Immuno 3, Immunosuppresive Therapy

Question 1

What immunosuppressive drugs are considered broadly active and non-specific?

Answer 1

Corticosteroids

IV immunoglobulins

Question 2

Which immunosuppressive drugs primarily target T lymphocytes?

Answer 2

1. Mycophenolate
2. Cyclosporine
3. Tacrolimus
4. Leflunomide
5. Oclacitinib
6. Azathioprine

Question 3

How do corticosteroids suppress the immune system?

Answer 3

• suppress cytokine production by activated MO, monos, and neuts
• suppress neut & MO phagocytosis
• suppress neut migration into tissues
• suppress T cell cytokine production
• induce T cell apoptosis

Question 4

What are the doses of steroids for…

physiological, anti-inflammatory, and immunosuppressive

Answer 4

Physiological = 0.025 - 0.1 mg/kg/day

Anti-inflammatory = 0.25 - 0.5 mg/kg/day

Immunosuppressive = 1-2 mg/kg/day

Question 5

What are extra-nuclear effects of corticosteroid and why are they important?

Answer 5

• dose <1mg/kg: primary effect is mediated by binding to the glucocorticoid receptor, which in turn alters cytokine gene transcription
• dose >1mg/kg: steroids insert into cell membrane and alter cell signaling and ion permeability
• very high pulse doses of steroids can rapidly and potently suppress immune responses

Question 6

What is the relative potency of different steroids?

Answer 6

• least potent = hydrocortisone
• intermediate = prednisone, prednisolone
• more potent = dexamethasone (8x pred)
• very potent (topicals) = triamcinolone, betamethasone,m fluticasone, budesonide

Question 7

Why do we often combine immunosuppressive drugs?

Answer 7

• reduce dose of steroids to minimize side-effects
• greater potency from combined therapy
• greater specificity for certain populations of immune effector cells (e.g. T cells)

Question 8

What do you need to know about using mycophenolate?

Answer 8

• more potent and more rapidly acting than azathioprine; can be administered IV
• MOA = suppress lymphocyte proliferation by inhibiting purine synthesis
• major SE = GI (V and D)
• used often for severe or refractory IMHA, IMTP, and SLE

Question 9

What do you need to know about using cyclosporine?

Answer 9

• slow onset of action (days to wks)
• MOA = inhibit IL2 production by CD4
• useful for maintenance therapy for refractory IMHA, IBD, IMTP, and PA
• useful as steroid alternative for atopy in dogs
• useful as topical drug for keratitis sicca in dogs
• useful for treating perineal fistulas in dogs

Question 10

What about leflunomide?

Answer 10

• MOA = similar to mycophenolate
• inhibits mitochondrial enzyme req’d for uridine synthesis
• potency and efficacy not well studied in dogs
• major SE is GI - V and D
• can be used for management of refractory IMHA or IMTP

Question 11

What about oclacitinib (Apoquel)?

Answer 11

• MOA = JAK kinase inhibitor
• broad suppression of cytokine signaling
• suppression of both innate and adaptive immunity
• approved for tx of atopy in dogs; being used now for immune suppressive therapy of IM disease in dogs, rhinitis in dogs and cats

Question 12

What about azathioprine?

Answer 12

• MOA = block lymphocyte proliferation by suppressing purine synthesis
• slow onset (1-2 wks)
• major SE is idiopathic and occasionally fatal hepatic necrosis; reversible if caught early
• can be combine with pred for IMHA, IMTP, and SLE
• *rarely used anymore

Question 13

What is IVIG and how does it work?

Answer 13

• IV human immunoglobulin = purified human IgG monomers
• potent and rapid immune suppression
• binding to MO inhibitory Fc receptors potently suppresses MO fxn

Question 14

How do mesenchymal stem cells suppress immune responses?

Answer 14

• MSC produce immunosuppressive factors: dogs - PGE2, TGFb, adenosine
• suppress lymphocyte proliferation, cytokine production, and DC and MO fxn
• both local and systemic immune suppressive effects induced