Other immunosuppressants

Question 1

What is Glatiramer?

Answer 1

• High molecular weight polypeptide (4-11kDa) of L-glutamic acid, L-alanine, L-tyrosine, and L-lysine.
• Approved for use in the treatment of multiple sclerosis.
• Inhibits auto-immune response.

Question 2

What is the MOA of Glatiramer?

Answer 2

• Induction of a specific Th2 population in periphery
• Reactivated in CNS due to cross-reactivity with myelin
• Secrete anti-inflammatory cytokines,
• Produce neurotrophic factors
  1. Remyelination and axonal protection.

Question 3

What is Dimethyl Fumarate?

Answer 3

• Orally active
• Approved for treatment of MS
• MOA unclear
  1. Activation of Nrf2 (nuclear factor (erythroid-derived 2)-like 2)?
  2. Modulation of response to oxidative stress?

Question 4

What are the effects of DMF?

Answer 4

Question 5

What is Imiquimod?

Answer 5

• Immune stimulator.
• Used to treat genital warts and basal cell carcinoma.
• Enhances cytokine production and increases infiltration of the tumour by immune cells.
• Induces apoptosis.

Question 6

What is intravenous IgG (IVIG)?

Answer 6

• Purified IgG from pooled plasma.
• Can be used to treat patients with low levels of IgG.
• Can be enriched for certain antibody types (e.g. anti-S. aureus antibodies).
• Blocks FcgRIIa receptor and thus has anti-inflammatory activity.
• Approved for:
  1. Immune thrombocytopenia
  2. Kawasaki syndrome
  3. Multifocal Motor Neuropathy
  4. Chronic Inflammatory Demyelinating Polyneuropathy

Question 7

What is the potential mechanisms of IVIG activity?

Answer 7

• They’re mediated by F(ab’)2-dependent and Fc-dependent pathways.

Question 8

What is Interferon?

Answer 8

• IFNb-1a has been shown to provide benefit in MS.
• Rebif and Avonex.
• IFNb-1b also approved.
• Precise mechanism of benefit is not known.

Question 9

What is the role of IFNα and IFNβ in systemic lupus erythematosus (SLE) pathogenesis?

Answer 9

• IFNα and IFNβ contribute to immune dysfunction and tissue pathology with:
  1. IFNβ altering T-cell function and contributing to immune-mediated tissue injury (a)
  2. IFNα amplifying autoimmunity and inflammation based on induction of hundreds of type I IFN-induced gene products (b).

**(cGAS, cyclic GMP-AMP synthase;
DC, dendritic cell; IFIH1, IFN-induced helicase C domain-containing protein 1; IFN, interferon; IFNAR, interferon-α/β receptor; RIG-I, retinoic acid-inducible gene I protein; TLR, Toll-like receptor).

Question 10

Discuss other targeted therapies.

Answer 10

1. IL-1:
   - Canakinumab (Multiple autoimmune disease including RA).
   - Anakinra (RA).
2. IL-4:
   - Dupilumab is an IL-4 receptor antagonist (psoriasis).
3. IL-6:
   - Tocilizumab (RA).
4. IL12 & 23:
   - Ustekinumab (psoriasis & Crohn’s disease).
5. IL-17:
   - Ixekizumab (psoriasis).
6. IL23:
   - Guselkumab (psoriasis).
7. CD20:
   - Rituximab (RA, B-cell lymphoma) & ocrelizumab (MS).
8. Complement C5:
   -Eculizumab (atypical haemolytic uremic syndrome & paroxysmal nocturnal hemoglobinuria).
9. CD3:
   - OKT3 Muromonab (organ transplant).

Question 11

Discuss disease modifying therapy (DMT).

Answer 11

• Drugs that alter the underlying disease.
• Do not provide symptomatic relief.
• Paradigm shift in treatment:
• Escalating therapy starts with mild treatment and progresses to more severe therapy.
• DMT works by using more effective immunotherapy early on.
• Agents are used in RA & MS.

Question 12

Discuss Relapsing remitting MS (RRMS).

Answer 12

Question 13

MOA of immune modulators.

Answer 13

• Cytotoxicity.
• Inhibition of DNA synthesis/replication.
• Cytokine targeted therapies:
• Inhibition of cytokine synthesis
• Inhibition of cytokine receptors
• Inhibition of cytokine binding
• Inhibition of cytokine signalling
• Inhibition of co-signalling systems
• Specific cell depletion
• Th 1-2 switching
• Inhibition of adhesion/extravasation.

Question 14

Discuss small molecules that are used as immunosuppressants for organ transplantation.

Answer 14