Exam 2: Immunopharmacology

Question 1

Immunopharmacological agents act to…

Answer 1

mobilize and/or modify the immune system

Question 2

Immune Mobilization

Answer 2

• Vaccines
  
  • Modulates [Ab]
• Cancer treatment
• Overcoming immunosuppressed states

Question 3

Immune Suppression

Answer 3

Used for:

• Transplantation
• Autoimmune diseases
• Allergies

Question 4

Immunopharmacologic

Targets

Answer 4

Question 5

Glucocorticoid

Actions

Answer 5

Functions by inhibiting gene expression.

• Immunosuppressive
  
  • ⊗ activation of innate and adaptive immune cells
    
    • T-cells more affected
    • ↓ 1° Ab responses
    • ↓ 2° Ab responses w/ prolonged use
• Anti-inflammatory
  
  • ⊗ Expression of inflammatory mediators
    
    • TNF & interleukins
  • ⊗ Phospholipase A₂
    
    • ↓ Eicosanoid production

Question 6

Glucocorticoid

Adverse Effects

Answer 6

• Adrenal suppression ⇒ taper therapy to avoid adrenal crisis
• Cushingoid reactions ⇒ having the constellation of signs and symptoms caused by excess cortisol
• Mood swings
• Diabetes
• ↓ resistance to infections
• Osteoporosis
• Cataracts
• Weight gain
• HTN

Question 7

Prednisone

Answer 7

Used in combo w/ other immunosuppressants for:

• Solid organ transplantation
• Hematopoietic stem cell transplantation
• Certain autoimmune diseases
  
  • RA
  • SLE
• Attenuate allergic reactions

Question 8

Azathioprine ⇒ Mercaptopurine

Actions

Answer 8

Cytotoxic agent

• Azathioprine (pro-drug) ⇒ Mercaptopurine (anti-metabolite)
  
  • Converted non-enzymatically in tissues by rxn with sulfhydryls
  • Slow release favors immunosuppressive activity
• Mercaptopurine interfers with purine nucleic acid synthesis
  
  • Required for lymphoid cell proliferation
• Uses:
  
  • Kidney transplantation
  • Autoimmune diseases

Question 9

Azathioprine ⇒ Mercaptopurine

Adverse Effects

Answer 9

• Low doses
  
  • Bone marrow suppression
    
    • Leukopenia
  • Rash
• High doses
  
  • GI disturbances
  • Hepatotoxicity

Question 10

Azathioprine/Mercaptopurine interacts with…

Answer 10

Allopurinol

(Xanthine oxidase inhibitor)

Question 11

Mycophenolate mofetil (MMF)

Actions

Answer 11

“Mycophenolic acid”

Cytotoxic agent

• Inhibits inosine monophosphate dehydrogenase II (IMPDHII)
  
  • Isoform expressed in lymphocytes
    
    • Less toxic to other cells
  • Rate limiting step in guanosine synthesis
    
    • Blocks de novo purine synthesis
• Cytostatic and can cause apoptosis in lymphocytes
• Uses:
  
  • Kidney transplant
    
    • More effect than Azathioprine in preventing rejection
    • Prevents chronic rejection in animal models
  • Autoimmune diseases

Question 12

Mycophenolate mofetil (MMF)

Adverse Effects

Answer 12

• GI disturbances
• Headache
• HTN

Question 13

Methotrexate

Answer 13

Cytotoxic agent

• Folate derivative
• ⊗ several enzymes responsible for nucleotide synthesis
• Used for immunosuppresion but not transplantation
  
  • RA
  • Psoriasis

Question 14

Cyclophosphamide

Answer 14

Cytotoxic agent

• Alkylates DNA and RNA ⇒ cross-linking of strands
  
  • ⊗ Protein synthesis
• Used for immunosuppression but not transplantation
  
  • Cancers
  • SLE

Question 15

Cyclosporine (Cyclosporin A)

Actions

Answer 15

Inhibition of lymphocyte signaling

• Decapeptide that binds cyclophilic
• Complex inhibits Calcineurin
  
  • Ca²⁺/calmodulin-dependent protein phosphatase
  • Normally dephosphorylates cytoplasmic transcription factors that controls IL-2 gene
• Highly selective action in inhibiting activation of T cells
  
