possible plasmid integration into host DNA -Possible response to DNA could lead to autoimmune diseases such as SLE
Which type of vaccine should NOT be given to an immunosuppressed individual?
Live attenuated vaccines (eg BCG)
Methods of replacing missing components of the immune system?
-Haematopoietic stem cell transplantation (Radical) -Antibody replacement -Adoptive Cell transfer (T cells)
Indications for Haematopoietic stem cell transplantation?
-Life-threatening immunodeficiencies -Haematological malignancies
Indications for antibody replacement therapy?
-Primary antibody deficiency (eg X linked agammaglobulinaemia) -Secondary antibody deficiency: -Haematological malignancies -After bone marrow transplantation
Describe CAR T cell therapy
-Inducing the patient’s own T cells to target CD19+ B cells -Used to treat ALL, NHL (+ other Haem malignancies)
Car T cell therapy indications?
ALL, NHL (Haem malignancies)
An immunosuppressed individual, who has not had chicken pox, is exposed to the infection. Which is the most appropriate treatment?
Human varicella-zoster specific immunoglobulin (Post exposure prophylaxis)
Blocking immune checkpoints: Examples?
-Ipilimumab: Antibody specific for CTLA4 -Pembrolizumab and Nivolumab: antibodies specific for PD-1
Indications for immune checkpoint blockers?
Melanoma (Especially advanced)
Outline the mechanisms of checkpoint inhibitors
-Example: Ipilimumab: Antibody specific for CTLA4 -Antibody binds to CTLA4 (T cell receptor) CTLA4 regulated T cell activation -Blocks immune checkpoint -Allows T cell activation -Complication: autoimmunity
Cytokine Therapy examples?
-//recombinant cytokines -Interferon alpha -Interferon beta -Interferon gamma -Interleukin 2
Clinical uses of recombinant cytokines?
-Aim: to modify (boost) the immune system Interferon alpha: Hairy cell leukaemia, chronic myeloid leukaemia, multiple myeloma -Interferon beta: Behcet’s -Interferon gamma: Chronic granulomatous disease -Interleukin 2: Renal cell cancer
-A 23 year old has metastatic melanoma. Which of the following may reduce disease progression? BCG vaccination Bone marrow transplantation CAR-T cells with specificity for CD19 Nivolumab, an antibody specific for PD-1 Normal human immunoglobulin
Nivolumab, an antibody specific for PD-1 //Checkpoint Inhibitor
6 Methods of suppressing the immune response?
-Steroids -Anti-proliferative agents -Plasmapheresis -Inhibitors of cell signalling -Agents directed at cell surface antigens -Agents directed at cytokines
What corticosteroids are used in immune suppression?
-Prednisolone (Glucocorticoid agonist) -Cortisone (Glucocorticoid agonist)
What are the indications of corticosteroids for immunosuppression?
-Allergic disorders -Auto-immune disease -Auto-inflammatory diseases -Transplantation -Malignant disease
How do corticosteroids lead to reduced inflammation/ immune activity?
-Work on many aspects of immune system -Corticosteroids inhibit phospholipase A2 -Blocks arachidonic acid and prostaglandin formation and so reduces inflammation -Phospholipase A2: Breaks down phospholipids to form arachidonic acid which is converted to eicosanoids (eg prostaglandin)s, leukotrienes) by cyclo-oxygenases -Leads to production of prostaglandins -Act broadly on phagocytes: -Causing decreased traffic of phagocytes to inflamed tissue -Decreased phagocytosis -Decreased release of proteolytic enzymes -Corticosteroids also act on lymphocytes -Sequester lymphocytes, so they stay in the lymphoid tissue (Causes lymphopenia in blood) -Furthermore, they block cytokine gene expression -Cause decreased antibody production -Promotes apoptosis (Basically quite a broad effect)
Side effects of corticosteroids
-(Metabolic) -Diabetes, central obesity -Moon face -Lipid abnormalities -Osteoporosis -Hirsuitism -Adrenal suppression -(Other) -Cataracts -Glaucoma -Peptic ulceration -Pancreatitis, -Avascular necrosis
Examples of antiproliferative immunosuppressants
-Cyclophosphamide -Mycophenolate -Azathioprine
Mechanism of action of antiproliferative agents?(immunosuppressants)
Inhibit DNA synthesis Cells with rapid turnover most sensitive
Side effects of antiproliferative agents?(immunosuppressants)
-Bone marrow suppression -Infection -Malignancy -Teratogenic
Give an indication for cyclophosphamide
-SLE -(Multisystem connective tissue disease or vasculitis with severe end-organ involvement or cancer)
What infection is cyclophosphamide associated with?
-Pneumocystis jiroveci
Indications for azathioprine?
-Transplantation -Auto-immune disease -Auto-inflammatory diseases, eg Crohn’s, ulcerative colitis
What is Mycophenolate?
-Anti-proliferative immunosuppressant
What is plasmapheresis
-Removal of pathogenic antibody -Patient’s blood passed through cell separator
Indications for plasmapheresis?
-Severe antibody-mediated disease -Goodpasture syndrome -(Anti-glomerular basement membrane antibodies) -Severe acute myasthenia gravis -(Anti-acetyl choline receptor antibodies) -Severe vascular rejection -(Antibodies directed at donor HLA molecules) -Mainly type II hypersensitivity reactions
What are the mechanisms of action of Ciclosporin and Tacrolimus?
-Calcineurin inhibitors -Block the process of T cell activation -Block cytokine transcription by T cells, therefore prevent lymphocyte proliferation and effector functions.
Side effects of Ciclosporin and Tacrolimus?
-Ciclosporin -(Dysmorphic features, nephro-neuro-toxicity, HTN) -Tacrolimus -(Diabetes, nephro-neuro-toxicity, HTN)
What is Tofacitinib?
-Immunosuppressant by inhibiting cell signalling -Inhibitor or JAK1 and JAK3 (non-receptor tyrosine kinases) ie a ‘Jakinib’ -Inhibits production of inflammatory molecules -Effective in Rheumatoid arthritis, psoriatic arthritis
What is Apremilast?
-Immunosuppressant by inhibiting cell signalling -Inhibitor of PDE4 (Inflammatory mediator) -Inhibition of PDE4 leads to increase in cAMP -Inhibits production of cytokines -Effective in psoriasis and psoriatic arthritis
//Agents directed at cell surface antigens
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