Immunomodulation and Immunotherapy L12 Flashcards

1
Q

Describe HPV and its vaccine.

A
  • Human papillomaviruses (HPV) is a sexually transmitted infection that invades epithelial cells
  • There are at least 120 types of HPV and of these 18 are associated with cervical cancer. HPV16 and 18 cause 70% of cervical cancer
  • HPV 6 and 11 cause 90% of cases of genital warts
  • Merck and Co, Inc have developed a new vaccine against HPV 6, 11, 16 and 18 (Gardasil) which has been licensed in the UK. As do GSK
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2
Q

Describe DNA free virus like particles (VLP).

A
  • DNA free virus like particles (VLP) have been manufactured in Saccharomyces cervisiae.
  • These VLP express the major capsid antigen (L1) of HPV and induce a strong immune response.
  • The neutralizing antibodies produced prevent infection of cells by HPV.
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3
Q

What are adjuvants?

A
  • Adjuvants are inorganic or organic chemicals, macromolecules or entire cells of killed bacteria that can increase the immune response.
  • They may be included in a vaccine to enhance the recipients immune response to the antigen or may be used in the production of antibodies from animals.
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4
Q

Describe the mechanisms of action of adjuvants.

A

a) Depot effect:
- soluble proteins converted to an insoluble form
- slower release of antigen
- more easily ingested and presented by APC

b) inducing inflammation (“danger” signal)
- additional microbial products induce co-stimulator molecules

c) Acting as a stabalizing agent

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5
Q

In adjuvants, the antigen is dispersed in ___1___ or adsorbed on ___2___ for slow release.

A
  1. Oil

2. Alum

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6
Q

Describe desensitization therapy in allergy.

A
  • Only treatment that ‘cures’ allergies (Discovered 1911).
  • Patients are given weekly injections with increasing doses aqueous allergen over 14-18 weeks. Once on a maintenance dose, intervals between injections are spaced out to 4-6 weeks for 3 years.
  • Used in patients with anaphylactic responses to insect venoms, and rhinoconjunctivitis not controlled by oral steroids. Asthma may be amenable for treatment but carries a high risk.
  • Mode of action is unknown
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7
Q

What are cytokines?

A
  • Biological response modifiers secreted by a range of cells
  • Multiple and diverse effects on immune function
  • May feature in disease processes
  • Cytokines or their antagonists can be used therapeutically
    Include interleukins, interferons, colony-stimulating factors (CSF), others (TNF-alpha, TGF-beta etc)
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8
Q

What is Interferon alpha used to treat?

A
  • Viral hepatitis
  • Basal cell carcinoma
  • External genital warts
  • Wide range of lymphoma and leukemias
  • Useful in treating some non-viral cancers (melanoma)
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9
Q

In cytokine therapy; what does IL2 do?

A

Stimulates T cells to divide.

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10
Q

In cytokine therapy; what does IL7 do?

A

Stimulates production of CD4 cells and B cells.

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11
Q

In cytokine therapy; what does IL15 do?

A

Preferentially stimulates the production of CD8 cells.

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12
Q

In cytokine therapy; what does IL1 do?

A

Binds to the receptor IL-1R as an antagonist.

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13
Q

Describe Antibody-based immunotherapies.

A
  • For diseases affecting the immune system and for other types of disease e.g. cancers, allergies
  • Antibodies to cell surface molecules may be used to interfere with molecular function or to kill cells
  • Antibodies to cytokines, growth factors or antibodies may be used to prevent these molecules having their biological effect
  • Used alone or in combination with other therapies
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14
Q

What is the side effect of anti-TNFalpha therapies?

A

Increased risk of infection, especially TB.

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15
Q

In antibody-based immunotherapies; what does anti-IgE do?

A

Used in allergic disease (particularly asthma but may be used in the treatment of allergic eczema).

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16
Q

In antibody-based immunotherapies; what does anti-CD52 do?

A

Used for B-chronic lymphocytic leukaemia.

17
Q

In antibody-based immunotherapies; what does anti-CD3 do?

A

Interferes with T cell function.

18
Q

In antibody-based immunotherapies; what does anti-LFA1 do?

A

Treats psoriasis.

19
Q

In antibody-based immunotherapies; what does anti-VLA4 do?

A

Treats Crohn’s disease and ulcerative colitis by interfering with lymphocyte trafficking.

