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FUN2: 11:00-12:00
Scribe: Ryan O’Neill
Friday, December 5, 2008
Proof: Caitlin Cox
Dr. King
Immunopharmacological Agents
Page 1 of 5
IL-2 – Interleukin 2, CSA – cyclosporine, MPA - mycophenolic acid
I. Outline [S2]
a. Immune Response
b. Immunosuppressants
c. Immunostimulants
II. The Immune System [S3]
a. Overall goal of immune system is to distinguish self from “nonself.”
b. Innate Immunity - what we are born with, also called non-specific immunity.
i. Initiates and activates the response to an offending agent.
c. Adaptive Immunity
i. Creates a response that specifically neutralizes or kills that agent.
ii. 2 Major Mechanisms of Adaptive Immunity
1. Cell mediated (cytotoxicity) immunity
2. Humoral (antibody) immunity
iii. Cytokines have a vital role in initiation and regulation of both immune responses.
III. Simplified Schematic of Immune Response [S4]
a. Helps illustrate the immune system.
b. Both humoral and cellular immunity work by identifying the Ag as part of a bacteria or virus.
c. In humoral immunity the B cell matures into a plasma cell, which secretes Abs and binds to Ag and identifies it
for destruction.
d. T cell matures into an active-killer T cell and the T cell binds to Ags on surface cell and helper T cells secrete
Interleukin which promote the growth of both B and T cells.
IV. General Principles Regarding Immunosuppression[S5]
a. Primary immune response is more easily suppressed than secondary (once memory has been established
therapy will only have modest effects).
b. Immunosuppressants have different effects on different immune reactions so the dose required to inhibit the
immune response to one Ag may differ from another.
c. Suppression more likely if therapy begins before exposure to immunogen; however, most immune disorders are
treated after auto-immunity has been established.
V. Clinical Indications for Use of Immunosuppressive Therapy [S6]
a. Treatment of Organ Transplantation
i. Liver
ii. Heart
iii. Kidney
b. Treatment of autoimmune disorders
VI. 5 Classes of Immunosuppressive Agents [S7]
a. T-cell blockers
b. Glucocorticoids
c. Cytotoxic Drugs
d. Antibody Reagents
e. Cytokine Inhibitors
VII. T-cell blockers Cyclosporine and Tacrolimus [S8]
a. Cyclosporine & Tacrolimus
b. Chemistry
i. Cyclic polypeptide derived from a fungus.
c. Mechanism of Action
i. Inhibits lymphocytic proliferation by binding to cyclophilin.
ii. Cyclosporine-cyclophilin complex inhibits calcineurin.
d. Tacrolimus Chemistry
i. Tacrolimus also inhibits calcineurin, but it is a macrolide antibiotic.
e. Mechanism of Action
i. Binds to FK506 binding protein.
ii. Tacrolimus-FK506 complex inhibits calcineurin.
VIII. Cyclosporine and Tacrolimus [S9]
a. When calcineurin is inhibited, then you have prevention of dephosphorylation of nuclear factor of activated Tcells. You also have inhibition of T-cell receptor-activated induction of IL-2.
b. Calcineurin inhibits the IL-2 induction by cyclosporine (CsA) binding to the cyclophilin (CpN) and FK506 binding
to a binding protein. That inhibits calcineurin and calcineurin is just a step in the pathway that inhibits the
induction of IL-2 and others like 3 and 4 and TNF- gene.
FUN2: 11:00-12:00
Scribe: Ryan O’Neill
Friday, December 5, 2008
Proof: Caitlin Cox
Dr. King
Immunopharmacological Agents
Page 2 of 5
IX. Cyclosporine [S10]
a. Dosage Forms
i. Intravenously
ii. Orally (2 formulations)
1. Soft gelatin capsules
2. Microemulsion formulation - higher F (bioavailability) and Cmax (max concentration after dose).
iii. Available as eye drops: The drug Restasis is cyclosporine and it restores tear production.
b. Toxicity
i. Oral and IV forms are cause nephrotoxicity and can cause hypertension.
c. Pharmacology
i. Extensive metabolism in gut and liver (CYP 450 3A4).
ii. Excreted in the bile.
iii. Significant drug interactions, we common measure drug concentrations in transplant patients.
d. Therapeutic Uses
i. Kidney, heart, liver transplant
ii. Rheumatoid Arthritis
iii. Psoriasis
iv. And dry eyes if you are using the Restasis form.
