Granulomatous disease

Cytokines, eg, interferons, interleukins, tumor necrosis factor (TNF), and certain growth factors, could have antitumor activity directiy, or may modulate cellular mechanisms of antitumor activity (2). Cytokines may be used to influence the proliferation and differentiation of T-ceUs, B-ceUs, macrophage—monocyte, myeloid, or other hematopoietic cells. Alternatively, the induction of interferon release may represent an important approach for synthetic—medicinal chemistry, to search for effective antiinflammatory and antifibrotic agents. Inducers of interferon release may also be useful for lepromatous leprosy and chronic granulomatous disease. The potential cytokine and cytokine-related therapeutic approaches to treatment of disease are summarized in Table 4. A combination of cytokines is a feasible modaUty for treatment of immunologically related diseases however, there are dangers inherent in such an approach, as shown by the induction of lethal disserninated intravascular coagulation in mice adrninistered TNF-a and IFN-y. 

NADPH-oxidase j 2O2 + NADPH 20p + NADP -F H+ Key component of the respiratory burst Deficient in chronic granulomatous disease... 

Mutations in the Genes for Components of the NADPH Oxidase System Cause Chronic Granulomatous Disease... 

Figure 52-7. Simplified scheme of the sequence of events involved in the causation of chronic granulomatous disease (MIM 306400). Mutations in any of the genes for the four polypeptides involved (two are components of cytochrome b55gand two are derived from the cytoplasm) can cause the disease. The polypeptide of 91 kDa is encoded by a gene in the X chromosome approximately 60% of cases of chronic granulomatous disease are X-linked, with the remainder being inherited in an autosomal recessive fashion.

Leukocytes are activated on exposure to bacteria and other stimuh NADPH oxidase plays a key role in the process of activation (the respiratory burst). Mutations in this enzyme and associated proteins cause chronic granulomatous disease. 

Interferon-/ 143 amino acids, glycosylated E. coli Chronic granulomatous disease Approved for sale In clinical trials for treatment of cancer and viral diseases... 

Babior, B.M. and Woodman, R.C. (1990). Chronic granulomatous disease. Semin. Flematol. 27, 247-259. 

Emmendorffer, A., Roesler, J., Eisner, J., Raeder, E., Lohmann-Mathes, M.L. and Meier, B. (1993). Production of oxygen radicals by fibroblasts and neutrophils from a patient with x-linked chronic granulomatous disease. Eur. J. Haematol. 51, 223—227. 

Chronic granulomatous disease is a rare inherited disorder characterized by the failure of neutrophils, eosinophils, monocytes and macrophages to produce the respiratory burst (Curnutte and Babior, 1987) this leads to recurrent bacterial and fungal infections often starting within the first year of life. 

Prednisone 20-40 mg enterally daily or equivalent if lymphoma or granulomatous disease-related... 

Actimmune Interferon y-lb Genentech Chronic granulomatous disease... 

Endocrine abnormalities Hypothyroidism Adrenal insufficiency Pituitary insufficiency Chronic renal disease Chronic inflammatory disease Granulomatous diseases Collagen vascular diseases Hepatic disease... 

Chronic granulomatous disease Severe, malignant osteopetrosis... 

IFN-y has therapeutic activity in chronic granulomatous disease (CGD).34 In CGD, the mechanism of therapeutic activity by IFN-y appears to be associated with enhanced phagocytic oxidase activity and increased superoxide production by neutrophils. However,... 

The International Chronic Granulomatous Disease Cooperative Study Group., A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease., N. Engl. J. Med, 324, 509, 1991. 

Woodman, R.C. et al., Prolonged recombinant interferon-gamma therapy in chronic granulomatous disease Evidence against enhanced neutrophil oxidase activity, Blood, 79, 1558, 1992. 

Ahlin, A. et al., Gamma interferon treatment of patients with chronic granulomatous disease is associated with augmented production of nitric oxide by polymorphonuclear neutrophils, Clin. Diagn. Lab Immunol, 6, 420, 1999. 

Baehner RL, Nathan DG (1967) Leukocyte oxidase defective activity in chronic granulomatous disease. Science 155 835-836... 

In mature neutrophils, interferon-7induces the expression of FC7RI, increases antibody-dependent cytotoxicity, primes the ability to generate reactive oxidants and selectively stimulates protein biosynthesis. These effects are described in detail in Chapter 7. Additionally, this cytokine has been used clinically for the treatment of chronic granulomatous disease (CGD), which is associated with an increased susceptibility to infections due to an impairment of NADPH oxidase function ( 8.2). 

Dinauer, M. C., Orkin, S. H., Brown, R., Jesaitis, A. J., Parkos, C. A. (1987). The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Nature 327, 717-20. 

Dinauer, M. C., Pierce, E. A., Bruns, G. A. P., Curnutte, J. T., Orkin, S. H. (1990). Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease. J. Clin. Invest. 86, 1729-37. 

Lomax, K. J., Leto, T. L., Nunoi, H., Gallin, J. I., Malech, H. L. (1989). Recombinant 47-kilodalton cytosol factor restores NADPH oxidase in chronic granulomatous disease. Science 245, 409-12. 

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