immunosuppressive agents

Normal immune responses

The immune system has evolved to protect the host from invading pathogens and to eliminate disease. When functioning at its best, the immune system is exquisitely responsive to invading pathogens while retaining the capacity to recognize self tissues and antigens to which it is tolerant. Protection from infection and disease is provided by the collaborative efforts of the innate and adaptive immune systems.
The Innate Immune System
The innate immune system is the first line of defense against invading pathogens (eg, bacteria, viruses, fungi, parasites) and consists of mechanical, biochemical, and cellular components. Mechanical components include skin/epidermis and mucus; biochemical components include antimicrobial peptides and proteins (eg, defensins), complement, enzymes (eg, lysozyme, acid hydrolases), interferons, acidic pH, and free radicals (eg, hydrogen peroxide, superoxide anions); cellular components include neutrophils, monocytes, macrophages, natural killer (NK), and natural killer-T (NKT) cells. Unlike adaptive immunity, the innate immune response exists prior to infection, is not enhanced by repeated infection, and is generally not antigen-specific.
The Adaptive Immune System
The adaptive immune system is mobilized by cues from the innate response when the innate processes are incapable of coping with an infection. The adaptive immune system has a number of characteristics that contribute to its success in eliminating pathogens. These include the ability to (1) respond to a variety of antigens, each in a specific manner; (2) discriminate between foreign (“non-self”) antigens (pathogens) and self antigens of the host; and (3) respond to a previously encountered antigen in a learned way by initiating a vigorous memory response. This adaptive response culminates in the production of antibodies, which are the effectors of humoral immunity; and the activation of T lymphocytes, which are the effectors of cell-mediated immunity.

ABNORMAL IMMUNE RESPONSES

Whereas the normally functioning immune response can successfully neutralize toxins, inactivate viruses, destroy transformed cells, and eliminate pathogens, inappropriate responses can lead to extensive tissue damage (hypersensitivity) or reactivity against self antigens (autoimmunity); conversely, impaired reactivity to appropriate targets (immunodeficiency) may occur and abrogate essential defense mechanisms.
Autoimmunity
Autoimmune disease arises when the body mounts an immune response against itself due to failure to distinguish self-tissues and cells from foreign (nonself) antigens or loss of tolerance to self. This phenomenon derives from the activation of selfreactive T and B lymphocytes that generate cell-mediated or humoral immune responses directed against self-antigens
IMMUNOSUPPRESSIVE THERAPY
Immunosuppressive agents have proved very useful in minimizing the occurrence or impact of deleterious effects of exaggerated or inappropriate immune responses. Unfortunately, these agents also have the potential to cause disease and to increase the risk of infection and malignancies

GLUCOCORTICOIDS

Glucocorticoids (corticosteroids) were the first hormonal agents recognized as having lympholytic properties. Administration of any glucocorticoid reduces the size and lymphoid content of the lymph nodes and spleen
Glucocorticoids are quite cytotoxic to certain subsets of T cells, but their immunologic effects are probably due to their ability to modify cellular functions rather than to direct cytotoxicity.
continuous administration of corticosteroid increases the fractional catabolic rate of IgG, the major class of antibody immunoglobulins, thus lowering the effective concentration of specific antibodies.
It is thought that the immunosuppressive and anti-inflammatory properties of corticosteroids account for their beneficial effects in diseases like idiopathic thrombocytopenic purpura and rheumatoid arthritis.
Glucocorticoids modulate allergic reactions and are useful in the treatment of diseases like asthma or as premedication for other agents (eg, blood products, chemotherapy) that might cause undesirable immune responses.
Glucocorticoids are first-line immunosuppressive therapy for both solid organ and hematopoietic stem cell transplant recipients
Calcineurin Inhibitors
Cyclosporine
Mechanism of action
Cyclosporine is a peptide antibiotic that appears to act at an early stage in the antigen receptor induced differentiation of T cells and blocks their activation. Cyclosporine binds to cyclophilin, a member of a class of intracellular proteins called immunophilins. Cyclosporine and cyclophilin form a complex that inhibits the cytoplasmic phosphatase, calcineurin, which is necessary for the activation of a T-cell-specific transcription factor. This transcription factor, NF-AT, is involved in the synthesis of interleukins (eg, IL-2) by activated T cells.
Pharmacokinetics
Cyclosporine may be given intravenously or orally, though it is slowly and incompletely absorbed (20–50%).
The absorbed drug is primarily metabolized by the P450 3A enzyme system in the liver with resultant multiple drug interactions. So cyclosporine requires individual patient dosage adjustments based on steady-state blood levels and the desired therapeutic ranges for the drug.
Cyclosporine ophthalmic solution is now available for severe dry eye syndrome, as well as ocular GVH disease.
Inhaled cyclosporine is being investigated for use in lung transplantation.