20
Q

In anti-growth factor immunotherapies; what does anti-VEGF do?

A

Prevents angiogenesis (growth of new blood vessels).

21
Q

In anti-growth factor immunotherapies; what does anti-EGFR do?

A

Interferes with cancer cell growth by modulating response to EGF.

22
Q

What are anti-growth factor immunotherapies used to treat?

A

Cancer.

23
Q

Describe anti-CD3 treatment for diabetes.

4

A
  • Antibodies teplizumab and otelixizumab
  • Range of doses (3 – 48 mg) and regimes (6-14 days)
  • Followed for a minimum of 2 years
  • Treated group showed reduction in circulating T cells but mechanisms may involve induction of regulator T cells
24
Q

Describe immunoglobulin replacement therapy.

A
  • Immunoglobulin replacement therapy is given to all children and adults with defective antibody production
  • Individuals with hypogammaglobulinaemia require 400-600 mg of immunoglobulin/kg/month to prevent infections and reduce complications such as chronic lung or gut disease
  • In many patients with B cell immunodeficiencies intravenous therapy is the treatment of choice and intravenous immunoglobulin (IVIG) is usually given at 2-3 weekly intervals.
25
Q

Describe intravenous immunoglobulin (IVIG) treatment.

A
  • IVIG is a highly purified preparation of pooled human plasma pool consisting of 6 000 – 30 000 donor units in order to give the widest possible range of protective antibodies.
26
Q

What does a deficiency in C1 esterase inhibitor (C1INH) do?

How is replacement of C1INH achieved?

A
  • Deficiency in C1 esterase inhibitor (C1INH) gives rise to HEREDITARY ANGIODEMA which manifests as localised swelling of the tissue (which may be fatal) following trauma.
    This typically presents itself with swelling of the face and throat or gut oedema. Dermal swellings may also be very painful.
  • C1INH is purified from blood products and can be used as prophylaxis or to treat acute symptoms.
27
Q

What is bone marrow transplantation used to treat?

A
  • SCID
  • Neutrophil disorders,
  • Inherited metabolic diseases
  • Marrow failure
  • Lymphoma
  • Leukaemia
  • Juvenile chronic arthritis
28
Q

BMT involves the re-consitution of the full haematopoietic system by transfer of pluripotent stem cells.

May be 1) Allogenic – DEFINE

         2) Autologous -  DEFINE

In a successful transplant introduced stem cells migrate to the cavities of the large bones, engrafts and starts producing new white blood cells.

A

Allogenic - another gentotypically matched individual acts as a donor (may be a sibling or a matched unrelated donor (MUD)

Autologous - patient acts as own source of stem cells

29
Q

What is conditioning within a bone marrow transplant?

A

Conditioning is required to eliminate any residual immune system in the recipient.

  • Normally treatment with cytoreductive drugs including busulphan or cyclophosphamide.
  • Patients must be kept in laminar flow isolation and can be treated with IVIG, antibiotics, antifungals and antivirals.
30
Q

What 8 things is the rate of immunological development after BMT is dependent on?

A
  1. Conditioning regime
  2. Stem cell dose
  3. Donor source
  4. Use and type of T cell depletion
  5. Matching of MHC
  6. Development of GvHD
  7. Use of immunomodulation after transplant
  8. Infection (both pre-exisiting and aquired post BMT)
31
Q

Describe the first gene therapy trials in ADA deficiency SCID.

A
  • The first gene therapy trials were carried out in 1990
  • An adenovirus, which is capable of transferring it’s DNA into normal eukaryotic cells (transfection), was engineered to contain the normal human ADA gene.
  • Isolated T-cells from the patient were exposed to the virus in cell culture, and took up the ADA gene.
32
Q

Describe the first gene therapy trials in X-SCID.

A
  • Gamma IL-R DNA was introduced into a retrovirus and this virus was exposed to CD34+ bone marrow stem cells in vitro.
  • The transformed cells were then re-infused back into the patients and both T cells and NK cells expressing the corrected gene have been observed.
33
Q

Name some diseases that have been successfully treated in trials with gene therapy.

A
  • SCID
  • Leber’s congenital amaurosis
  • Adrenoleukodystrophy
  • Chronic lymphocytic leukaemia
  • Acute lymphocytic leukaemia
  • Multiple mysleoma
  • Haemophilia
  • Parkinsons disease