Impaired interferon production and natural killer cell activation in patients with the skin cancer-prone disorder, xeroderma pigmentosum.

Gaspari, Anthony A.; Fleisher, TA; Kraemer, Kenneth H.

doi:10.1172/jci116682

Cited by 74 publications

(69 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The IFN-␥ dose-response and the kinetics of induction of ICAM-1 mRNA and surface expression by rhIFN-␥ were essentially identical in all cell lines tested (data not shown), confirming previous findings that cells from DNA-repairdeficient individuals are not deficient in their capacity to respond to IFN-␥ stimulation (30). UVB irradiation inhibited IFN-␥-induced ICAM-1 mRNA expression in normal fibroblasts in a dose-dependent manner (mean ED 50 : 45 J͞m 2 UVB; Fig.…”

Section: Resultssupporting

confidence: 88%

“…Recently an XPA knockout mouse has been generated, and the immune response in these repair-deficient mice is clearly hypersensitive to UVB irradiation (32). If our interpretation of our data is correct, our results strengthen the evidence for a contribution of defective immune functions in carcinogenesis in these patients and indicate that strategies directed at supporting or enhancing immunity against skin tumors may be of benefit for these patients (30)(31)(32)(33). Consistent with this assumption is the previously described beneficial effect of intralesional IFN-␣ application into melanoma of an XP patient (34).…”

Section: Discussionsupporting

confidence: 77%

“…Gaspari et al (30) found that in 8 of 8 XP patients NK (natural killer) cells were defective in poly(I)⅐poly(C) induction of IFN-␥. Recently an XPA knockout mouse has been generated, and the immune response in these repair-deficient mice is clearly hypersensitive to UVB irradiation (32).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Photocarcinogenesis and inhibition of intercellular adhesion molecule 1 expression in cells of DNA-repair-defective individuals

Ahrens

Grewe

Berneburg

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cells from patients with xeroderma pigmentosum complementation group D (XP-D) and most patients with trichothiodystrophy (TTD) are deficient in excision repair of ultraviolet (UV) radiation-induced DNA damage. Although in both syndromes this defect is based on mutations in the same gene, XPD, only XP-D, not TTD, individuals have an increased risk of skin cancer. Since the reduction in DNA repair capacity is similar in XP-D and TTD patients, it cannot account for the difference in skin cancer risk. The features of XP-D and TTD might therefore be attributable to differences in the immune response following UV-irradiation, a factor which is presumed to be important for photocarcinogenesis. Sunlight-induced skin cancer represents the most prevalent malignancy in the Caucasian population, and its incidence is increasing (1). The pathogenesis of photocarcinogenesis is complex and only partially understood. Sunlight is a complete carcinogen, and it is generally accepted that ultraviolet B (UVB; 290-320 nm) radiation-induced DNA mutations constitute the initiation event for the generation of malignant skin cells (2). Studies in animals, however, provide evidence for a second mechanism for the development of clinically apparent skin cancer following UVB radiation exposure. In these studies, UVB radiation at subcarcinogenic doses was found to inhibit the surveillance function of the skin immune system directed against UVB radiation-induced skin tumors (3, 4). The importance of this second mechanism for photocarcinogenesis was demonstrated in tumor transplantation studies in mice, which cannot be carried out in humans. The evidence for a role of UVB radiation-induced immunosuppression in human skin cancer is therefore inevitably circumstantial and includes the observation that immunosuppressed humans who have received renal transplants have an increased frequency of sunlight-induced skin cancers (5-8).Here we take advantage of two human syndromes associated with defects in excision repair of UV-induced DNA lesions, namely xeroderma pigmentosum complementation group D (XP-D) and trichothiodystrophy (TTD) (9-11). Cells derived from XP-D and the majority of TTD patients have a defect in nucleotide excision repair (12, 13), which results from mutations in the same gene (XPD) (refs. 14-16 and unpublished results of B. C. Broughton and A.R.L.). Despite this similarity and a similar frequency of UV-induced mutations (17), only XP-D patients have an increased risk of developing skin cancer (10, 11). Since the increased risk of skin cancer in XP-D, as compared with TTD patients, cannot be explained simply by differences in DNA repair capacity, we hypothesized that XP-D and TTD cells might differ in some aspect of the immune response after UVB radiation.To test this hypothesis, the capacity of UVB radiation to suppress transcriptional expression of the intercellular adhesion molecule 1 (ICAM-1) was assessed in comparative studies employing XP-D and TTD cells. ICAM-1 serves as a ligand for leukocyte function-associated antige...

show abstract

Section: Resultssupporting

confidence: 88%

Section: Discussionsupporting

confidence: 77%

See 1 more Smart Citation

Photocarcinogenesis and inhibition of intercellular adhesion molecule 1 expression in cells of DNA-repair-defective individuals

Ahrens

Grewe

Berneburg

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…For example, IFN deficiency states may be involved in a number of diseases. With the possible connection between cytokines and DNA repair (204,205), the decline in IFN levels, resulting from aging or environmental insults (206), may be involved in the pathogenesis of tumors. For the treatment of chronic diseases, prolonged use of IFN-a may be required, as is the practice with hormone replacement or antihypertensive therapy.…”

Section: Perspectivementioning

confidence: 99%

Cytokine therapeutics: lessons from interferonalpha.

Gutterman

1994

Proc. Natl. Acad. Sci. U.S.A.

638

356

View full text Add to dashboard Cite

Cytokines are soluble proteins that allow for communication between cells and the external environment.Interferon (IFN) a, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator ofgrowth and differentiation, affecting cellular communication and signal transduction pathways as well as immunological control. This review focuses on the biological and clinical activities of the cytokine. Originally discovered as an antiviral substance, the efficacy of IFN-a in malignant, viral, immunological, angiogenic, inflammatory, and fibrotic diseases suggests a spectrum of interrelated pathophysiologies. The principles learned from in vivo studies will be discussed, particulady hairy cell leukemia, chronic myelogenous leukemia, certain angiogenic diseases, and hepatitis. After the surprising discovery of activity in a rare B-cell neoplasm, IFN-a emerged as a prototypic tumor suppressor protein that represses the dinhl tumorigenic phenotype in some malgancies capable of differentiation. Regulatory agencies throughout the world have approved IFN-a for treatment of 13

show abstract

“…Heterozygous Xpa mice did not show this cancer prone phenotype after UV exposure, not even when the Xpa mutation was crossed in in hairless mice . Skin cancer predisposition in XP mice might not only involve NER deficiency, but several reports indicate enhanced immunosuppression and impaired natural killer cell function are involved (Gaspari et al,1993;Horio et al,2001;Miyauchi-Hashimoto et al,2001). Xpa mice were also predisposed to tumors of the cornea when exposed to UV radiation, see Table 3 (de .…”

Section: Xpa Deficient Mouse Modelmentioning

confidence: 99%