인터페론 감마: 두 판 사이의 차이

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새 문서: {{#invoke:Infobox_gene|getTemplateData|QID=Q18027639}} {{Infobox protein family | Symbol = IFN gamma | Name = 인터페론 감마 | image = PDB 1eku EBI.jpg | width = | caption = 인간 인터페론 감마의 결정 구조 | Pfam = PF00714 | Pfam_clan = CL0053 | InterPro = IPR002069 | SMART = | PROSITE = | MEROPS = | SCOP = 1rfb | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = }} {{Drugbox | Verifiedfields = changed | verifiedrevid = 458270952 | IUPAC_name = Hu...
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2022년 4월 22일 (금) 06:35 판

IFNG
사용 가능한 구조
PDB동원체 검색: PDBe RCSB
식별자
다른 이름IFNG, IFG, IFI, interferon, gamma, interferon gamma, IMD69
외부 IDOMIM: 147570 MGI: 107656 HomoloGene: 55526 GeneCards: IFNG
RNA 발현 패턴
Bgee
인간쥐(동원체)
최상위 발현
  • 림프절

  • 골수세포

  • 충수

  • 앞정강근

  • 쓸개

  • 혈액

  • 비장

  • 간오른엽

  • 민무늬근

  • 곧은창자
최상위 발현
  • 회장 (해부학)

  • 공장

  • 골수

  • 비장

  • 가슴샘

  • 샘창자

  • 방광

  • 가슴

  • 순환계통

  • 심장
추가 참조 발현 데이터
BioGPS
추가 참조 발현 데이터
위키데이터
인간 보기/편집쥐 보기/편집
인터페론 감마
인간 인터페론 감마의 결정 구조
식별자
상징IFN gamma
PfamPF00714
Pfam clanCL0053
InterProIPR002069
SCOP1rfb
SUPERFAMILY1rfb
인터페론 감마
체계적 명칭 (IUPAC 명명법)
Human interferon gamma-1b
식별 정보
CAS 등록번호 98059-61-1
ATC 코드 L03AB03
PubChem ?
드러그뱅크 DB00033
ChemSpider none
화학적 성질
화학식 C761H1206N214O225S6 
분자량 ?
약동학 정보
생체적합성 ?
동등생물의약품 ?
약물 대사 ?
생물학적 반감기 ?
배출 ?
처방 주의사항
임부투여안전성 ?
법적 상태
투여 방법 ?

인터페론 감마 (interferon gamma, IFN-γ)는 dimerized soluble cytokine that is the only member of the type II class of interferons.[5] The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes.[6] It was also shown to be produced in human lymphocytes.[7] or tuberculin-sensitized mouse peritoneal lymphocytes[8] challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene.[9][10]

Function

IFN-γ, or type II interferon, is a cytokine that is critical for innate and adaptive immunity against viral, some bacterial and protozoan infections. IFN-γ is an important activator of macrophages and inducer of major histocompatibility complex class II molecule expression. Aberrant IFN-γ expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFN-γ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects. IFN-γ is produced predominantly by natural killer cells (NK) and natural killer T cells (NKT) as part of the innate immune response, and by CD4 Th1 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops[11][12] as part of the adaptive immune response. IFN-γ is also produced by non-cytotoxic innate lymphoid cells (ILC), a family of immune cells first discovered in the early 2010s.[13]

Structure

The IFN-γ monomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region.[14][15] This is shown in the structural models below. The α-helices in the core of the structure are numbered 1 to 6.

Figure 1. Line and cartoon representation of an IFN-γ monomer.[15]

The biologically active dimer is formed by anti-parallel inter-locking of the two monomers as shown below. In the cartoon model, one monomer is shown in red, the other in blue.

Figure 2. Line and cartoon representation of an IFN-γ dimer.[15]

Receptor binding

Figure 3. IFN dimer interacting with two IFNGR1 receptor molecules.[15]
<nowiki /> Interferon-gamma receptor 문서를 참고하십시오.