X. Tacrolimus (Prograf, FK506) [S11]
a. Dosage Forms
i. Intravenously
ii. Orally
iii. 10-100x more potent than cyclosporine in its ability to inhibit IL-2.
b. Toxicity
i. Nephrotoxicity
ii. Neurotoxicity
iii. Hypertension
iv. Hyperglycemia
c. Pharmacology
i. Metabolized by liver CYP 450 3A4 (so we have to measure drug concentration).
d. Therapeutic Uses
i. Used predominantly in transplant patients.
ii. Hepatic Transplantation
iii. Kidney Transplantation
iv. Therapeutic Drug Monitoring
1. Drugs that have a narrow therapeutic index where the concentrations that are required to be
effective are close to the concentrations that cause toxicity, those are the ones that we measure and
monitor.
XI. T-cell blockers Sirolimus (Rapamune) [S12]
a. Chemistry
i. Antifungal agent formerly known as rapamycin.
b. Mechanism of Action
i. Similar to the other two agents (CSA and FK506), but not a calcineurin inhibitor.
ii. Inhibits intracellular signal pathway from the IL-2 receptor to DNA synthesis.
iii. Less effective inhibitor of cytokine synthesis than CSA, but just as potent at preventing the proliferation of
T-cells and B-cells.
c. Pharmacology
i. CYP 450 mediated metabolism.
d. Therapeutic Uses
i. Indicated for acute renal rejection in combination with cyclosporine and steroids.
e. Toxicities
i. Leukopenia, thrombocytopenia
ii. Hypertriglyceridemia
iii. Less renal toxicity compared to CSA and Tacrolimus, possibly due to lack of calcineurin inhibition.
XII. Corticosteroids [S13] Just a brief review, will see it again later
a. Mechanism of Action
i. Reduces circulation of lymphocytes
ii. Inhibits antibody formation and binding to target cells
iii. Anti-inflammatory properties
FUN2: 11:00-12:00
Scribe: Ryan O’Neill
Friday, December 5, 2008
Proof: Caitlin Cox
Dr. King
Immunopharmacological Agents
Page 3 of 5
iv. Prevents B and T-cell proliferation
b. Pharmacology
i. Rapidly removed from blood and distributed to muscles, liver, skin and intestines.
ii. Prednisolone is the biologically active preparation, but is converted in the body to other forms.
iii. Short half-life, but its capacity to inhibit lymphokine production persists for 24 hours.
c. Therapeutic Uses
i. Combination therapy with other immunosuppressive agents
d. Toxicities
i. Increase of incidence of infections
ii. Impaired growth, bone disease, diabetes and obesity
iii. Taper dose to prevent acute adrenal insufficiency
XIII. Cytotoxic Drugs - Azathioprine (Imuran) [S14]
a. Mechanism of action
i. Pro-drug metabolized to 6-mercaptopurine (6-MP) which antagonizes purine metabolism thus preventing
DNA synthesis and T-cell proliferation.
b. Pharmacology
i. Half-life is short, in minutes, but pharmacodynamic impact on inhibition of purine synthesis persists for
days.
ii. Dose is decreased in hepatic dysfunction because you have reduced conversion to the active 6-MP.
iii. Accumulation of metabolites in renal insufficiency causing pancytopenia (decrease dose).
c. Drug Interactions
i. If azathioprine is given with allopurinol (an agent used for gout) it inhibits xanthine oxidase.
1. XO inactivates 6-MP → Increased 6-MP levels and pancytopenia
d. Therapeutic Uses
i. Renal Transplantation--effective for prevention of acute rejection (not treatment).
ii. Rheumatoid Arthritis
e. Toxicities
i. Bone marrow suppression, neoplasia, irreversible liver damage
XIV.
