Immunomodulators

Immunomodulators include both immunosuppressants as well as immunostimulants.
The important group of immunosuppressants are glucocorticoids, calcineurin inhibitors, antiproliferative and antimetabolic agents and antibodies.
Among the group of immunostimulants, the main drugs are Levamisole, thalidomide, BCG vaccine, recombinant cytokines, interferons & interleukin-2.
Clinical role of Immunosuppressants
Glucocorticoids:
1. To prevent and treat transplant rejection
2. autoimmune disorders like rheumatoid and other arthritides, systemic lupus erythematosus, systemic dermatomyositis, psoriasis and other skin conditions
3. Treatment of graft-versus-host disease in bone-marrow transplantation. asthma and other allergic disorders
4. inflammatory bowel disease,
5. inflammatory ophthalmic diseases
6. autoimmune hematologic disorders
7. acute exacerbations of multiple sclerosis
Calcineurin inhibitors
Cyclosporine suppresses some humoral immunity, but is more effective against T-cell-dependent immune mechanisms such as those underlying transplant rejection and some forms of autoimmunity
Therapeutic uses:
1. kidney, liver, heart, and other organ transplantation
2. Rheumatoid arthritis
3. Psoriasis
4. Behcet’s acute ocular syndrome
5. endogenous uveitis,
6. atopic dermatitis,
7. inflammatory bowel disease, and
8. Nephrotic syndrome, when standard therapies have failed
Antiproliferative agents
Sirolimus is an antiproliferative agent.
Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus
Sirolimus inhibits T-lymphocyte activation and proliferation downstream of the IL-2 and other T-cell growth factor receptors
Sirolimus is indicated for prophylaxis of organ transplant rejection in combination with a calcineurin inhibitor and glucocorticoids
Azathioprine is a purine antimetabolites
Azathioprine was first introduced as an immunosuppressive agent in 1961, helping to make allogeneic kidney transplantation possible
Severe rheumatoid arthritis
Other antiproliferative & cytotoxic agents
Many of the cytotoxic and antimetabolic agents used in cancer chemotherapy are immunosuppressive due to their action on lymphocytes and other cells of the immune system. Other cytotoxic drugs that have been used as immunosuppressive agents include methotrexate, cyclophosphamide thalidomide, and chlorambucil
Methotrexate is used for treatment of graft-versus-host disease, rheumatoid arthritis, and psoriasis, as well as in anticancer therapy
Cyclophosphamide and chlorambucil are used in treating childhood nephrotic syndrome and a variety of malignancies

Antibody
Both polyclonal and monoclonal antibodies against lymphocyte cell-surface antigens are widely used for prevention and treatment of organ transplant rejection
The advent of hybridoma technology to produce monoclonal antibodies was a major advance in immunology
Both polyclonal and monoclonal products have a place in immunosuppressive therapy.
The important antibodies which are used in immunosuppression are
Antithymocyte Globulin: used for treatment of acute renal transplant rejection
Anti-CD3 Monoclonal Antibodies: (Muromonab-CD3) is indicated for treatment of acute organ transplant rejection
Anti-TNF Reagents.
Infliximab Infliximab is a chimeric anti-TNF-? monoclonal antibody used in rheumatoid arthritis

Immunostimulants:
Levamisole. Levamisole was synthesized originally as an anthelmintic but appears to “restore” depressed immune function of B lymphocytes, T lymphocytes, monocytes, and macrophages.
Its only clinical indication is as adjuvant therapy with 5-fluorouracil after surgical resection in patients with Dukes’ stage C colon cancer where it occasionally has been associated with fatal agranulocytosis

Thalidomide. Thalidomide is best known for the severe, life-threatening birth defects it caused when administered to pregnant women
Thalidomide should never be taken by women who are pregnant or who could become pregnant while taking the drug.
Nevertheless, it is indicated for the treatment of patients with erythema nodosum leprosum and also is used in conditions such as multiple myeloma.
Its mechanism of action is unclear
Alternatively, it has been suggested that the drug affects angiogenesis
The anti-TNF-? effect has led to its evaluation as a treatment for severe, refractory rheumatoid arthritis

Bacillus Calmette-Guerin (BCG)
It is live attenuated vaccine for tuberculosis.
By unclear mechanisms, this preparation is active against tumors and is indicated for treatment and prophylaxis of carcinoma in situ of the urinary bladder
Interferons.Although interferons (alpha, beta, and gamma) initially were identified by their antiviral activity, these agents also have important immunomodulatory activities
Interleukin-2: Human recombinant interleukin-2 (aldesleukin) is indicated for the treatment of adults with metastatic renal cell carcinoma and melanoma
(Reference: Goodman & Gillman’s, The Pharmacological Basis of Therapeutics 11th edition)