  • Esp. T_h cells
• Uses:
  
  • Organ transplantation
    
    • Renal, heart, liver, bone marrow, lung, pancreas
    • Proactively & graft-vs-host reactions
  • Psoriasis
  • RA
  • Rare autoimmune diseases refractive to other treatments
• Often used in combo with other immunosuppressants ⇒ ↓ effective dose & ↓ adverse effects
  
  • Corticosteroids
  • Rapamycin

Question 16

Cyclosporine

Adverse Effects

Answer 16

• Nephrotoxicity
  
  • Dose-related
  • Caused by vasoconstriction
  • Important to monitor drug levels & creatinine clearance
• Neurotoxicity
  
  • Paresthesia, tremor, seizures
• Hepatotoxicity
• HTN
• HLD

Question 17

Cyclosporine

Metabolism

Answer 17

Metabolized by cytochrome p450

• Interpatient variability in response
• Potential for drug interactions

Question 18

Tacrolimus (FK506)

Actions

Answer 18

Inhibition of lymphocyte signaling

• Macrolide abx with immunosuppressive properties
• Similar to cyclosporine but 10-100x more potent
• Binds to FK-binding proteins (FKBP)
• Complex:
  
  • Inhibits calcineurin
  • Inhibits IL-3, IL-4, IFN-γ, and TNF-α
• Uses:
  
  • 2nd line med after standard therapy fails
    
    • Organ transplants
    • Autoimmune diseases
  • Standard prophylactic agent used in combo for graft-vs-host
  • Topical prep available
    
    • Atopic dermatitis
    • Psoriasis

Question 19

Tacrolimus (FK506)

Adverse Effects

Answer 19

Similar to cyclosporin but more severe.

Higher potency and solubility.

• Nephrotoxicity
• Neurotoxicity
• Hepatotoxicity
• HTN
• HLD

Question 20

Sirolimus (Rapamycin)

Actions

Answer 20

Inhibition of lymphocyte signaling.

• Macrolide abx w/ immunosuppresive activity
• Binds to FK-binding proteins (FKBP)
• Mechanism:
  
  • Inhibits molecular target of rapamycin (mTOR)
    
    • mTOR normally phosphorylates
      
      • p70 S6 kinase
        
        • Involved in protein synthesis
      • PHAS-1
        
        • ℗ results in release of initiation factor involved in translation
  • Results in inhibition of IL-2 stimulated protein synthesis
  • Arrests lymphocytes in G1 phase
• Used alone or in combo with other immunosuppressants for solid organ transplant
• Sirolimus-eluting stents
  
  • Inhibits proliferation of smooth muscle cells

Question 21

Sirolimus (Rapamycin)

Adverse Effects

Answer 21

• HLD
• Leukopenia
• Thrombocytopenia
• Hepatotoxicity
• NOT nephrotoxic alone
  
  • Cyclosporine + sirolimus ⇒ more impaired renal function
    
    • Likely d/t pharmacokinetic interaction where sirolimus ↑ [cyclosporine]
  • Sirolimus + glucocorticoids + mycophenolate used instead for pts with or high risk for calcineurin inhibitor associated nephrotoxicity

Question 22

Sirolimus (Rapamycin) is metabolized by…

Answer 22

cytochrome p450

Potential for drug interactions.

Question 23

OKT3

Actions

Answer 23

“Muromonab-CD3”

Selective depletion of T cells

• Monoclonal Ab against CD3 on T-cells
  
  • Mouse Ab so body can make Ab against it
• Depletes T cells through Ab activation of complement
• Uses:
  
  • Preparation for transplant
  • Prevent acute rejection
    
    • Renal, liver, heart
  • Suppresses T-cell mediated responses against transplants
  • Deplete T-cells from donor bone marrow prior to transplant

Question 24

OKT3

Adverse Effects

Answer 24

• Profound but transient immunosuppression
• Can sometimes activate T cells ⇒ Cytokine release syndrome
  
  • Occurs if T cells release cytokines before being eliminated
  • Usually occurs after first few doses
  • See fever, myalgia, nausea, diarrhea

Question 25

ATG (Anti-thymocyte Ab)

or

ALG (Anti-lymphocyte Ab)