Cytotoxic Drugs Mycophenylate Mofetil (CellCept) [S15]
a. Mechanism of Action
i. Prodrug of mycophenolic acid (MPA)
ii. Inhibits inosine monophosphate dehydrogenase → depletes endogenous purine nucleotide pools, which
leads to inhibition of de novo purine biosynthesis.
iii. Slows T and B cell growth.
b. Pharmacology
i. Hydrolyzed by the liver after GI absorption. It is hydrolyzed to MPA, which undergoes glucuronidation.
ii. Goes back through the liver known as enterohepatic circulation, which converts inactive metabolite back to
active MPA.
c. Therapeutic Uses
i. Renal and cardiac transplantation (with steroids and cyclosporine)
d. Drug Interactions
i. Tacrolimus
ii. Antacids
iii. Ganciclovir
e. Toxicities
i. Gastrointestinal, hematologic and increased risk of infections
XV. Cytotoxic Drugs - Cyclophosphamide (Cytoxan) [S16]
a. Mechanism of action
i. Nitrogen mustard derivative
ii. Interferes with DNA replication and transcription of RNA.
b. Therapeutic Uses
i. Rejection following renal, liver, heart, and bone marrow transplants
ii. Possibly as effective as azathioprine for maintenance of renal transplants and better for liver transplants.
c. Toxicities
i. Bone marrow suppression
ii. Incidence of neoplasms, specifically bladder cancer, which is thought to be due to one of the metabolites –
acrolein.
XVI.
Antibody Reagents Immunoglobulins [S17]
a. Antibodies against human lymphocytes or their surface protein can have significant immunosuppressant action.
FUN2: 11:00-12:00
Scribe: Ryan O’Neill
Friday, December 5, 2008
Proof: Caitlin Cox
Dr. King
Immunopharmacological Agents
Page 4 of 5
b. Two types: Polyclonal and Monoclonal antibodies.
c. Polyclonal antibodies
i. Polyclonal antibodies are non-specific.
ii. Binds to protein on the surface of lymphocyte triggering the complement response and subsequently lysis
of the lymphocyte.
iii. Essentially targets all T-cells which results in a broad immunosuppression that can lead to infection, so
again, it is non-specific.
d. The two main agents that are polyclonal antibodies are Thymoglobulin and ATGAM.
e. Antilymphocyte immunoglobulin (Thymoglobulin)
i. Derived from rabbits
f. Antithymocyte immunoglobulin (ATGAM)
i. Derived from horses
XVII. Antibody Reagents Immunoglobulins [S18]
a. Polyclonal antibodies (cont.)
i. Pharmacology—must be administered IV.
1. Bind to circulating lymphocytes, bone marrow cells, and visceral tissues, but do not distribute into
lymphoid tissues (spleen, lymph nodes).
ii. Clinical Notes
1. Efficacy varies from batch to batch which creates a significant risk for allergic reaction, mainly this
occurs because the drugs are derived from animals.
2. Duration of therapy: 7 to 14 days
3. ASE: Fever, chills, N/V (nausea/vomiting), anaphylactic reaction (rare) and serum sickness
XVIII. Antibody Reagents Immunoglobulins [S19]
a. Monoclonal antibodies
i. Process by which large quantities of antibodies (targeted against a particular antigen-specific) can be
produced.
ii. OKT3 & Anti-CD25 monoclonal antibodies will be discussed
1. Basiliximab
2. Daclizumab
XIX.
Antibody Reagents Immunoglobulins [S20]
a. This picture helps explain how monoclonal antibodies are produced.
b. Top left hand corner: Mouse immunized by injecting antigen X, which stimulates antibodies against the antigen.
c. Antibody forming cells are isolated from the mouse's spleen.
d. Monoclonal antibodies produced by fusing single antibody-forming cells to tumor cells grown in culture which
results in a hybridoma.
e. Each hybridoma produces large quantities of identical antibody molecules.
f. Once a monoclonal antibody is made, it can be used as a specific probe to track down and purify the specific
protein.
