Roles in disease and therapeutic applications

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A better understanding of the roles of IFNy in the intact organism is emerging from studies with animals in which either the gene encoding IFN7 or the gene encoding the a chain of the IFN7 receptor has been inactivated by gene targeting. The major defect in animals that lack functional IFN7 (but retain the functions of IFNa/p) is a decreased ability to resist infection with some bacteria (Listeria, Mycobacteria), parasites (Leisbmania) and viruses (vaccinia, Theiler's virus). Other changes seen in mice lacking functional IFNy include an increased resistance to the toxic action of bacterial LPS and a decreased production of some other cytokines (TNFa, IL-1, IL-6 and IL-12). Such mice also showed a decreased capacity to develop protective immunity against Plasmodium yoelli sporozoites and against pseudorabies virus. There was also an altered pattern of generation of immunoglobulin isotypes, most notably a decrease in IgG2a production.

Several studies investigated the consequences of an aberrant expression of IFN7 in transgenic mice. Overexpression of murine IFN7 led to increased class I and II MHC expression, localized inflammation and tissue destruction. In a recent study aberrant expression of IFN7 in the neuromuscular junctions produced myasthenia gravis-like symptoms.

In view of its stimulatory action on MHC expression and antigen presentation IFN7 has long been suspected to play a role as a mediator of autoimmunity. However, it appears that the role of IFN7 in autoimmune disease may vary depending on the stage of the disease process or site of action. McDev-itt and coworkers showed that in complete Freund's adjuvant (CFA)-induced arthritis in rats, administration of IFN7 24 h before CFA caused an enhancement of arthritis, whereas injection of IFN7 24-48 h after CFA suppressed the disease. In collagen-induced arthritis in mice, locally injected IFN7 promoted arthritis whereas systemically administered IFN7 was protective. There are other diseases in which IFN7 apparently plays a dual role. While there is evidence that IFN7 is an important factor in host defenses against some infections, recent data from animal models suggest that IFN7 may contribute to the pathology in septic shock, cerebral malaria and cachexia associated with tumor growth. These adverse effects may be due at least partly to the ability of IFN7 to promote the generation of toxic-levels of TNFa and to synergize with TNFa.

Many recent studies have investigated the effects of artificial overexpression of IFN7 (by introduction of cDNA expression vectors) on the ability of tumor cell lines to generate tumors in mice. In several models IFN7-producing tumor cells were rejected due to the efficient generation of tumor-specific cytotoxic CD81 T cells. However, in one study tumor cells transfected with IFN7 cDNA showed an increased metastatic potential.

In view of its many immunoregulatory actions, recombinant IFN7 has been tested in clinical trials in humans. Many of the trials were in patients with malignancies. Although some clinical responses have been seen (e.g. in renal cell cancer), the value of IFN7 in neoplastic diseases has not been confirmed in controlled clinical trials. One approved therapeutic application of IFN7 is in patients with chronic granulomatous disease, a rare genetic disorder in which defective phagocyte function represents the major clinical problem. Administration of IFN7 in these patients resulted in a significant improvement in the ability of their phagocytes to kill bacteria and reduced the incidence of life-threatening infections. The use of IFN7 for the treatment of some chronic infections affecting macrophages (e.g. leishmaniasis, toxoplasmosis, tuberculosis) is under consideration. Low doses of IFN7 were reported to have a beneficial effect in some patients with rheumatoid arthritis and in Germany IFN7 has been licensed for the treatment of this disease.

See also: Autoimmune diseases; Autoimmunity; Cytokine assays; Cytokine genes, regulation of; Cytokines; Cytokine receptors; Interferon a; Interferon P; Interferon 7; Macrophage activation; T lymphocyte activation.

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