Review -- Recall that the immune response is mediated by the presentation of some antigen or foreign protein (via antibodies and the formation of a major histocompatability complex, forming an antigen presenting cell) to T helper cells.  The Antigen-MHC complex will interact with a receptor on the T helper (or CD-4) cell activating a second messenger system mediated by the protein calcineurin.  Calcineurin will cause DNA mediated production of cytokines such as interleukins (IL), interferons (IFN), colony stimulating factors (CSF), and tumour necrosis factors (TNF), all of which have specific actions when they are released, including increased activity of T cells, killer cells, mast cells, eosinophils, and chemotaxis, and even decreased T cell activity (moderating effect).  Additionally, the presentation of the antigen will stimulate the differentiation of CD-4 cells into CD-8 cells which further differentiate to form cytotoxic or T-killer cells (which have cytotoxic activity on foreign cells) or B cells which further differentiate to form plasma cells.

Many drugs possess the ability to alter the immune response, either by increasing or decreasing the body's defense mechanism.

Immunosuppressants --
These drugs will decrease the body's normal immune response to a variety of stimuli.  This is the goal of therapy when treating conditions such as organ or graft rejection, autoimmune diseases, or Rh factor reactions in infants.

Two classes of immunosuppressants have already been covered or will be covered later in this course.

Glucocorticoids -- These drugs decrease T cell proliferation and suppress the immune response by inhibiting gene expression for cytokines and prostaglandins.

Antineoplastics such as azathioprine, cyclophosphamide, and methotrexate are used to decrease the formation of immune cells (B and T cells).  Their mechanism of action will be discussed in the anti-neoplastic section that follows.

Cyclosporin and Tacrolimus
Mechanism of Action -- These drugs bind to proteins within the CD-4 cell (cyclosporin to cyclophillin and tacrolimus to FK-binding protein or FKBP).  This complex will then bind to and inhibit the second messenger system mediated by calcineurin.  This inhibits the synthesis and release of cytokines and prevents the differentiation of the CD-4 cells to immune cells.

Adverse Effects --
Cyclosporin may cause nephrotoxicity and this is the primary concern.  It may also cause hypertension, hepatotoxicity, neurotoxicity, hirsutism, and gingival hyperplasia as well as GI upset.  Additionally, cyclosporin is metabolised by the cytochrome P₄₅₀ system and is therefore the target of numerous drug interactions.

Tacrolimus may also cause nephrotoxicity, neurotoxicity, hypertension, and GI upset.  In addition to these effects, it may cause metabolic disturbances including hyperkalæmia, hypomagnesæmia, and hyperglycæmia.
 

Therapeutic Uses -- These drugs are used to prevent rejection in kidney, heart, and liver transplant.  They may also be useful in bone marrow, lung, and pancreas transplants.

Mycophenolate mofetil
This drug is converted in vivo to the active form, mycophenolic acid.
Mechanism of Action -- Mycophenolic acid inhibits the enzyme inosine monophosphate dehydrogenase, which is necessary for the de novo synthesis of purines.  This is relevant for immunosuppression because T cells and B cells are among the very few cells of the body that cannot salvage purines from extracellular sources.  They must synthesise their own purine bases for DNA and RNA production and protein synthesis.  Therefore mycophenolate mofetil will decrease T and B lymphocytes, thereby decreasing antibody formation and lessening the immune response.  There may also be a decrease in chemotaxis in response to the drug.

Therapeutic Use -- Primarily used for kidney transplants

Antibody Therapy
Anti-thymocyte globulin (ATG)
Mechanism of Action -- ATG is an immunoglobulin the binds to and prevents the binding of the Ag-MHC to the CD-4 helper cell.  Prevention of binding will inhibit further immune reaction.

Adverse Effects -- Since ATG is a foreign protein itself, patients may exhibit an allergic reaction including serum sickness, nephritis, chills, fever, leukopænia, and rash.  Anaphylaxis is rare.

Therapeutic Uses -- ATG is only used for the treatment of acute allograft rejection of solid organs.

Muromonab-CD3
Muromonab is a monoclonal antibody derived from mice that is specific for the CD3 protein.
Mechanism of Action -- Muromonab binds to the CD-3 protein on T lymphocytes (antigen presenting cells).  When this binding takes place, the binding site for CD-4 helper cells is obscured, preventing binding of the Ag-MHC to the CD-4 helper cell.

Adverse Effects -- Patients may initially experience an activation of T cells and the release of cytokines, which may cause flu-like syndromes and even life-threatening shock.  This may be avoided by the administration of high-dose glucocorticoids 1-4 hr prior to administration of muromonab.

Therapeutic Uses -- Muromonab is used to prevent the rejection of graft.  It may also be used to deplete T cells prior to bone marrow transplant.

