Immunopharmacology Introduction

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 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.

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

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

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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

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

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 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