Cellular responses to IFN-γ are activated through its interaction with a heterodimeric receptor consisting of Interferon gamma receptor 1 (IFNGR1) and Interferon gamma receptor 2 (IFNGR2). IFN-γ binding to the receptor activates the JAK-STAT pathway. Activation of the JAK-STAT pathway induces upregulation of interferon-stimulated genes (ISGs), including MHC II.[16] IFN-γ also binds to the glycosaminoglycan heparan sulfate (HS) at the cell surface. However, in contrast to many other heparan sulfate binding proteins, where binding promotes biological activity, the binding of IFN-γ to HS inhibits its biological activity.[17]

The structural models shown in figures 1-3 for IFN-γ[15] are all shortened at their C-termini by 17 amino acids. Full length IFN-γ is 143 amino acids long, the models are 126 amino acids long. Affinity for heparan sulfate resides solely within the deleted sequence of 17 amino acids.[18] Within this sequence of 17 amino acids lie two clusters of basic amino acids termed D1 and D2, respectively. Heparan sulfate interacts with both of these clusters.[19] In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFN-γ-receptor complexes form.[17] Interactions between the D1 cluster of amino acids and the receptor may be the first step in complex formation. By binding to D1 HS may compete with the receptor and prevent active receptor complexes from forming.

The biological significance of heparan sulfates interaction with IFN-γ is unclear; however, binding of the D1 cluster to HS may protect it from proteolytic cleavage.[19]

Biological activity

IFN-γ is secreted by T helper cells (specifically, Th1 cells), cytotoxic T cells (TC cells), macrophages, mucosal epithelial cells and NK cells. IFN-γ is both an important autocrine signal for professional APCs in early innate immune response, and an important paracrine signal in adaptive immune response. The expression of IFN-γ is induced by the cytokines IL-12, IL-15, IL-18, and type I IFN.[20] IFN-γ is the only Type II interferon and it is serologically distinct from Type I interferons; it is acid-labile, while the type I variants are acid-stable.

IFN-γ has antiviral, immunoregulatory, and anti-tumor properties.[21] It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are:

IFN-γ is the primary cytokine that defines Th1 cells: Th1 cells secrete IFN-γ, which in turn causes more undifferentiated CD4+ cells (Th0 cells) to differentiate into Th1 cells ,[25] representing a positive feedback loop—while suppressing Th2 cell differentiation. (Equivalent defining cytokines for other cells include IL-4 for Th2 cells and IL-17 for Th17 cells.)

NK cells and CD8+ cytotoxic T cells also produce IFN-γ. IFN-γ suppresses osteoclast formation by rapidly degrading the RANK adaptor protein TRAF6 in the RANK-RANKL signaling pathway, which otherwise stimulates the production of NF-κB.

Activity in granuloma formation

A granuloma is the body's way of dealing with a substance it cannot remove or sterilize. Infectious causes of granulomas (infections are typically the most common cause of granulomas) include tuberculosis, leprosy, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and toxoplasmosis. Examples of non-infectious granulomatous diseases are sarcoidosis, Crohn's disease, berylliosis, giant-cell arteritis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, pulmonary rheumatoid nodules, and aspiration of food and other particulate material into the lung.[26] The infectious pathophysiology of granulomas is discussed primarily here.

The key association between IFN-γ and granulomas is that IFN-γ activates macrophages so that they become more powerful in killing intracellular organisms.[27] Activation of macrophages by IFN-γ from Th1 helper cells in mycobacterial infections allows the macrophages to overcome the inhibition of phagolysosome maturation caused by mycobacteria (to stay alive inside macrophages).[28][29] The first steps in IFN-γ-induced granuloma formation are activation of Th1 helper cells by macrophages releasing IL-1 and IL-12 in the presence of intracellular pathogens, and presentation of antigens from those pathogens. Next the Th1 helper cells aggregate around the macrophages and release IFN-γ, which activates the macrophages. Further activation of macrophages causes a cycle of further killing of intracellular bacteria, and further presentation of antigens to Th1 helper cells with further release of IFN-γ. Finally, macrophages surround the Th1 helper cells and become fibroblast-like cells walling off the infection.

Activity during pregnancy

Uterine Natural Killer cells (NK) secrete high levels of chemoattractants, such as IFN-γ in mice. IFN-γ dilates and thins the walls of maternal spiral arteries to enhance blood flow to the implantation site. This remodeling aids in the development of the placenta as it invades the uterus in its quest for nutrients. IFN-γ knockout mice fail to initiate normal pregnancy-induced modification of decidual arteries. These models display abnormally low amounts of cells or necrosis of decidua.[30]

In humans, elevated levels of IFN-γ have been associated with increased risk of miscarriage. Correlation studies have observed high IFN-γ levels in women with a history of spontaneous miscarriage, when compared to women with no history of spontaneous miscarriage.[31] Additionally, low-IFN-γ levels are associated with women who successfully carry to term. It is possible that IFN-γ is cytotoxic to trophoblasts, which leads to miscarriage.[32] However, causal research on the relationship between IFN-γ and miscarriage has not been preformed due to ethical constraints.

