Medical applications of interferony

The most notable medical application of IFN-y relates to the treatment of CGD, a rare genetic condition with a population incidence of between 1 in 250 00 and 1 in 1 000 000. Phagocytic cells of patients suffering from CGD are poorly capable/incapable of ingesting or destroying infectious agents such as bacteria or protozoa. As a result, patients suffer from repeated infections (Table 8.10), many of which can be life threatening.

Phagocytes from healthy individuals are normally capable of producing highly reactive oxida-tive substances, such as hydrogen peroxide and hypochlorous acid, which are lethal to pathogens. Production of these oxidative species occurs largely via a multicomponent NADPH oxidase system (Figure 8.8). CGD is caused by a genetic defect in any component of this oxidase system that compromises its effective functioning.

In addition to recurrent infection, CGD sufferers also exhibit abnormal inflammatory responses which include granuloma formation at various sites of the body (granuloma refers to a tissue outgrowth that is composed largely of blood vessels and connective tissue). This can lead to obstruction of various ducts, e.g. in the urinary and digestive tracts.

Traditionally, treatment of CGD entailed prophylactic administration of antimicrobial agents in an attempt to prevent occurrence of severe infection. However, affected individuals still experience life-threatening infections, requiring hospitalization and intensive medical care, as often as once a year. Attempts to control these infections rely on strong antimicrobial agents and leukocyte transfusions.

Long-term administration of IFN-y to CGD patients has proven effective in treating/moderating the symptoms of this disease. The recombinant human IFN-y used therapeutically is produced in E. coli, and is termed IFN-y1b. It displays identical biological activity to native human IFN-y, although it lacks the carbohydrate component. The product, usually sold in liquid form, is manufactured by Genentech, who market it under the tradename Actimmune. The product is administered on an ongoing basis, usually by s.c. injection three times weekly. In clinical trials, its administration, when compared with a control group receiving a placebo, resulted in a reduction in the:

• incidence of life-threatening infections by 50 per cent or more;

• incidence of total infections by 50 per cent or more;

• number of days of hospitalization by threefold (and even when hospitalization was required, the average stay was cut in half).

cytosolic factors

Figure 8.8 Production of reactive oxygen species by phagocytes. In addition to degrading foreign substances via phagocytosis, phagocytes secrete reactive oxygen species into their immediate environment. This can kill microorganisms (and indeed damage healthy tissue) in the vicinity, thus helping control the spread of infection. The reactive oxygen species are produced by an NADPH oxidase system, the main feature of which is a plasma membrane-based electron transport chain. NADPH represents the electron donor. The first membrane carrier is NADPH oxidase, which also requires interaction with at least two cytosolic proteins for activation. The electrons are passed via a number of carriers, including a flavoprotein, to cytochrome b558. This is a haem protein consisting of two subunits (22 and 91 kDa). The cytochrome, in turn, passes the electrons to oxygen, generating a superoxide anion (O~). The superoxide can be converted to hydrogen peroxide (H2O2) spontaneously, or enzymatically, by superoxide dismutase. A genetic defect affecting any element of this pathway will result in a compromised ability/inability to generate reactive oxygen species, normally resulting in CGD. Over 50 per cent of CGD sufferers display a genetic defect in the 91 kDa subunit of cytochrome b558

cytosolic factors

Figure 8.8 Production of reactive oxygen species by phagocytes. In addition to degrading foreign substances via phagocytosis, phagocytes secrete reactive oxygen species into their immediate environment. This can kill microorganisms (and indeed damage healthy tissue) in the vicinity, thus helping control the spread of infection. The reactive oxygen species are produced by an NADPH oxidase system, the main feature of which is a plasma membrane-based electron transport chain. NADPH represents the electron donor. The first membrane carrier is NADPH oxidase, which also requires interaction with at least two cytosolic proteins for activation. The electrons are passed via a number of carriers, including a flavoprotein, to cytochrome b558. This is a haem protein consisting of two subunits (22 and 91 kDa). The cytochrome, in turn, passes the electrons to oxygen, generating a superoxide anion (O~). The superoxide can be converted to hydrogen peroxide (H2O2) spontaneously, or enzymatically, by superoxide dismutase. A genetic defect affecting any element of this pathway will result in a compromised ability/inability to generate reactive oxygen species, normally resulting in CGD. Over 50 per cent of CGD sufferers display a genetic defect in the 91 kDa subunit of cytochrome b558

The molecular basis by which IFN-y induces these effects is understood, at least in part. In healthy individuals this cytokine is a potent activator of phagocytes. It potentiates their ability to generate toxic oxidative products (via the NADPH oxidase system), which they then use to kill infectious agents. In CGD sufferers, IFN-y boosts flux through the NADPH oxidative system. As long as the genetic defect has not totally inactivated a component of the system, this promotes increased synthesis of these oxidative substances. IFN-y also promotes increased expression of IgG Fc receptors on the surface of phagocytes. This would increase a phagocyte's ability to destroy opsonized infectious agents via phagocytes (Figure 8.9).

Additional molecular mechanisms must also mediate IFN-y effects, as it promotes a marked clinical improvement in some CGD patients without enhancing phagocyte activity. IFN-y's demonstrated ability to stimulate aspects of cellular and humoral immunity (e.g. via T- and B-lymphocytes), as well as NK cell activity, is most likely responsible for these observed improvements.

IFN-y may also prove valuable in treating a variety of other conditions, and clinical trials for various indications are currently underway. This cytokine shows promise in treating leishmania-sis, a disease common in tropical and subtropical regions. The causative agent is a parasitic protozoan of the genus Leishmania. The disease is characterized by the presence of these protozoa inside certain immune cells, particularly macrophages. IFN-y appears to stimulate the infected macrophage to produce nitric oxide, which is toxic for the parasite.

Figure 8.9 Increased expression of IgG Fc receptors on phagocytes results in enhanced phagocytosis. These receptors will retain opsonized (i.e. antibody-coated) infectious agents at their surface by binding the Fc portion of the antibody. This facilitates subsequent phagocytosis

Figure 8.9 Increased expression of IgG Fc receptors on phagocytes results in enhanced phagocytosis. These receptors will retain opsonized (i.e. antibody-coated) infectious agents at their surface by binding the Fc portion of the antibody. This facilitates subsequent phagocytosis

Additional studies illustrate that IFN-y stimulates phagocytic activity in humans suffering from various cancers, AIDS and lepromatous leprosy (leprosy is caused by the bacterium Mycobacterium leprae. Lepromatous leprosy is a severe contagious form of the disease leading to disfigurement). IFN-y may thus prove useful in treating such conditions.

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