Immunopharmacology Introduction

Introduction to Immunopharmacology

• The immune system plays a crucial role in protecting the body against harmful foreign molecules.
• However, in some cases, this protection can result in serious problems, such as rejection of transplanted organs or tissues.
• Immunosuppressive drugs are used to prevent or treat graft rejection.

The Immune Activation Cascade

• The immune activation cascade is a three-signal model:
  1. Signal 1: T-cell triggering at the CD3 receptor complex by an antigen on the surface of an antigen-presenting cell (APC).
  2. Signal 2: Engagement of CD80 and CD86 on APCs with CD28 on T cells.
  3. Signal 3: IL-2 binds to CD25 on the surface of other T cells to activate mTOR, stimulating T-cell proliferation.

Classification of Immunosuppressive Drugs

• Immunosuppressive drugs can be categorized according to their mechanisms of action:
  1. Interference with cytokine production or action
  2. Disruption of cell metabolism, preventing lymphocyte proliferation
  3. Blockade of T-cell surface molecules

Selective Inhibitors of Cytokine Production and Function

• Examples include cyclosporine, everolimus, sirolimus, and tacrolimus.
• These drugs target specific cytokines, such as IL-2, to dampen the immune response.

Cyclosporine

• Mechanism of action: binds to cyclophilin, forming a complex that inhibits calcineurin, preventing the production of cytokines such as IL-2.
• Used to prevent rejection of kidney, liver, and cardiac allogeneic transplants.
• Adverse effects: nephrotoxicity, hypertension, hyperlipidemia, hyperkalemia, tremor, hirsutism, glucose intolerance, and gum hyperplasia.

Tacrolimus (FK506)

• Mechanism of action: similar to cyclosporine, but binds to a different immunophilin, FKBP-12.
• Used to prevent rejection of liver and kidney transplants.
• Adverse effects: nephrotoxicity, neurotoxicity, hyperlipidemia, hypertension, and diabetes mellitus.

Sirolimus

• Mechanism of action: binds to mTOR, interfering with Signal 3, and blocking the progression of activated T cells from the G1 to the S phase of the cell cycle.
• Used in renal transplantation, and in combination with cyclosporine and corticosteroids.
• Adverse effects: hyperlipidemia, impaired or delayed wound healing, and enhanced nephrotoxicity in combination with higher doses of cyclosporine.

Everolimus

• Mechanism of action: same as sirolimus, inhibiting mTOR and blocking T-cell proliferation.
• Used in renal transplantation, and in combination with low-dose cyclosporine and corticosteroids.
• Adverse effects: similar to sirolimus, including hyperlipidemia, impaired or delayed wound healing, and enhanced nephrotoxicity.

Immunosuppressive Antimetabolites

• Examples include azathioprine, mycophenolate mofetil, and mycophenolate sodium.
• These drugs are used in combination with corticosteroids and calcineurin inhibitors to prevent rejection of transplanted organs.

Azathioprine

• Mechanism of action: converted to 6-mercaptopurine, which inhibits the synthesis of inosine monophosphate, a key component of nucleic acid synthesis.
• Used to prevent rejection of transplanted organs.
• Adverse effects: bone marrow suppression, nausea, and vomiting.

Mycophenolate Mofetil

• Mechanism of action: inhibits the synthesis of guanosine monophosphate, blocking the proliferation of T and B cells.
• Used in combination with corticosteroids and calcineurin inhibitors to prevent rejection of transplanted organs.
• Adverse effects: diarrhea, nausea, vomiting, abdominal pain, leukopenia, and anemia.

Antibodies

• Examples include antithymocyte globulins, muromonab-CD3, daclizumab, and basiliximab.
• These drugs are used to prevent or treat rejection of transplanted organs.

Antithymocyte Globulins

• Mechanism of action: binds to the surface of circulating T lymphocytes, leading to their destruction and lymphopenia.
• Used to prevent or treat rejection of transplanted organs.
• Adverse effects: chills, fever, leukopenia, thrombocytopenia, infections, and skin rashes.

Corticosteroids

• Mechanism of action: inhibits the synthesis of prostaglandins, leukotrienes, cytokines, and other signaling molecules that participate in immune responses.
• Used to suppress immunologic reactions in patients who undergo organ transplantation.
• Adverse effects: adrenal suppression, growth inhibition, osteoporosis, salt retention, glucose intolerance, and behavioral changes.

Immunomodulating Agents

• Examples include aldesleukin, which is recombinant interleukin-2 (IL-2).
• These drugs are used to stimulate immune responses, and have the potential to treat immune deficiency diseases, chronic infectious diseases, and cancer.

Mechanisms of Drug Allergy

• Immunologic reactions to drugs can fall into any of the 4 categories of hypersensitivity reactions: Type I (Immediate), Type II, Type III, and Type IV.### Type I (Immediate) Sensitivity Allergy

• Occurs when a drug covalently links to a host carrier protein (hapten)

• The immune system detects the drug-hapten conjugate and initiates B-cell proliferation and formation of IgE antibodies

• Fixation of IgE antibodies to high-affinity Fc receptors (FcRs) on blood basophils or mast cells sets the stage for an acute allergic reaction

• Examples of drugs that commonly cause type I reactions include penicillins and sulfonamides

Autoimmune (Type II) Reactions to Drugs

• Certain autoimmune syndromes can be induced by drugs
• Examples of autoimmune syndromes include hemolytic anemia from methyldopa, systemic lupus erythematosus from hydralazine, thrombocytopenic purpura from quinidine, and agranulocytosis from exposure to many drugs such as clozapine
• In these drug-induced autoimmune states, IgG antibodies bind to drug-modified tissue and are destroyed by the complement system or by phagocytic cells with Fc receptors
• Autoimmune reactions to drugs usually subside within several months after the offending drug is withdrawn

Type III Drug Allergy

• Immunologic reactions to drugs resulting in serum sickness
• Clinical features include urticarial and erythematous skin eruptions, arthralgia or arthritis, lymphadenopathy, glomerulonephritis, peripheral edema, and fever
• Reactions generally last 6–12 days and usually subside once the offending drug is eliminated
• Antibodies of the IgM or IgG class are usually involved
• Mechanism of tissue injury involves immune complex formation and deposition on basement membranes, followed by complement activation and infiltration of leukocytes, causing tissue destruction
• Examples of type III reactions include drug-induced serum sickness and vasculitis, and Stevens-Johnson syndrome

Type IV Drug Allergy

• Type IV hypersensitivity is often called delayed type hypersensitivity
• Reaction takes two to three days to develop
• Unlike the other types, it is not antibody-mediated but rather is a type of cell-mediated response
• Occurs from topical application of drugs
• Results in contact dermatitis