Production

Recombinant human IFN-γ, as an expensive biopharmaceutical, has been expressed in different expression systems including prokaryotic, protozoan, fungal (yeasts), plant, insect and mammalian cells. Human IFN-γ is commonly expressed in Escherichia coli, marketed as ACTIMMUNE®, however, the resulting product of the prokaryotic expression system is not glycosylated with a short half-life in the bloodstream after injection; the purification process from bacterial expression system is also very costly. Other expression systems like Pichia pastoris did not show satisfactory results in terms of yields.[33][34]

Therapeutic use

Interferon-γ 1b is approved by the U.S. Food and Drug Administration to treat chronic granulomatous disease[35] (CGD) and osteopetrosis.[36] The mechanism by which IFN-γ benefits CGD is via enhancing the efficacy of neutrophils against catalase-positive bacteria by correcting patients' oxidative metabolism.[37]

It was not approved to treat idiopathic pulmonary fibrosis (IPF). In 2002, the manufacturer InterMune issued a press release saying that phase III data demonstrated survival benefit in IPF and reduced mortality by 70% in patients with mild to moderate disease. The U.S. Department of Justice charged that the release contained false and misleading statements. InterMune's chief executive, Scott Harkonen, was accused of manipulating the trial data, was convicted in 2009 of wire fraud, and was sentenced to fines and community service. Harkonen appealed his conviction to the U.S. Court of Appeals for the Ninth Circuit, and lost.[38] Harkonen was granted a full pardon on January 20, 2021.[39]

Preliminary research on the role of IFN-γ in treating Friedreich's ataxia (FA) conducted by Children’s Hospital of Philadelphia has found no beneficial effects in short-term (< 6-months) treatment.[40][41][42] However, researchers in Turkey have discovered significant improvements in patients' gait and stance after 6 months of treatment.[43]

Although not officially approved, Interferon-γ has also been shown to be effective in treating patients with moderate to severe atopic dermatitis.[44][45][46] Specifically, recombinant IFN-γ therapy has shown promise in patients with lowered IFN-γ expression, such as those with predisposition to herpes simplex virus, and pediatric patients.[47]

Potential use in immunotherapy

IFN-γ increases an anti-proliferative state in cancer cells, while upregulating MHC I and MHC II expression, which increases immunorecognition and removal of pathogenic cells.[48] IFN-γ also reduces metastasis in tumors by upregulating fibronectin, which negatively impacts tumor architecture.[49]

IFN-γ is not approved yet for the treatment in any cancer immunotherapy. However, improved survival was observed when IFN-γ was administrated to patients with bladder carcinoma and melanoma cancers. The most promising result was achieved in patients with stage 2 and 3 of ovarian carcinoma. On the contrary, it was stressed: "Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth."[50] The in vitro study of IFN-γ in cancer cells is more extensive and results indicate anti-proliferative activity of IFN-γ leading to the growth inhibition or cell death, generally induced by apoptosis but sometimes by autophagy.[33] In addition, it has been reported that mammalian glycosylation of recombinant human IFN-γ, expressed in HEK293, improves its therapeutic efficacy compared to the unglycosylated form that is expressed in E. coli.[51]

Interactions

Interferon-γ has been shown to interact with Interferon gamma receptor 1 and Interferon gamma receptor 2.[52][53]

Diseases

Interferon-γ has been shown to be a crucial player in the immune response against some intracellular pathogens, including that of Chagas disease.[54] It has also been identified as having a role in seborrheic dermatitis.[55]

IFN-γ has a significant anti-viral effect in herpes simplex virus I (HSV) infection. IFN-γ compromises the microtubules that HSV relies upon for transport into an infected cell's nucleus, inhibiting the ability of HSV to replicate.[56][57] Studies in mice on acyclovir resistant herpes have shown that IFN-γ treatment can significantly reduce herpes viral load. The mechanism by which IFN-γ inhibits herpes reproduction is independent of T-cells, which means that IFN-γ may be an effective treatment in individuals with low T-cells.[58][59][60]

Chlamydia infection is impacted by IFN-γ in host cells. In human epithelial cells, IFN-γ upregulates expression of indoleamine 2,3-dioxygenase, which in turn depletes tryptophan in hosts and impedes chlamydia's reproduction.[61][62] Additionally, in rodent epithelial cells, IFN-γ upregulates a GTPase that inhibits chlamydial proliferation.[63] In both the human and rodent systems, chlamydia has evolved mechanisms to circumvent the negative effects of host cell behavior.[64]

