Lecture 8 - Immunosuppressants Flashcards
Allograft
One donating to another within the same species
Autograft
One donating within itself
Xenograft
Donation from a different species
There are 3 stages of graft (organ) rejection: Describe them
Hyperacute: happens in minutes
Acute: happens within 7-21 days
Chronic: happens within 3 months
The success of organ transplantation is due largely to the availability of effective ____________ agents
immunosuppressive
All current anti-rejection drugs target ____ and _____ activation/clonal expansion, cytokine production or antibody action
T-cell
B-cell
Describe how organ rejection happens
Foreign organ proteins are present and bind to a macrophage or other antigen presenting cell.
This activates the formation or Th cells and B cells which produce antibodies.
Neutralizaiton
Opsonization
Phagocytosis
Ultimately leads to:
ORGAN REJECTION
When an antigen binds to an antigen receptor and activates B cell, they proliferate to form ??
clone of B cells
Then the clones of B cells proliferate and differentiation into two cell types: what are they?
Plasma cell (antibody secreting cell)
Memory cell (dormant cell)
What are anti-rejection drugs?
Drugs that act on the induction and/or effector phase of the immune response.
Describe the induction phase of the immune response
Activated T cells cause antigen recognition and then B-cells proliferate into the two types of cells (plasma cells and memory cells)
Describe the effector phase of the immune response
Differentiation of B cells results in the two different types of cells (plasma cells and memory cells). This triggers T cells or antibodies. Causes interaction. Causes complement pathway. Produces antigen. Results in tissue injury.
List 2 types of anti-rejection drugs (remember they act on the induction phase of the immune response)
- Inhibitors of interleukin-2 production (cyclosporine, tacrolimus)
- Inhibitor of cytokine gene expression (glucocorticoids)
Cyclosporine is a ??
interleukin-2 production inhibitor
Describe cyclosporine (IL-2 production inhibitor)
- A fat soluble cyclic peptide with 11 amino acids derived from fungus Tolypocladium inflatum
- Extensively used in the treatment of organ transplantation (kidney, heart, bone marrow)
- Low doses have also proved useful in autoimmune diseases (ex. RA)
Cyclosporine:
MOA
-Antigen-MHC 2 complex binds to Th2 cell receptor and increases intracellular Ca2+
-Ca2+/calmodulin complex stimulates phosphatase called Calcineurin which increases activation of transcription factor (NF-AT).
This increases IL2 gene transcription
- *Cyclosporine binds to cytosolic protein, Cyclophilin (immunophilin)
- *Cyclosporine-Cyclophilin complex inhibits calcineurin/NF-AT activation and blocks IL-2 gene transcription
Cyclosporine:
Describe the results of the MOA
- Decreases activation of T cells
- Inhibit IL-2 release
- Decrease expression of IL-2 receptors
- Reduce function of the effector T cells that mediate cell mediated response
- Reduction of T cell dependent B cell response
Cyclosporine (IL-2 Production Inhibitor):
Given ___ or ____
orally or IV
Cyclosporine (IL-2 Production Inhibitor):
____ absorption is slow and incomplete
Oral
Cyclosporine (IL-2 Production Inhibitor):
Metabolism occurs in both the ___ and _____
GI and liver
Cyclosporine (IL-2 Production Inhibitor):
Plasma half-life is ??
24 hours
Cyclosporine (IL-2 Production Inhibitor):
Cyclosporine is concentrated in _____ tissue (lymphomyeloid and adipose tissue)
peripheral
Cyclosporine (IL-2 Production Inhibitor):
Adverse effects?
- Nephrotoxicity
- Hypertension
- Increase risk of infection
- Liver dysfunction (regular blood level monitoring to avoid kidney and liver toxicity)
- Others: hyperglycemia, anorexia, lethargy, hirsutism, tremore, paraesthesia, gum hypertrophy, GI upset
List some drugs that inhibit Cyclosporine metabolism
- calcium channel blockers
- antifungal agnets (ketoconazole, fluconazole)
- antibacterial agents (erythromycin, clarithromycin)
- grapefruit juice
List some drugs that induce cyclosporine metabolism
Anticonvulsants (phenytoin) Antituberculosis agents (isoniazid, rifampin)
______ = macrolide antibiotic produced by Streptomyces tsukubaensis
Tacrolimus
Tacrolimus MOA
Similar to cyclosporine:
- At cellular level, it binds to the immunophilin FK binding protein (FKBP) which inhibits Calcineurin phosphatase which decreases activation of transcription factor (NF-AT) which decrease IL-2 gene transcription
- Prevents IL-2 gene activation
Look at picture on slide 21
Tacrolimus (Prevents IL-2 gene activation):
Given ____ or ___
orally or IV
Tacrolimus (Prevents IL-2 gene activation):
Plasma half life?