Answer 25

Selective Depletion of T cells

• Polyclonal Ab against whole human lymphocytes
  
  • Made by injecting rabbits or larger animals
• Targets many epitopes
• Act on long-lived peripheral lymphocytes
  
  • Little effect on B cells
• Similar uses to OKT3
  
  • Preparation for transplantation
  • Acute rejection
  • Preparing donor bone marrow
• Similar side effects to OKT3 but much broader immunosuppresion b/c polyclonal

Question 26

Anti-CD25 mAb

(Daclizumab)

Answer 26

Selective depletion of T-cells

• Humanized Ab against CD25 ⇒ α-subunit of IL-2 receptor
  
  • Only expressed on activated T-cells
• Used for induction
• Used in combo to prevent rejection

Question 27

Organ Transplantation Treatment

Summary

Answer 27

Host vs graft reactions:

1. Preparation (induction) ⇒ several days - 1 week before
   
   • Immunosuppressive regimen
     
     • Daclizumab, ATG, or anti-CD3
2. Hyperacute rejection ⇒ mins - hours
   
   • Cannot be stopped by immunosuppressive drugs
3. Acute rejection ⇒ weeks to months
   
   • Generally treated with combo of immunosuppressive drugs
     
     • Calcineurin inhibitor ⇒ cyclosporine or tacrolimus
     • Cell cycle inhibitor ⇒ Mycophenolate mofetil or sirolimus
     • ± Steroids
4. Chronic rejection ⇒ months - years
   
   • Cannot be stopped by immunosuppressive drugs

Question 28

Graft vs Host

Disease

Answer 28

Major complication of bone marrow and stem cell transplantation

• Transplanted immune cells attack host cells
• Start w/ high dose steroids
• Add drugs:
  
  • Cytotoxic agents
    
    • Mycophenolate mofetil
  • Inhibition of lymphocyte signaling
    
    • Tacrolimus
    • Daclizumab
  • Inhibit cell cycle
    
    • Sirolimus

Question 29

Immune checkpoint signals used to…

Answer 29

inhibit the immune response

Question 30

Checkpoint Inhibitors

Answer 30

• Block immune checkpoint signals
• Facilitates ability of immune system to attack tumors
• Consists of:
  
  • CTLA-4 blockade
  • PD-1 blockade

Question 31

CTLA-4

Blockade

Answer 31

• Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4)
  
  • Expressed on surface of activated T-cells
  • Competes with CD28 for binding of B7 on APC
  • Prevents co-stimulation of T cells
  • Modulatory mechanism where CTLA-4 attenuates activation of the T-cell
• Block CTLA-4 wiith Ipilimumab
  
  • T-cell remains active
  • Enhances immune response to cancer
• ↑ immune response ⇒ immune-related adverse events common

Question 32

PD-1

Blockade

Answer 32

• T-cells express programed cell death protein (PD-1)
  
  • Probes cells for PD-L1
  • Cells with PD-L1 avoids attack
    
    • e.g. human cells
    • Some cancers express PD-L1
• Nivolumab and Pembrolizumab
  
  • Humanized monoclonal Ab against PD-1
  • Block interaction with PD-L1
  • Inhibits the inhibition of T-cell proliferation and cytokine production
  • Anti-tumor immune response allowed to proceed
• Recommended for unresectable or metastatic melanoma that has not responded to ipilimumab/other first line treatments
• PD-1 blockade more focused @ level of the tumor
  
  • More favorable adverse effect profile

Question 33

Immunoglobulin Preparations

Answer 33

• IV-IG
• Rho Immunoglobulin
• Hyperimmune immunoglobulin

Question 34

Immune Globulin Intravenous

(IV-IG)

Answer 34

• Preparation of immunoglobulin pooled from large population of donors ⇒ normalized serum
• Used @ low doses in humoral deficiency
• Used @ high doses
  
  • Severe asthma
  • Some autoimmune disorders
  • Kawasaki syndrome

Question 35

Rho Immunoglobulin

(Rhogam)

Answer 35

• Human IgG against Rho(D) Ag of RBC
• Prevents sensitization of Rh^⊖ mother
• Administered to mother within 24-72 hours after birth of Rh^⊕ infant

Question 36

Hyperimmune Immunoglobulin

Answer 36

• Made from pools of selected human or animal donors w/ high titer to particular Ag
• Ex. cytomegalovirus or respiratory syncytial virus