Regulation

There is evidence that interferon-gamma expression is regulated by a pseudoknotted element in its 5' UTR.[65] There is also evidence that interferon-gamma is regulated either directly or indirectly by the microRNAs: miR-29.[66] Furthermore, there is evidence that interferon-gamma expression is regulated via GAPDH in T-cells. This interaction takes place in the 3'UTR, where binding of GAPDH prevents the translation of the mRNA sequence.[67]

References

  1. ↑ 가 나 다 GRCh38: Ensembl release 89: ENSG00000111537 - 앙상블, May 2017
  2. ↑ 가 나 다 GRCm38: Ensembl release 89: ENSMUSG00000055170 - 앙상블, May 2017
  3. ↑ “Human PubMed Reference:”. 《National Center for Biotechnology Information, U.S. National Library of Medicine》. 
  4. ↑ “Mouse PubMed Reference:”. 《National Center for Biotechnology Information, U.S. National Library of Medicine》. 
  5. ↑ Gray PW, Goeddel DV (August 1982). “Structure of the human immune interferon gene”. 《Nature》 298 (5877): 859–863. Bibcode:1982Natur.298..859G. doi:10.1038/298859a0. PMID 6180322. S2CID 4275528. 
  6. ↑ Wheelock EF (July 1965). “Interferon-Like Virus-Inhibitor Induced in Human Leukocytes by Phytohemagglutinin”. 《Science》 149 (3681): 310–311. Bibcode:1965Sci...149..310W. doi:10.1126/science.149.3681.310. PMID 17838106. S2CID 1366348. 
  7. ↑ Green JA, Cooperband SR, Kibrick S (June 1969). “Immune specific induction of interferon production in cultures of human blood lymphocytes”. 《Science》 164 (3886): 1415–1417. Bibcode:1969Sci...164.1415G. doi:10.1126/science.164.3886.1415. PMID 5783715. S2CID 32651832. 
  8. ↑ Milstone LM, Waksman BH (November 1970). “Release of virus inhibitor from tuberculin-sensitized peritoneal cells stimulated by antigen”. 《Journal of Immunology》 105 (5): 1068–1071. PMID 4321289. 
  9. ↑ Naylor SL, Sakaguchi AY, Shows TB, Law ML, Goeddel DV, Gray PW (March 1983). “Human immune interferon gene is located on chromosome 12”. 《The Journal of Experimental Medicine》 157 (3): 1020–1027. doi:10.1084/jem.157.3.1020. PMC 2186972. PMID 6403645. 
  10. ↑ “Entrez Gene: IFNGR2”. 
  11. ↑ “Entrez Gene: INFG”. 
  12. ↑ Schoenborn JR, Wilson CB (2007). 〈Regulation of Interferon‐γ During Innate and Adaptive Immune Responses〉. 《Regulation of interferon-gamma during innate and adaptive immune responses》. 《Advances in Immunology》 96. 41–101쪽. doi:10.1016/S0065-2776(07)96002-2. ISBN 978-0-12-373709-0. PMID 17981204. 
  13. ↑ Artis D, Spits H (January 2015). “The biology of innate lymphoid cells”. 《Nature》 517 (7534): 293–301. Bibcode:2015Natur.517..293A. doi:10.1038/nature14189. PMID 25592534. S2CID 4386692. 
  14. ↑ Ealick SE, Cook WJ, Vijay-Kumar S, Carson M, Nagabhushan TL, Trotta PP, Bugg CE (May 1991). “Three-dimensional structure of recombinant human interferon-gamma”. 《Science》 252 (5006): 698–702. Bibcode:1991Sci...252..698E. doi:10.1126/science.1902591. PMID 1902591. 
  15. ↑ 가 나 다 라 마 PDB 1FG9; Thiel DJ, le Du MH, Walter RL, D'Arcy A, Chène C, Fountoulakis M, 외. (September 2000). “Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex”. 《Structure》 8 (9): 927–936. doi:10.1016/S0969-2126(00)00184-2. PMID 10986460. 
  16. ↑ Hu X, Ivashkiv LB (October 2009). “Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases”. 《Immunity》 31 (4): 539–550. doi:10.1016/j.immuni.2009.09.002. PMC 2774226. PMID 19833085. 
