Immune modulating therapies (1)

Question 1

How can the immune response be boosted?

Answer 1

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

Question 2

Describe the following about the adaptive immune response

1. Adaptive immune response cells
2. Wide repertoire of antigen receptors
3. Specificity

Answer 2

1. Adaptive Immune Response
   * B cells and T cells
2. Wide repertoire of antigen receptors

• Receptor repertoire is not entirely genetically encoded
• Genes for segments of receptors are rearranged and nucleic acids deleted/added at the sites of rearrangement almost randomly
• Potential to create in order of 1011 to 1012 receptors
• Autoreactive cells are likely to be generated
• Mechanisms must exist to delete or tolerise these autoreactive cells

3. Exquisite specificity
   * able to discriminate between very small differences in molecular structure

Question 3

What are antigen presenting cells (APC)?

Answer 3

• APCs are cells that can present peptides to T lymphocytes to initiate an acquired immune response
• These cells include:
  
  • Dendritic cell
  • Macrophage - include Langerhans cells, mesangial cels, Kupffer cells (liver), osteoclasts, microglia etc.
  • B lymphocyte

Question 4

Describe clonal expansion following exposure to antigen in the adaptive immune system

Answer 4

Clonal expansion following exposure to antigen:

• 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

There is then immunological memory - following infection, residual pool of specific cells with enhanced capacity to respond if re-infection occurs

Question 5

Describe the CD8 T cell response to an infection

Answer 5

Question 6

Describe CD4 T cell response to infection

Answer 6

Question 7

What are the different CD4 T cell subsets?

Answer 7

• Help CD8 T cells and macrophages
• Help neutrophil recruitment
• IL-10/TGF beta expressing
• CD25+ Foxp3+
• Follicular helper T cells
• Helper T cells

Question 8

Describe T cell memory, how long it lasts and action

Answer 8

Longevity

• Memory T cells are maintained for a long time without antigen by continual low-level proliferation in response to cytokines

Different pattern of expression of cell surface proteins involved in chemotaxis cell adhesion

• These allow memory cells to access non-lymphoid tissues, the sites of microbial entry.

Rapid, robust response to subsequent antigen exposure

• There are more memory cells
• These cells are more easily activated than naïve cells

Question 9

Describe the B cell response to an infection

Answer 9

Question 10

Describe B cell memory - how lomg it lasts, action etc.

Answer 10

Longevity

• Long lived memory B cells and plasma cells

Rapid, robust response to subsequent antigen exposure

• There are more memory cells
• These cells are more easily activated than naïve cells

Pre-formed antibody

• Circulating high affinity IgG antibodies

Question 11

What do we want from a vaccine?

Answer 11

1. Generate protective, long-lasting immune response
2. No adverse reactions
3. Single shot
4. Easy storage

Question 12

What part of the influenza virus causes the infection?

Answer 12

• Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies.

In influenza CD8 T cells controls the virus load and it is the antibody which provides a protective response

Question 13

Describe the haemagglutination inhibition assay

Answer 13

Detection of virus specific antobodies

• Sialic acid receptors on RBC bind to haemagluttin of influenza virus to ‘haemagluttinate’

Reaction inhibited by antibodies to haemagluttin

Question 14

Describe how the mantoux test is done

Answer 14

• Inject 0.1 ml of 5 tuberculin units of liquid tuberculin intradermally.
• The tuberculin used in the Mantoux skin test is also known as purified protein derivative, or PPD.
• The patient’s arm is examined 48 to 72 hours after the tuberculin is injected.
• The reaction is an area of induration (swelling that can be felt) around the site of the injection.

Question 15

1. What is the BCG?
2. What does the BCG do?
3. What response is important?

Answer 15

1. BCG is an attenuated, strain of bovine tuberculosis
2. Protects against primary inection, as well as progression to active TB
3. T cell response is important in protection

Question 16

Describe the maintenance of responses for the:

1. Influenza vaccine
2. TB vaccine

Answer 16

1. Influenza

Antibody protection begins within 7 days after immunization. Protection can last for approximately 6 months or longer in the general population.

2. TB

Protection in the UK after BCG lasts about 10-15 years.

Question 17

What the types of vaccines?

Answer 17

• Live vaccines
• Inactivated/Component/Conjugate vaccines
• • Adjuvants to increase immunogenicity
• DNA vaccines
• Dendritic cell vaccines

Question 18

What is a live attenuated vaccine? Examples?

Answer 18

• A live attenuated vaccines use a live organism to induce an immune response
• Organism is modified, (attenuated) to limit pathogenesis
• Examples:
  
  • MMR
  • BCG
  • Yellow fever

Question 19

1. What are the advantages of live vaccines?
2. What are the problems with live vaccines?

Answer 19

1. Pros

• 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

2. Cons

• Storage problems
• Possible reversion to virulence (recombination, mutation).
  
  • Vaccine associated paralytic poliomyelitis (VAPP, ca. 1: 750,000 recipients)
• Spread to contacts
  
  • Spread to contacts of vaccinee who have not consented to be vaccinated
  • Spread to immunosuppressed/immunodeficient patients

Question 20

Describe the different inactivated/component vaccines

Answer 20

Inactivated Vaccines

• Influenza, Cholera, Bubonic plague, Polio (Salk), Hepatitis A, Pertussis, Rabies.