Trastuzumab
Trastuzumab is a monoclonal antibody that is specific for human epidermal growth factor (receptor 2).
Mechanism of Action -- Many breast cancers are dependent upon epidermal growth factors (EGF) to maintain cellular replication and subsequent metastasis.  Trastuzumab, as an antibody to the 2-type receptor for EGF prevents the binding of EGF to the, thus limiting the growth of metastatic cells.

Therapeutic Uses -- Trastuzumab is used in the treatment of metastatic breast cancer.
 

Infliximab
Infliximab is a monoclonal antibody specific for tumour necrosis factor (TNF).
Mechanism of Action -- Infliximab prevents the binding of TNF to its receptor, thus inhibiting TNF-mediated events.

Therapeutic Uses -- Since TNF has been implicated in the inflammatory associated processes involved in Crohn's disease, infliximab is used in the treatment of this disease.
 

Basiliximab
Basiliximab is also a newer monoclonal antibody that is used in the treatment of renal transplant rejection.  Mechanistically, it inhibits those immune components that are responsible for graft rejection.

Palivizumab
Palivizumab is a monoclonal antibody that has proven effective in the treatment of respiratory syncytial virus (RSV) presumably by blocking either the immune response to the virus or the actions of the virus uptake by host cells.

RhO (D) Immunoglobulin -- This immunoglobulin is specific for the D antigen of +/- blood types.

Mechanism of Action -- The Ig binds to and inhibits the D antigen from binding to lymphocytes, so that antibodies to the protein will not be formed.

Therapeutic Uses -- RhO Ig is used to treat Rh- mothers who are carrying Rh+ children to prevent the formation of RhO antibodies (development of antibodies will result in the second Rh+ child being exposed to the antibodies which results in hæmolytic disease of the newborn or erythroblastosis fœtalis).
 

Other Immunosuppressants
Methoxsalen -- This drug is used only in the treatment of resistant T cell lymphoma.  It is administered orally.  Following the dose, blood is drawn from the patient, exposed to UV light and returned to the patient.  Exposure to UV radiation activates the drug-DNA complex that has formed to decrease the number of malignant cells.  Re-introduction to the blood stream of the patient results in increased immune response to destroy other malignant T cells.

Thalidomide -- The exact immunosuppressant effect of this drug is not known, but it does cause a shift in T cell responses.  It is used primarily to suppress the immune responses associated with Hansen's disease, cutaneous lupus erythemotosus, and is being investigated for use in lung transplants.

Bacillus Calmette-Guérin -- This is a viable, attenuated Mycobacterium bovis preparation.  The active component is muramyl dipeptide.
Mechanism of Action -- BCG stimulates the activity of natural killer cells.
Adverse Effects -- Hypersensitivity
Therapeutic Use -- BCG is primarily used in the treatment of bladder cancer, to increase neoplastic cell death resulting from killer cell activity.

Immune Globulin Complex -- This is a complex of immunoglobulins that is collected from donors.
Mechanism of Action -- This complex simply serves as replacement therapy for those patients that are deficient in immune globulins (and therefore have a suppressed immune response).

Adverse Effects -- Hypersensitivity and increased risk of infectious diseases from contaminated donations.

Therapeutic Uses -- Ig deficiency, idiopathic thrombocytopænic purpura, autoimmune hæmolytic anæmia, measles, hepatitis, and to prevent infection with lymphocytic leukæmia.
 

Levamisole -- This is an anthelminthic that also exhibits immunostimulant properties.
Mechanism of Action -- The exact mechanism is not know, but levamisole increases the development of delayed hypersensitivity reactions, and increases T-cell mediated immunity.  It also activates macrophages.  It appears that levamisole restores immune function to its normal level but does not elevate it above that level.

Adverse Effects -- Agranulocytosis, GI upset (including taste perversion), rash, and fatigue

Therapeutic Uses -- Hodkin's Disease, as an adjunct in colorectal cancer, and rheumatoid arthritis (its mechanism is not know in this autoimmune disease).

Isoprinosine -- The mechanism of action of this investigational drug is not known.  It does, however, increase monocyte, T cell, and natural killer cell activity.

Cytokines
Interferon alpha -- This drug has already been covered in the previous section.
Mechanism of Action -- Its effects on the immune system include activation of macrophages, T lymphocytes, and natural killer cells.

Therapeutic Uses -- Hairy cell leukæmia, chronic myeloid leukæmia, and Kaposi's sarcoma

Interleukin 2 --
This cytokine increases the proliferation and differentiation of T helper cells and T killer cells.  It also increases the activity of B cells, macrophages, and natural killer cells.

Adverse Effects -- Hypotension (that may be life-threatening) and pulmonary œdema (secondary to capillary leak) are the two primary precautions. Other effects include nephrotoxicity, myelosuppression, CNS toxicity (delirium and somnolence), rash, and GI upset.

Therapeutic Uses -- Metastatic melanoma and renal cell carcinoma (often as an adjunct to natural killer cell administration).