  17. ↑ 가 나 Sadir R, Forest E, Lortat-Jacob H (May 1998). “The heparan sulfate binding sequence of interferon-gamma increased the on rate of the interferon-gamma-interferon-gamma receptor complex formation”. 《The Journal of Biological Chemistry》 273 (18): 10919–10925. doi:10.1074/jbc.273.18.10919. PMID 9556569. 
  18. ↑ Vanhaverbeke C, Simorre JP, Sadir R, Gans P, Lortat-Jacob H (November 2004). “NMR characterization of the interaction between the C-terminal domain of interferon-gamma and heparin-derived oligosaccharides”. 《The Biochemical Journal》 384 (Pt 1): 93–99. doi:10.1042/BJ20040757. PMC 1134092. PMID 15270718. 
  19. ↑ 가 나 Lortat-Jacob H, Grimaud JA (March 1991). “Interferon-gamma binds to heparan sulfate by a cluster of amino acids located in the C-terminal part of the molecule”. 《FEBS Letters》 280 (1): 152–154. doi:10.1016/0014-5793(91)80225-R. PMID 1901275. S2CID 45942972. 
  20. ↑ Castro F, Cardoso AP, Gonçalves RM, Serre K, Oliveira MJ (2018). “Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion”. 《Frontiers in Immunology》 9: 847. doi:10.3389/fimmu.2018.00847. PMC 5945880. PMID 29780381. 
  21. ↑ Schroder K, Hertzog PJ, Ravasi T, Hume DA (February 2004). “Interferon-gamma: an overview of signals, mechanisms and functions”. 《Journal of Leukocyte Biology》 75 (2): 163–189. doi:10.1189/jlb.0603252. PMID 14525967. S2CID 15862242. 
  22. ↑ Konjević GM, Vuletić AM, Mirjačić Martinović KM, Larsen AK, Jurišić VB (May 2019). “The role of cytokines in the regulation of NK cells in the tumor environment”. 《Cytokine》 117: 30–40. doi:10.1016/j.cyto.2019.02.001. PMID 30784898. S2CID 73482632. 
  23. ↑ Hoyer FF, Naxerova K, Schloss MJ, Hulsmans M, Nair AV, Dutta P, 외. (November 2019). “Tissue-Specific Macrophage Responses to Remote Injury Impact the Outcome of Subsequent Local Immune Challenge”. 《Immunity》 51 (5): 899–914.e7. doi:10.1016/j.immuni.2019.10.010. PMC 6892583. PMID 31732166. 
  24. ↑ Yao Y, Jeyanathan M, Haddadi S, Barra NG, Vaseghi-Shanjani M, Damjanovic D, 외. (November 2018). “Induction of Autonomous Memory Alveolar Macrophages Requires T Cell Help and Is Critical to Trained Immunity”. 《Cell》 175 (6): 1634–1650.e17. doi:10.1016/j.cell.2018.09.042. PMID 30433869. 
  25. ↑ Luckheeram RV, Zhou R, Verma AD, Xia B (2012). “CD4⁺T cells: differentiation and functions”. 《Clinical & Developmental Immunology》 2012: 925135. doi:10.1155/2012/925135. PMC 3312336. PMID 22474485. 
  26. ↑ Mukhopadhyay S, Farver CF, Vaszar LT, Dempsey OJ, Popper HH, Mani H, 외. (January 2012). “Causes of pulmonary granulomas: a retrospective study of 500 cases from seven countries”. 《Journal of Clinical Pathology》 65 (1): 51–57. doi:10.1136/jclinpath-2011-200336. PMID 22011444. S2CID 28504428. 
  27. ↑ Wu C, Xue Y, Wang P, Lin L, Liu Q, Li N, 외. (September 2014). “IFN-γ primes macrophage activation by increasing phosphatase and tensin homolog via downregulation of miR-3473b”. 《Journal of Immunology》 193 (6): 3036–3044. doi:10.4049/jimmunol.1302379. PMID 25092892. S2CID 90897269. 
  28. ↑ Herbst S, Schaible UE, Schneider BE (May 2011). “Interferon gamma activated macrophages kill mycobacteria by nitric oxide induced apoptosis”. 《PLOS ONE》 6 (5): e19105. Bibcode:2011PLoSO...619105H. doi:10.1371/journal.pone.0019105. PMC 3085516. PMID 21559306. 
  29. ↑ Harris J, Master SS, De Haro SA, Delgado M, Roberts EA, Hope JC, 외. (March 2009). “Th1-Th2 polarisation and autophagy in the control of intracellular mycobacteria by macrophages”. 《Veterinary Immunology and Immunopathology》 128 (1–3): 37–43. doi:10.1016/j.vetimm.2008.10.293. PMC 2789833. PMID 19026454. 
