IMMUNOMODULATORS are agents that modify the body’s immunological responses. Some agents specifically boost the body’s immune responses, and can be referred to as immunostimulants. Others have a more complex role, and are best referred to by the more general term of immunomodulators, and will be dealt with first.
Interferons are inducible polypeptide and glycoprotein (15,000-27,600 daltons) mediators synthesized by mammalian cells, but produced by recombinant technology for biomedical use. They have been used as ANTIVIRALS (e.g. including for hepatitis B and C), as ANTICANCER AGENTS (e.g. for AIDS-related Kaposi’s sarcoma) and also to treat chronic granulatomatous disease and Relapsing-Remitting Multiple Sclerosis. There are three or more types, alpha-, beta- and gamma-interferon: see interferon α, interferon β and interferon γ. They can modify the host response by inducing production of enzymes that inhibit translocation of viral mRNA into viral protein, and thus prevent virus reproduction. They can be administered as immunomodulators by intravenous or intramuscular injection in the treatment of AIDS, cancer and other chemotherapy.
Interleukins are similarly naturally synthesized by mammalian cells, mainly white cells, and are produced by recombinant technology for biomedical use. They have been used as adjuncts in anticancer chemotherapy and radiotherapy, for antiviral therapy, in treating burns and wounds, and for autoimmune diseases. They help in a variety of ways, including activating haemopoietic stem cells to promote proliferation for leukaemia treatment and activating stromal bone marrow cells to produce colony-stimulating factors also in the treatment of leukaemia. See interleukin-1, interleukin-2 (a lymphokine from T-cell lymphocytes with a number of variants; celmoleukin, c cytokine), interleukin-3 (multipotential colony-stimulating factor), interleukin-4, interleukin-5, interleukin-6 and interleukin-8. Anakinra is a recombinant human interleukin receptor antagonist active against IL-1, which was isolated from human monocytes and is now cloned, and can be used for inflammatory bowel disease.
Colony-stimulating factors (CSFs) are glycopeptide factors containing 100-224 amino acid residues and are endogenous factors produced by many cell types and act as immunomodulators that stimulate proliferation and differentiation of progenitor cells in the monocyte/macrophage white blood cell lineage in vitro. There are different forms that act as haemtopoietic agents and stimulate different cell lines. Granulocyte-macrophage-colony-stimulating factor (GM-CSF) is a (GM-CSF subtype) cytokine receptor agonist, and stimulates production of monocytes, neutrophil, eosinophils, erythrocytes and platelets. The granulocyte-colony-stimulating factor (G-CSF) is a (G-CSF subtype) cytokine receptor agonist, and stimulates neutrophil production. Biosynthetic forms are generally used therapeutically (see filgrastim).
Turning to immunostimulants, the therapeutic use of nonspecific immunostimulation originated in the last century in the use of mixed bacterial toxins (Coley toxins’) to treat cancer. A large number of types of microbially derived substances have received clinical approval since then (mainly in the USA). They have been tried in the treatment of bladder, gastric and other cancers. However, they are of variable purity and have been unreliable, with variable side-effects. The preparation of inactivated Corynebacterium parvum (Coparvax) formerly available in the UK, and used by the intracavitary route for malignant effusions, has now been discontinued. Adjuvant peptide (muramy! dipeptide) is identified as the minimum structural constituent of the mycobacterial cell wall component of Freund’s complete adjuvant, which is necessary for adjuvant activity. It and many of its analogues have been investigated as adjuvants in the immunization of animals, as immunostimulants (e.g. almurtide) Many microbially derived macrophage activators have been clinically licensed (only in some countries) and mainly for cancers. Some fungal products, glycans. enhance macrophage microbiocidal and antitumouricidal activity and induce release of IL-1, TNF and CSFs. A number of vaccines used in conventional therapy can be regarded as immunostimulants. These include agents such as BCG vaccine (bacillus Calmette-Guerin vaccine), antitubercular vaccine and a number of thymus-derived T-cell stimulant preparations (e.g. thymostimulin), which are thymic peptide extracts for treatment of cancer or infection. Other agents include levamisole hydrochloride and inosine pranobex (an inositol-salt complex, for infection). Some chemically defined structures in earlier stages of development include thymosin rxi (a peptide T-lymphocyte promoter proposed for cancer and hepatitis), bropirimine (an IFN inducer/natural killer and macrophage activator) and methyl inositol monophosphate (macrophage activator proposed for HIV/infection).