XX. Antibody Reagents Murine Monoclonal Antibody (Orthoclone, OKT3) [S21]
a. 3 types that we are going to discuss. The first is OKT3.
b. Mechanism of action
i. Is a murine (mouse IgG2a immunoglobulin) binds to the CD3 antigen of human T cells.
ii. Reverses graft rejection most probably by blocking the function of all T cells which play a major role in
acute rejection.
c. Pharmacology
i. IV administration
d. Toxicities
i. Cytokine-release syndrome (higher frequency after first and second doses).
ii. Flu-like symptoms
iii. CNS symptoms
iv. Acute reversible renal dysfunction
e. Therapeutic Uses
i. The steroid methylprednisolone is given 1- 4 hours prior to the first dose to decrease the incidence and
severity of reaction.
XXI.
Antibody Reagents Daclizumab (Zenapax) [S22]
a. Mechanism of Action
i. It is a monoclonal antibody-recombinant DNA technology that contains 90% human and 10% murine
antibody sequences.
ii. Binds to the  -subunit of the IL-2 receptor expressed only on the surface of activated lymphocytes
FUN2: 11:00-12:00
Scribe: Ryan O’Neill
Friday, December 5, 2008
Proof: Caitlin Cox
Dr. King
Immunopharmacological Agents
Page 5 of 5
iii. Thus, it is an IL-2 receptor antagonist that inhibits IL-2 binding, which is important for the activation of T
cells in the acute rejection process.
b. Pharmacology
i. IV administration only; has fairly long half-life.
ii. The pharmacodynamic effect is long; it lasts for 120 days.
c. Therapeutic Uses
i. Indicated for the prophylaxis to prevent the transplant rejections in combination with other drugs.
d. Has a few side effects listed.
XXII. Antibody Reagents Basiliximab (Simulect) [S23]
a. Mechanism of Action
i. Same mechanism of action. It also contains human and murine (produced by human and murine
antibodies).
b. Pharmacology
i. Intravenous administration
ii. Shorter half-life, but is still relatively long.
c. Therapeutic Uses
i. Indicated for prophylaxis.
d. Toxicities
i. Minor toxicities of hypersensitivity reactions.
XXIII. Cytokine Inhibition [S24]
a. Specifically talk about TNF-α and IL inhibitor.
b. For the sake of time, read the slide. (This is what she said.)
XXIV. Cytokine Inhibitor Etanercept (Enbrel) [S25]
a. Mechanism of Action
i. Binds to tumor necrosis factor alpha (TNF) and TNF.
ii. Prevents TNF from binding with its receptors thus preventing all of the other activities.
b. Pharmacology
i. Subcutaneous injection twice weekly.
c. Therapeutic Uses
i. Rheumatoid Arthritis, Crohn’s Disease
d. Has a few toxicities listed.
XXV. Cytokine Inhibitor Infliximab (Remicade) [S26]
a. Mechanism of Action
i. Binds to TNF
ii. Read the rest of the slide on your own.
XXVI. General Principles Regarding Immunostimulation [S27]
a. Most of these drugs are used for:
i. AIDS
ii. Chronic infectious diseases
iii. Cancers
XXVII. Intravenous Immune Globulins [S28]
a. You would think an increase in the immune system would have benefits.
b. IV IGs are pooled plasma from donors.
c. IM or IV administration; very long half-life.
d. Specific preparations also available
i. Hepatitis B, botulism, diptheria, tetanus, rabies
e. Allergic reactions: anaphylaxis (biggest side effect)
XXVIII. Cytokines as Immunostimulants [S29]
a. Interferon (alpha, beta and gamma)
i. γ-1b prevention of infections in chronic granulomatous disease
ii. α
iii. β
b. Interleukin-2
i. Stimulates T-helper and T cytotoxic cells
ii. Metastatic melanoma and renal cell carcinoma
[end 17 min]