Toxoids (inactivated toxins)

• Diphtheria, Tetanus.

Component/subunit vaccines

• Hepatitis B (HbS antigen), HPV (capsid), Influenza (haemagglutinin, neuraminidase).

Question 21

What are the advantages and disadvantages of inactivated/component vaccines?

Answer 21

Advantages:

• No mutation or reversion
• Can be used with immunodeficient patients
• Can lead to elimination of wild type virus from the community
• Storage easier
• Lower cost

Disadvantages:

• 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 22

Describe conjugate vaccines, and examples

Answer 22

Conjugate vaccines:

• 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

e.g.

• Haemophilus Influenzae B
• Meningococcus
• Pneumococcus

Question 23

Describe adjuvant vaccines and some examples

Answer 23

• Adjuvant increases the immune response without altering its specificity
• Mimic action of PAMPs (pathogen associated molecular patterns) on TLR (toll-like receptors) and other PRR (pattern recognition receptors)

Examples:

• Aluminium salts (humans)
• Lipids – monophosphoryl lipid A (humans)
• Oils -Freund’s adjuvant (animals)
• ISCOMS
• CpG DNA

Question 24

Describe the actions of aluminum salts as an adjuvant therapy in humans

Which vaccines is it used in?

Answer 24

• Primary adjuvant utilized in humans – safe and effective
• Mechanism not fully elucidated
  
  • Alum may allow antigens to be slowly released, prolonging the immune stimulation
  • Alums induce a mild inflammatory reaction that will then promote development of adaptive immune response
  • Alum activates Gr1+ IL4+ eosinophils to help prime naïve B cells leading to antibody response

Used in many vaccines including hepatitis A, hepatitis B, Hib

Question 25

Describe how experimental DNA vaccines act

Answer 25

Question 26

What are the advantages and disadvantages of DNA vaccines?

Answer 26

Advantages * Mimics a virally infected cell * Stimulates T cell responses Disadvantages * Possible plasmid integration into host DNA * Possible response to DNA could lead to autoimmune diseases such as SLE Experimental in humans

Question 27

Describe dendritic cell vaccines

Answer 27

* Acquired defects in DC maturation and function associated with some malignancy suggests a rationale for using ex vivo–generated DC pulsed with tumour antigens as vaccines * Need to find antigens that clearly mark the cancer cells as different from host cells

Question 28

Replacement of missing components of immune system ## Footnote What are the indications for haematopoietic stem cell transplantation?

Answer 28

• Life-threatening primary immunodeficiencies –Severe combined immunodeficiency –Leukocyte adhesion defect •Haematological malignancy etc Offers potential for complete and permanent cure

Question 29

Describe antibody replacement as a replacement for components of the immune system

Answer 29

* Human normal immunoglobulin * Prepared from pools of \>1000 donors * Contains preformed IgG antibody to a wide range of unspecified organisms * Blood product: * Donors screened for Hep B, Hep C and HIV * Further treated to kill any live virus * Administration * IV or SC

Question 30

What are the indications for antibody replacement therapy?

Answer 30

Primary antibody deficiency * X linked agammaglobulinaemia * X linked hyper IgM syndrome * Common variable immune deficiency Secondary antibody deficiency * Haematological malignancies * Chronic lymphocytic leukaemia * Multiple myeloma * After bone marrow transplantation * Can also be used for passive immunisation - CMV, VZ immunoglobulin etc.

Question 31

What are specific immunoglobulins and their uses?

Answer 31

* Human immunoglobulin used for post-exposure prophylaxis (passive immunisation) * Derived from plasma donors with high titres of IgG antibodies to specific pathogens Examples: * Hepatitis B immunoglobulin * Tetanus immunoglobulin * Rabies immunoglobulin * Varicella Zoster immunoglobulin

Question 32

What groups of transplant patients can recieve T cells as a replacement to the immune system to boost the immune system?

Answer 32

* Immunosuppression results in failure to control infection with persistent viruses – CMV, EBV * Patients develop CMV pneumonitis, retinitis….. * Patients develop EBV related B cell lymphoproliferative disease

Question 33

Recombinant cytokines 1. What do they aim to do? 2. Describe the use of the following: * Interferon alpha * Interferon Beta * Interferon gamma

Answer 33

1. Aim : Modify immune response 2. * Interferon alpha * Hepatitis C, Hepatitis B, Kaposi’s sarcoma * Hairy cell leukaemia, chronic myeloid leukaemia, multiple myeloma * Interferon beta * Behcet’s * Relapsing multiple sclerosis (past) * Interferon gamma * Chronic granulomatous disease

Question 34

* What is Ipilimumab? * How does it act? * Indications?

Answer 34

* Ipilimumab is a an antibody that is specific for CTLA4 * Blocks immune checkpoint between T cells and APC * Antibody binds to CTLA4 on T cells * Blocks immune checkpoint * Allows T cell activation * Indications: Advanced melanoma

Question 35

1. What are Pembrolizumab and Nivolumab? 2. How do they act? 3. Indications?

Answer 35

1.Specific antibodies for PD-1 2. * Antibody binds to PD-1 * Blocks immune checkpoint * Allows T cell actiavtion 3. Indications: Advanced melanoma