The Use of Interferon-Gamma Therapy in Chronic Granulomatous Disease

Abstract

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by early onset of recurrent and severe infections. The molecular defects causing CGD are heterogeneous and lead to absence, low expression, or malfunctioning of one of the phagocyte NADPH oxidase components. It is known that mutations leading to CGD reside within the genes encoding four essential components of the oxidase designated as gp91-phox (phagocyte oxidase), p22-phox, p47-phox and p67-phox. gp91- together with p22-phox form the membrane cytochrome b(558) and play an essential role in the transfer of electrons following assembly of the active oxidase with the cytoplasmic p47- and p67-phox components. In hematopoietic cells, CYBB expression (the gene encoding gp91-phox) is limited to the granulocyte and monocyte/macrophage lineages during the process of terminal differentiation. CYBB is responsive to a number of inflammatory cytokines, especially interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). Cytokines have been also studied for activation of phagocytes respiratory burst. IFN-gamma stimulates superoxide release and is a prophylactic agent for CGD. It has been shown in vitro and in vivo to correct at least in part alterations of the oxidative metabolism, and to improve their microbicidal function. It has demonstrated clinical benefit in the majority of patients with CGD, reducing the relative risk of severe infections in 70%. In this study, we review mechanisms showing that IFN-gamma improves the splicing efficiency of CYBB gene transcripts in a particular group of CGD patients. The present article is an informative review of recent patents related to the use of interferon gamma therapy in chronic granulomatous disease.

Interferon-γ Promotes Antibody-mediated Fratricide of Acute Myeloid Leukemia Cells

“…IFN␥ (IFN␥1b, Actimmune, Horizon Pharma, Inc.) is an approved treatment for preventing infections in chronic granulomatous disease and for delaying severe malignant osteopetrosis (45)(46)(47)(48). IFN␥ is also being evaluated in combination with checkpoint inhibitors (nivolumab) in solid tumors (NCT02614456).…”

The renaissance of interferon therapy for the treatment of myeloid malignancies

“…1,[15][16][17] Patients with chronic granulomatous disease, a rare genetic disorder of superoxide generation, respond to therapy with IFN␥ with increased superoxide generation resulting in fewer bacterial infections. 21 Patients with severe congenital osteopetrosis have decreased bone resorption associated with defective leukocyte superoxide generation. 22 IFN␥ therapy in these patients also results in a reduced incidence of infections as well as a reduction in trabecular bone mass.…”

“…22 IFN␥-1b is currently approved for the treatment of patients with these 2 genetic disorders. 21,22 IFN␣ binds to a cell-surface complex consisting of 2 transmembrane type 1 IFN receptor subunits, IFNAR1 and IFNAR2, which are members of the class II cytokine receptor superfamily. 16,17,23 The genes for these receptors are clustered on chromosome 21.…”

Uma nova abordagem para o estudo dos defeitos genético-moleculares da doença granulomatosa crônica e análise de suas relações genótipo-fenótipo.

“…Os pilares do tratamento da DGC são: 1) prevenção das infecções por meio de imunizações e remoção das fontes de patógenos, 2) uso profilático de trimetoprinsulfametoxazol ou outro antimicrobiano com penetração intracelular, 3) uso profilático de IFN-, 4) uso precoce e agressivo de antibióticos parenterais, 5) drenagem cirúrgica ou ressecção de focos infecciosos persistentes. Dos cinco itens, o mais importante é a intervenção precoce nas infecções, antes que elas sobrepujem o comprometido sistema imunológico do paciente com DGC Heyworth et al, 2003;Holland, 2010 Errante et al, 2008). O IFN- continua sendo uma terapia segura para a prevenção de infecções graves em pacientes com DGC (Marciano et al, 2004;Errante et al, 2008).…”

“…Dos cinco itens, o mais importante é a intervenção precoce nas infecções, antes que elas sobrepujem o comprometido sistema imunológico do paciente com DGC Heyworth et al, 2003;Holland, 2010 Errante et al, 2008). O IFN- continua sendo uma terapia segura para a prevenção de infecções graves em pacientes com DGC (Marciano et al, 2004;Errante et al, 2008).…”