Uses
Cyclosporine may be used alone or in combination with other immunosuppressants, particularly glucocorticoids.
It has been used successfully as the sole immunosuppressant for cadaveric transplantation of the kidney, pancreas, and liver, and it has proved extremely useful in cardiac transplantation as well.
In combination with methotrexate, cyclosporine is a standard prophylactic regimen to prevent GVH disease after allogeneic stem cell transplantation.
Cyclosporine has also proved useful in a variety of autoimmune disorders, including uveitis, rheumatoid arthritis, psoriasis, and asthma
Toxicities
Nephrotoxicity, hypertension, hyperglycemia, liver dysfunction, hyperkalemia, altered mental status, seizures, and hirsutism.
Cyclosporine causes very little bone marrow toxicity.
Tacrolimus
Mechanism of action:
TAC exerts its immunosuppressive effect in the same manner as CsA, except that it binds to a different immunophilin, FKBP-12
Uses, pharmacokinetics and adverse effect
Tacrolimus is utilized for the same indications as cyclosporine, particularly in organ and stem cell transplantation.
On a weight basis, tacrolimus is 10–100 times more potent than cyclosporine in inhibiting immune responses.
Tacrolimus has proven to be effective therapy for preventing rejection in solid-organ transplant patients even after failure of standard rejection therapy, including anti-T-cell antibodies.
Tacrolimus can be administered orally or intravenously.
The half-life of the intravenous form is approximately 9–12 hours.
Like cyclosporine, tacrolimus is metabolized primarily by P450 enzymes in the liver, and there is potential for drug interactions
. Its toxic effects are similar to those of cyclosporine and include nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkalemia, and gastrointestinal complaints.
Because of the effectiveness of systemic tacrolimus in some dermatologic diseases, a topical preparation is now available.
Tacrolimus ointment is currently used in the therapy of atopic dermatitis and psoriasis.
PROLIFERATION SIGNAL INHIBITORS
A new class of immunosuppressive agents called proliferation-signal inhibitors (PSIs) includes sirolimus (rapamycin) and its derivative everolimus. The mechanism of action of PSIs differs from that of the calcineurin inhibitors. PSIs bind to mTOR (a serine/threonine kinase), interfering with signal 3. Binding of sirolimus to mTOR blocks the progression of activated T cells from the G1 to the S phase of the cell cycle and, consequently, the proliferation of these cells
Sirolimus is available only as an oral drug. Its half-life is about 60 hours, while that of everolimus is about 43 hours.
Both drugs are rapidly absorbed and elimination is similar to that of cyclosporine and tacrolimus, being substrates for both cytochrome P450 3A and P-glycoprotein. Hence, significant drug interactions can occur. For example, use with cyclosporine can increase the plasma levels of both sirolimus and everolimus such that drug levels need to be monitored.
Uses
Sirolimus has been used effectively alone and in combination with other immunosuppressants (corticosteroids, cyclosporine, tacrolimus, and mycophenolate mofetil) to prevent rejection of solid organ allografts.
It is used as prophylaxis and as therapy for steroid-refractory acute and chronic GVH disease in hematopoietic stem cell transplant recipients.
Topical sirolimus is also used in some dermatologic disorders and, in combination with cyclosporine, in the management of uveoretinitis.
Recently, sirolimus-eluting coronary stents have been shown to reduce restenosis


Toxicities
myelosuppression (especially thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and headache. Because nephrotoxicity is of major concern when administering calcineurin inhibitors, and since renal toxicity is less common with PSIs, there is interest in increased early use of the latter agents.
Mycophenolate Mofetil
Mycophenolate mofetil (MMF) is a potent, reversible, noncompetitive inhibitor of inosine monophosphate dehydrogenase, which blocks the de novo formation of guanosine phosphate. Thus, like 6-MP, it deprives the rapidly proliferating T and B cells of a key component of nucleic acids
Mycophenolate mofetil is available in both oral and intravenous forms. The oral form is rapidly metabolized to mycophenolic acid.
Mycophenolate mofetil is used in solid organ transplant patients for refractory rejection and, in combination with prednisone, as an alternative to cyclosporine or tacrolimus in patients who do not tolerate those drugs.
Its antiproliferative properties make it the first-line drug for preventing or reducing chronic allograft vasculopathy in cardiac transplant recipients.
Newer immunosuppressant applications for MMF include lupus nephritis, rheumatoid arthritis, inflammatory bowel disease, and some dermatologic disorders.
Toxicities include gastrointestinal disturbances (nausea and vomiting, diarrhea, abdominal pain) headache, hypertension, and reversible myelosuppression (primarily neutropenia).