9-12 hours
Tacrolimus (Prevents IL-2 gene activation):
Metabolized by the ____
liver (99%)
Tacrolimus (Prevents IL-2 gene activation):
Active in preventing ??
organ transplant rejection
Tacrolimus (Prevents IL-2 gene activation):
Toxic effects similar to _____
cyclosporine
Cyclosporine and Tacrolimus both affect the _____ phase the immune response
induction
List some drugs acting on the effector phase of the immune response
- Inhibit action of IL-2 (Sirolimus)
- Inhibitors of purine synthesis (Mycophenolate mofetil, Azathioprine)
- Aklylating cytotoxic agents (Cyclophosphamide)
- Supressor of immune response (Glucocorticoids)
- Immunosuppressive antibodies (Polyclonal and monoclonal antibodies)
______ = new macrolide antibiotic derived from Streptomyces hygroscopicus
Sirolimus
Sirolimus:
MOA
- Binds to intracellular immunophilins but DOES NOT block IL-2 gene transcription
- Interferes with IL-2 signal transduction pathway in activated T cells
Result: decreased clonal proliferation of T cells and B cells
*prevents active cell proliferation (slide 26)
- Before we were blocking IL-2 production
- Now were are blocking IL-2 signal transduction pathway of already produced IL-2
What is Mycophenolate Mofetil converted to?
converted to mycophenolic acid
Mycophenolate Mofetil:
MOA
- Selectively inhibits proliferation of both T and B lymphocytes, and cytotoxic T cells
- MOA: Potent inhibitor of inosine 5’ mono-phosphate dehydrogenase (a crucial enzyme in purine synthesis)
- T cells and B cells are particularly dependent on this pathway for proliferation
**Inhibits purine synthesis therefore inhibits proliferation of B and T cells
Mycophenolate Mofetil (purine synthesis inhibitor): \_\_\_\_\_ administration (well absorbed)
oral
Mycophenolate Mofetil (purine synthesis inhibitor): What impairs absorption?
magnesium and aluminum
**therefore caution with antacids
Mycophenolate Mofetil (purine synthesis inhibitor): Metabolite mycophenolic acid and glucuronide conjugate undergoes \_\_\_\_\_\_ \_\_\_\_\_\_\_
enterohepatic circulation
Mycophenolate Mofetil (purine synthesis inhibitor): Eliminated by \_\_\_\_\_ as inactive glucuronide
kidney
Mycophenolate Mofetil (purine synthesis inhibitor): Indicated in transplant recipients with \_\_\_\_ and \_\_\_\_\_
cyclosporine and steroids
Azathioprine is metabolized to __________ which is a purine antimetabolite - remember anti-cancer drugs
6-mercaptopurine
Azathioprine:
MOA
- Interferes with purine synthesis (inhibits HGPRT enzyme - catalyzes conversion of purine base to purine ribosyl monophosphate). Cytotoxic on dividing cells
- Inhibit clonal T cell and B cell proliferation of immune response
- Inhibits both cell-mediated and antibody mediated immune reactions
*similar mechanism to Mycophenolate Mofetil
Azathioprine (purine synthesis inhibitor):
_____ loading dose on day of transplantation
IV
Azathioprine (purine synthesis inhibitor):
____ dosing for maintenance
Oral
Azathioprine (purine synthesis inhibitor):
Clinically used in combo with other ________ drugs (kidney, liver transplants, RA)
immunosuppressant
Azathioprine (purine synthesis inhibitor):
Major side effect ?
bone marrow depression
What is Cyclophosphamide?
A nitrogen mustard, an alkylating agent
Cyclophosphamide:
___ absorbed
orally
Cyclophosphamide:
half life ?
6.5 hours
Cyclophosphamide:
_______ until metabolized by the liver into the active phosphoramide mustard
inactive
Cyclophosphamide:
MOA
- Alkyl groups cross-react with two DNA nucleophilic sites (intra/inter guanine) which inhibits DNA replication
- Results in subsequent cell death (apoptosis)
- Used for treatment of Lupus and RA
Cyclophosphamide (DNA replication inhibitor):
Pronounced effect on _____
lymphocytes
Cyclophosphamide (DNA replication inhibitor):
Adverse effects?
- Bone marrow depression. Affects more white blood cells than platelets.
- GI disturbance
Cyclophosphamide (DNA replication inhibitor):
What is a toxic metabolite and what does it cause?
acrolein
causes hemorrhagic cystitis
List some glucocorticoids
- Prednisone
- Methylprednisolone
- Dexamethasone
What do high doses of Glucocorticoids do?
- High doses induce lymphocyte migration to extravascular space - subsequently reduce lymphocyte proliferation
- Size reduction in lymphoid tissues
- Affect more T cells than B cells
Glucocorticoids:
Suppress what phase of the immune response?
BOTH induction and effector phases of immune response
Glucocorticoids:
MOA
- Inhibit macrophage activation (antigen presenting cell) and release of IL-1B
- Decrease clonal expansion of T and B cells and IL-2 secreting T cells
- Decrease production and action of cytokines (interleukins, TNF gamma)
- Decrease generation of IgG
Glucocorticoids:
Clinical use
Anti-inflammatory and immunosuppressive therapy:
-Asthma, allergic rhinitis, eczema, severe drug allergic reaction, RA, organ transplant
Glucocorticoids:
Used for Neoplastic diseases such as ??
