Immunology: Immune modulating therapies (1+2)

Question 1

Two types of immune modulation

Answer 1

-Boosting immune response -Suppression of immune response

Question 2

List the 4 ways in which the immune system can be boosted

Answer 2

-Vaccination -Replacement of missing components -Blocking immune checkpoints -Cytokine therapy

Question 3

Outline the immunological mechanisms involved in vaccines

Answer 3

-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

Question 4

What is an APC?

Answer 4

APCs (Antigen presenting cells) are cells that can present peptides to T lymphocytes to initiate an acquired immune response

Question 5

3 examples of antigen presenting cells (APCs)?

Answer 5

-Dendritic cell -Macrophage -B lymphocyte

Question 6

What Virus is associated with excess stimulation of clonal CD8+ T cells?

Answer 6

Epstein Barr Virus

Question 7

Immunological memory is mediated by:

Answer 7

-B and T lymphocytes

Question 8

What do we want from a vaccine?

Answer 8

-MEMORY - Generate protective, long-lasting immune response -No adverse reactions -Practical considerations – one shot, easy storage, inexpensive…

Question 9

How is the effectiveness of the flu vaccine measured?

Answer 9

-Haemaglutinin inhibition assay

Question 10

What is a mantoux test?

Answer 10

-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

Question 11

What are the types of vaccines? (Give examples)

Answer 11

-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)

Question 12

Advantages of Live vaccines?

Answer 12

-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

Question 13

Problems with live vaccines

Answer 13

-Reversion to virulence -Spread to contacts

Question 14

Advantages of Inactivated/ component vaccines?

Answer 14

-No mutation or reversion -Can be used with immunodeficient patients -Storage easier -Lower cost

Question 15

Problems with Inactivated/ component vaccines?

Answer 15

-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

Question 16

Risks or complication of vaccines?

Answer 16

-Live attenuated vaccines can cause reversion to virulence

Question 17

Describe how conjugate vaccines are formed

Answer 17

-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

Question 18

How are adjuvants used in vaccines?

Answer 18

-Adjuvant increases the immune response without altering its specificity (eg aluminium salts, lipids)

Question 19

DNA vaccines: Advantages and disadvantages?

Answer 19

-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

Question 20

Which type of vaccine should NOT be given to an immunosuppressed individual?

Answer 20

Live attenuated vaccines (eg BCG)

Question 21

Methods of replacing missing components of the immune system?

Answer 21

-Haematopoietic stem cell transplantation (Radical) -Antibody replacement -Adoptive Cell transfer (T cells)

Question 22

Indications for Haematopoietic stem cell transplantation?

Answer 22

-Life-threatening immunodeficiencies -Haematological malignancies

Question 23

Indications for antibody replacement therapy?

Answer 23

-Primary antibody deficiency (eg X linked agammaglobulinaemia) -Secondary antibody deficiency: -Haematological malignancies -After bone marrow transplantation

Question 24

Describe CAR T cell therapy

Answer 24

-Inducing the patient’s own T cells to target CD19+ B cells -Used to treat ALL, NHL (+ other Haem malignancies)

Question 25

Car T cell therapy indications?

Answer 25

ALL, NHL (Haem malignancies)

Question 26

An immunosuppressed individual, who has not had chicken pox, is exposed to the infection. Which is the most appropriate treatment?

Answer 26

Human varicella-zoster specific immunoglobulin (Post exposure prophylaxis)

Question 27

Blocking immune checkpoints: Examples?

Answer 27

-Ipilimumab: Antibody specific for CTLA4 -Pembrolizumab and Nivolumab: antibodies specific for PD-1

Question 28

Indications for immune checkpoint blockers?

Answer 28

Melanoma (Especially advanced)

Question 29

Outline the mechanisms of checkpoint inhibitors

Answer 29

-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

Question 30

Cytokine Therapy examples?

Answer 30

-//recombinant cytokines -Interferon alpha -Interferon beta -Interferon gamma -Interleukin 2

Question 31

Clinical uses of recombinant cytokines?

Answer 31

-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

Question 32

-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

Answer 32

Nivolumab, an antibody specific for PD-1 //Checkpoint Inhibitor

Question 33

6 Methods of suppressing the immune response?

Answer 33

-Steroids -Anti-proliferative agents -Plasmapheresis -Inhibitors of cell signalling -Agents directed at cell surface antigens -Agents directed at cytokines

Question 34

What corticosteroids are used in immune suppression?

Answer 34

-Prednisolone (Glucocorticoid agonist) -Cortisone (Glucocorticoid agonist)

Question 35

What are the indications of corticosteroids for immunosuppression?

Answer 35

-Allergic disorders -Auto-immune disease -Auto-inflammatory diseases -Transplantation -Malignant disease

Question 36

How do corticosteroids lead to reduced inflammation/ immune activity?

Answer 36

-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)

Question 37

Side effects of corticosteroids

Answer 37

-(Metabolic) -Diabetes, central obesity -Moon face -Lipid abnormalities -Osteoporosis -Hirsuitism -Adrenal suppression -(Other) -Cataracts -Glaucoma -Peptic ulceration -Pancreatitis, -Avascular necrosis

Question 38

Examples of antiproliferative immunosuppressants

Answer 38

-Cyclophosphamide -Mycophenolate -Azathioprine

Question 39

Mechanism of action of antiproliferative agents?(immunosuppressants)

Answer 39

Inhibit DNA synthesis Cells with rapid turnover most sensitive

Question 40

Side effects of antiproliferative agents?(immunosuppressants)

Answer 40

-Bone marrow suppression -Infection -Malignancy -Teratogenic

Question 41

Give an indication for cyclophosphamide

Answer 41

-SLE -(Multisystem connective tissue disease or vasculitis with severe end-organ involvement or cancer)

Question 42

What infection is cyclophosphamide associated with?

Answer 42

-Pneumocystis jiroveci

Question 43

Indications for azathioprine?

Answer 43

-Transplantation -Auto-immune disease -Auto-inflammatory diseases, eg Crohn’s, ulcerative colitis

Question 44

What is Mycophenolate?

Answer 44

-Anti-proliferative immunosuppressant

Question 45

What is plasmapheresis

Answer 45

-Removal of pathogenic antibody -Patient’s blood passed through cell separator

Question 46

Indications for plasmapheresis?

Answer 46

-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

Question 47

What are the mechanisms of action of Ciclosporin and Tacrolimus?

Answer 47

-Calcineurin inhibitors -Block the process of T cell activation -Block cytokine transcription by T cells, therefore prevent lymphocyte proliferation and effector functions.

Question 48

Side effects of Ciclosporin and Tacrolimus?

Answer 48

-Ciclosporin -(Dysmorphic features, nephro-neuro-toxicity, HTN) -Tacrolimus -(Diabetes, nephro-neuro-toxicity, HTN)

Question 49

What is Tofacitinib?

Answer 49

-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

Question 50

What is Apremilast?

Answer 50

-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

Question 51

//Agents directed at cell surface antigens

Answer 51

-