Overview of Immune Function
● Innate Immunity
○ Structural/Chemical barriers
○ Phagocytic/Scavenger Cells
○ Inflammation
○ Plasma protein systems (e.g. Complement system)
● Adaptive Immunity
○ B Lymphocytes (antibody mediated immunity)
○ T Lymphocytes (cell-mediated immunity)
● Pathogens
○ Viruses
○ Bacteria
○ Protozoans
○ Fungi
○ Parasitic worms
○ Prions
Immunosuppressants
● Inhibit immune response
● Uses:
○ Prevention of organ rejection
○ Treatment of autoimmune diseases
● Toxicity
○ Increased risk of infection
○ Increased risk of neoplasms
Calcineurin Inhibitors
● Principal use: prevention of organ rejection in transplant recipients
● Most effective immunosuppressants available: Cyclosporine, tacrolimus, pimecrolimus
● Differ in structure, but share the same mechanism
○ Inhibition of calcineurin suppresses production of interleukin (IL-2)
○ IL-2 needed for T-cell proliferation
● Cyclosporine was developed first and is used more than tacrolimus
Cyclosporine [Sandimmune]
● Mechanism
○ Suppresses the production of IL-2, interferon gamma, and other cytokines
● Therapeutic uses:
○ Drug of choice for organ rejection (kidney, liver, and heart) of an allogenic
transplant
○ Some autoimmune diseases
● Pharmacokinetics
● Adverse effects:
○ Nephrotoxicity
○ Infection
○ Hepatotoxicity
○ Lymphoma
○ Hypertension
○ Tremor
○ Hirsutism
○ Leukopenia, gingival hyperplasia, gynecomastia, sinusitis, hyperkalemia
○ Anaphylactic reactions
● Drug and food interactions:
○ Drugs that can decrease cyclosporine levels (CYP3A4 inducers: phenytoin,
Phenobarbital, carbamazepine, rifampin, etc.)
○ Drugs that can increase cyclosporine levels (CYP3A4 inhibitors: azole
antifungals, macrolide antibiotics, amphotericin B)
○ Nephrotoxic drugs
○ Grapefruit juice
○ Repaglinide (cyclosporine increases levels of this anti-diabetic drug)
Neoral or Gengraf
● Rheumatoid arthritis
● Psoriasis
Tacrolimus [Prograf]
● An alternative to cyclosporine
● Somewhat more effective, but also more toxic
● Narrow therapeutic index
● Concurrent use with glucocorticoids
● Therapeutic use:
○ Prophylaxis of organ rejection (liver, kidney, or heart)
● Mechanism of action very similar to cyclosporine
● Adverse effects:
○ Nephrotoxicity is the major concern
○ Neurotoxicity
○ GI effects
○ Hypertension
○ Hyperkalemia
○ Hyperglycemia
○ Hirsutism
○ Gum hyperplasia
○ Anaphylaxis with IV administration
● Drug and food interactions:
○ Agents that inhibit CYP3A (isozyme of cytochrome P450)
○ Grapefruit juice
○ Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided (both are
nephrotoxic)
mTOR Inhibitors
● Enzyme known as mammalian target of rapamycin (mTOR)
○ Protein kinase that helps regulate cell growth, proliferation, and survival
○ Suppresses B and T cell proliferation
● Structurally similar to tacrolimus
● Somewhat different mechanism
● Does not involve inhibition of calcineurin
Sirolimus [Rapamune]
● mTOR inhibitor
● Actions and therapeutic use:
○ Only for prevention of renal transplant rejection
○ Used in conjunction with cyclosporine and glucocorticoids
● Adverse effects:
○ Increased risk of infection
○ Raises levels of cholesterol and triglycerides
○ Risk of renal injury
○ Severe complications in the liver and lung transplant recipients
○ Rash, acne, anemia, thrombocytopenia, joint pain, diarrhea, hypokalemia
● Drug and food interactions:
○ Drugs that inhibit or induce CYP3A4
○ High-fat foods (can increase absorption by 35%)
○ Grapefruit juice (inhibits metabolism)
Everolimus [Zortress]
● mTOR inhibitor
● Therapeutic use (prevent organ rejection in patients age 18 and older following liver or
kidney transplant)
● Adverse effects:
○ Peripheral edema
○ Constipation
○ Hypertension
○ Nausea
○ Anemia
○ Urinary tract infection
○ Hyperlipidemia
● Effects in pregnancy and lactation (animals studies show teratogenicity, enters breastmilk)
● Drug and food interactions:
○ Drugs that inhibit or induce CYP3A4
○ High-fat foods
○ Grapefruit juice
Glucocorticoids
● Used to widely suppress immune response
○ Suppression of allograft rejection, treatment of asthma, rheumatoid arthritis,
systemic lupus erythematosus (SLE), and multiple sclerosis
● Large doses used to prevent rejection
○ Increased risk of infection, thinning of skin, bone dissolution with fracture,
impaired growth in children, and suppression of hypothalamic-pituitary-adrenal
axis
Cytotoxic Drugs
● Suppress immune response by killing B and T lymphocytes undergoing proliferation
● Nonspecific: Toxic to all proliferating cells
● Adverse effects:
○ Bone marrow suppression
■ Neutropenia
■ Thrombocytopenia
○ GI disturbances
○ Reduced fertility
○ Alopecia
Azathioprine [Imuran]
● Suppresses cell-mediated and humoral immune responses
● Therapeutic uses:
○ Adjuvant treatment with transplants
○ Autoimmune disorders
● Adverse effects:
○ Blood dyscrasias
○ Nausea and vomiting
○ Mutagenic and teratogenic
○ Neoplasms (with long term therapy)
○ Pancreatitis
Other Cytotoxic Drugs
● Cyclophosphamide
○ Anti-cancer drug
● Methotrexate [Rheumatrex, Trexall]
○ Rheumatoid arthritis
○ Psoriasis
○ Suppression of B and T lymphocytes by interfering with folate metabolism
● Mitoxantrone [Novantrone]
○ Anti-cancer agent
○ Reduction of neurologic disability and clinical relapse for multiple sclerosis (MS)
patients
○ Hazardous drug reserved for patients who are not responsive to safer drugs
● Mycophenolate mofetil
○ Approved for prophylaxis of organ rejection
○ Acts on B and T lymphocytes to inhibit inosine monophosphate dehydrogenase
○ Selective inhibition of B- and T-lymphocyte proliferation
Antibodies
● Basiliximab
○ Monoclonal antibodies
○ Blocks activation of T cells by IL-2
○ Prophylaxis of acute organ rejection after renal transplantation
○ Adverse effects:
■ Generally well tolerated, does not increase the risk of opportunistic
infections, and no cancers have been observed 1 year after treatment
● Lymphocyte immune globulin [Atgam], antithymocyte [equine]
○ Prepared by extraction from the serum of horses that have been inoculated with
human T lymphocytes
○ Therapeutic effects:
■ Decrease in the number and activity of thymus-derived lymphocytes
○ Uses:
■ Prevents rejection of renal transplants, treating aplastic anemia
○ Adverse effects:
■ Hypersensitivity, anaphylaxis