Hodgkin’s disease
Acute lymphocytic leukemia
Glucocorticoids:
Used as replacement therapy for ?
Addison’s syndrome (autoimmune polyendocrine syndrome)
Glucocorticoids:
Adverse effects
- Insomnia and mood changes (Cause is unknown - take it in the morning)
- Increased appetite and weight gain
- Suppress response to injury or infection
- Metabolic effects
- Fluid retention (Na+ retention and K+ depletion)
- Osteoporosis
- GI bleeding
- Hyperglycemia
slide 38 - good review
swag
Describe immunosuppressive antibodies
Antibodies against human lymphocytes or their surface receptors have significant immunosuppressant actions
List 2 types of immunosuppressive antibodies
1) Polyclonal antibodies
2) Monoclonal antibodies
Describe Polyclonal antibodies
Anti-lymphote immunoglobulin:
-Inhibits T cells. Lysis
- Bind to proteins on the surface of lymphocytes triggering the complement response - Lysis of lymphocytes
- Indiscriminate action on all T cells
Describe Monoclonal antibodies
Antibodies against interleukin 2 receptors:
-Prevents T cell and B cell activation and proliferation
- Directly against a specific surface component of T cells
- Affects the induction and effector phases of immune response to allograft
Polyclonal Antibodies:
Adverse effects
Newly synthesized antibodies against these polyclonal antibodies could produce anaphylactic reactions
Monoclonal antibody targets?
- CD3 proteins with antigen receptors
- CD4 co-receptors
- IL-2 receptors
What is TNF alpha ?
a pro-inflammatory cytokine
What is Infliximab?
chimeric human/mouse monoclonal antibody directed to TNF alpha
42 - good summary slide
ya man
Describe the prevention of acute rejection of organ transplants
-High does glucocorticoids, purine synthesis inhibitors, immunosuppressive antibodies
Describe the prevention of chronic rejection of organ transplant
Triple drug therapy consisting of low dose:
- Calcenurin inhibitor (Cyclosporine, Tacrolimus)
- Inhibitor of purine synthesis (Mycophenolate, Azathioprine)
- Glucocorticoid
Alkylating - cytotoxic mechanisms:
-cyclophosphamide
Immunosuppressive antibodies:
-Polyclonal and monoclonal antibodies
Anti-TNF therapy
When do autoimmune diseases occur?
When the adaptive immune system loses self-tolerance rendering the system unable to distinguish between self and non-self antigens
Describe self-tolerance
- The immune system protects itself against auto reactive B and T cells via primary and peripheral tolerance.
- In central tolerance, negative selection results in the clonal deletion of immature lymphocytes in the bone marrow (B cells) and thymus (T cells) that recognize self-antigens with high affinity.
- In peripheral tolerance (beyond the lymphoid organs), mature auto reactive lymphocytes are inactivated or killed by mechanisms including anergy, immunological ignorance/antigen sequestration, programmed cell death (PCD) or suppression by regulatory T cells (Tregs)
Describe loss of self-tolerance
When these self-tolerance mechanisms fail, the adaptive immune system responds as it would to non-self antigens and mounts an immune response.
The body’s inability to eliminate the self-antigen results in a sustained response that leads to chronic inflammation.
List some causes of loss of self-tolerance
- Viral infection of a tissue can activate non-virus specific T cells
- Molecular mimicry (microbial antigens share epitopes similar to human self-proteins and induce an inflammatory response agains the self antigen
- Immune cells targeting tumors may become or remain active and target healthy cells. Similarly, immunoediting theory suggests that antigens derived from cancer cells containing somatic mutations induce an adaptive immune response and generate cross-reactivity against native proteins
- Damage associated molecular patterns
List some drugs used in RA therapy
- NSAIDs
- Glucocorticoids
- Disease-Modifying Antirheumatic Drugs (DMARDs)
- Methotrexate
- Sulfasalazine
- Leflunomide
- Anti-TNF alpha therapies
- Anti-IL therapies
Describe the 3 phases of RA
1) Initiation phase
- Inflammation within joint
2) Amplification phase
- T cell activation
3) Chronic inflammatory phase
- Tissue injury due to destruction of bone and remodelling of joint
Why are anti-TNF and anti-IL effective DMARDs (disease-modifying anti rheumatic drugs)?
- Are released within joint during chronic inflammatory phase
- Are early participants in the inflammatory cascade
List some anti-TNF based therapeutics
- Entanercept
- Infliximab
- Adalimumab
- Certolizumab
- Golimumab
Describe Etanercept
- Only soluble receptor TNF antagonist
- Fully human protein
- Binds TNF, soluble and cell bound
- No neutralizing antibodies; low immunogenicity
- Does not bind complement, no cell lysis
List some Anti-IL based therapeutics
- Anakinra
- Canakinumab
- Tocilizumab
The rest of this lecture is UC and CD - so see GI lecture flashcards
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