Cytotoxic Agents

Azathioprine
Azathioprine was the first agent to achieve widespread use in organ transplantation. It is a prodrug that is converted first to 6-mercaptopurine (6-MP) and then to the corresponding nucleotide, thioinosinic acid. The immunosuppressive effects of azathioprine are due to this nucleotide analog. Because of their rapid proliferation in the immune response and their dependence on the de novo synthesis of purines required for cell division, lymphocytes are predominantly affected by the cytotoxic effects of azathioprine.
Uses
Azathioprine and mercaptopurine appear to be of definite benefit in maintaining renal allografts
in the management of acute glomerulonephritis, in the renal component of systemic lupus erythematosus, and in some cases of rheumatoid arthritis, Crohn’s disease, and multiple sclerosis.
The drugs have been of occasional use in prednisone-resistant antibody-mediated idiopathic thrombocytopenic purpura and autoimmune hemolytic anemias
Adverse effect
The chief toxic effect of azathioprine and mercaptopurine is bone marrow suppression, usually manifested as leukopenia, although anemia and thrombocytopenia may occur. Skin rashes, fever, nausea and vomiting, and sometimes diarrhea occur
ANTIBODIES
The use of antibodies plays a central role in prolonging allograft survival. They are prepared by immunization of either rabbits or horses with human lymphoid cells (producing a mixture of polyclonal antibodies or monoclonal antibodies) or by hybridoma technology (producing antigen-specific monoclonal antibodies). Hybridomas are produced by fusing mouse antibody-producing cells with tumor cells. Hybrid cells are selected and cloned, and then antibody specificity of the clones is determined. Clones of interest can be cultured in large quantities to produce clinically useful amounts of the desired antibody.
A. Antithymocyte globulins
Antithymocyte globulins are polyclonal antibodies that are primarily used at the time of transplantation to prevent early allograft rejection along with other immunosuppressive agents. They may also be used to treat severe rejection episodes or corticosteroid-resistant acute rejection. The antibodies bind to the surface of circulating T lymphocytes, which then undergo various reactions, such as complement mediated destruction, antibody-dependent cytotoxicity, apoptosis, and opsonization. The antibody-bound cells are phagocytosed in the liver and spleen, resulting in lymphopenia and impaired T-cell responses. The antibodies are slowly infused intravenously, and their half-life extends from 3 to 9 days.
Because the humoral antibody mechanism remains active, antibodies can be formed against these foreign proteins.
Other adverse effects include chills and fever, leukopenia and thrombocytopenia, infections due to CMV or other viruses, and skin rashes.
B. Muromonab-CD3
Muromonab-CD3 is a murine (mouse) monoclonal antibody that is directed against the glycoprotein CD3 antigen of human T cells. Muromonab-CD3 was the first monoclonal antibody approved for clinical use in 1986, indicated for the treatment of corticosteroid-resistant acute rejection of kidney, heart, and liver allografts. The drug has been discontinued from the market due to the availability of newer biologic drugs with similar efficacy and fewer side effects.
C. Basiliximab
The antigenicity and short serum half-life of the murine monoclonal antibody have been averted by replacing most of the murine amino acid sequences with human ones by genetic engineering. Basiliximab is said to be “chimerized” because it consists of 25% murine and 75% human protein.
Basiliximab is approved for prophylaxis of acute rejection in renal transplantation in combination with cyclosporine and corticosteroids.
Basiliximab is an anti-CD25 antibody that binds to the α chain of the IL-2 receptor on activated T cells and, thus, interferes with the proliferation of these cells.
It is given as an IV infusion. The serum half-life of basiliximab is about 7 days. Usually, two doses of this drug are administered—the first at 2 hours prior to transplantation and the second at 4 days after the surgery. The drug is generally well tolerated, with GI toxicity as the main adverse effect.