  30. ↑ Ashkar AA, Di Santo JP, Croy BA (July 2000). “Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy”. 《The Journal of Experimental Medicine》 192 (2): 259–270. doi:10.1084/jem.192.2.259. PMC 2193246. PMID 10899912. 
  31. ↑ Micallef A, Grech N, Farrugia F, Schembri-Wismayer P, Calleja-Agius J (January 2014). “The role of interferons in early pregnancy”. 《Gynecological Endocrinology》 30 (1): 1–6. doi:10.3109/09513590.2012.743011. PMID 24188446. S2CID 207489059. 
  32. ↑ Berkowitz RS, Hill JA, Kurtz CB, Anderson DJ (January 1988). “Effects of products of activated leukocytes (lymphokines and monokines) on the growth of malignant trophoblast cells in vitro”. 《American Journal of Obstetrics and Gynecology》 158 (1): 199–203. doi:10.1016/0002-9378(88)90810-1. PMID 2447775. 
  33. ↑ 가 나 Razaghi A, Owens L, Heimann K (December 2016). “Review of the recombinant human interferon gamma as an immunotherapeutic: Impacts of production platforms and glycosylation”. 《Journal of Biotechnology》 240: 48–60. doi:10.1016/j.jbiotec.2016.10.022. PMID 27794496. 
  34. ↑ Razaghi A, Tan E, Lua LH, Owens L, Karthikeyan OP, Heimann K (January 2017). “Is Pichia pastoris a realistic platform for industrial production of recombinant human interferon gamma?”. 《Biologicals》 45: 52–60. doi:10.1016/j.biologicals.2016.09.015. PMID 27810255. 
  35. ↑ Todd PA, Goa KL (January 1992). “Interferon gamma-1b. A review of its pharmacology and therapeutic potential in chronic granulomatous disease”. 《Drugs》 43 (1): 111–122. doi:10.2165/00003495-199243010-00008. PMID 1372855. S2CID 46986837. 
  36. ↑ Key LL, Ries WL, Rodriguiz RM, Hatcher HC (July 1992). “Recombinant human interferon gamma therapy for osteopetrosis”. 《The Journal of Pediatrics》 121 (1): 119–124. doi:10.1016/s0022-3476(05)82557-0. PMID 1320672. 
  37. ↑ Errante PR, Frazão JB, Condino-Neto A (November 2008). “The use of interferon-gamma therapy in chronic granulomatous disease”. 《Recent Patents on Anti-Infective Drug Discovery》 3 (3): 225–230. doi:10.2174/157489108786242378. PMID 18991804. 
  38. ↑ Silverman E (September 2013). “Drug Marketing. The line between scientific uncertainty and promotion of snake oil”. 《BMJ》 347: f5687. doi:10.1136/bmj.f5687. PMID 24055923. S2CID 27716008. 
  39. ↑ “Statement from the Press Secretary Regarding Executive Grants of Clemency”. 《whitehouse.gov》. 2021년 1월 20일 – National Archives 경유. 
  40. ↑ Wells M, Seyer L, Schadt K, Lynch DR (December 2015). “IFN-γ for Friedreich ataxia: present evidence”. 《Neurodegenerative Disease Management》 5 (6): 497–504. doi:10.2217/nmt.15.52. PMID 26634868. 
  41. ↑ Seyer L, Greeley N, Foerster D, Strawser C, Gelbard S, Dong Y, 외. (July 2015). “Open-label pilot study of interferon gamma-1b in Friedreich ataxia”. 《Acta Neurologica Scandinavica》 132 (1): 7–15. doi:10.1111/ane.12337. PMID 25335475. S2CID 207014054. 
  42. ↑ Lynch DR, Hauser L, McCormick A, Wells M, Dong YN, McCormack S, 외. (March 2019). “Randomized, double-blind, placebo-controlled study of interferon-γ 1b in Friedreich Ataxia”. 《Annals of Clinical and Translational Neurology》 6 (3): 546–553. doi:10.1002/acn3.731. PMC 6414489. PMID 30911578. 
  43. ↑ Yetkİn MF, GÜltekİn M (December 2020). “Efficacy and Tolerability of Interferon Gamma in Treatment of Friedreich's Ataxia: Retrospective Study”. 《Noro Psikiyatri Arsivi》 57 (4): 270–273. doi:10.29399/npa.25047. PMC 7735154. PMID 33354116. 
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