Suppression of lupus nephritis and skin lesions in MRL/lpr mice by administration of the topoisomerase I inhibitor irinotecan.

Keil, Andreas; Hall, Sean; Körner, Meike; Herrmann, Martin; Schmid, Ralph; Frese, Steffen R. (2016). Suppression of lupus nephritis and skin lesions in MRL/lpr mice by administration of the topoisomerase I inhibitor irinotecan. Arthritis research & therapy, 18(243), p. 243. BioMed Central 10.1186/s13075-016-1144-5

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BACKGROUND

Since the precise mechanism for the pathogenesis of systemic lupus erythematosus (SLE) is unknown, no targeted therapies in addition to immunosuppression are available so far. We recently demonstrated that administration of the topoisomerase I (topo I) inhibitor irinotecan at extremely low concentrations reversed established lupus nephritis in NZB/NZW mice. While profound immunosuppression was absent, we proposed changes in DNA relaxation and anti-double-stranded (ds)DNA antibody binding as the underlying mechanism. To exclude that these effects were restricted to NZB/NZW mice, irinotecan was used in a genetically different strain of lupus-prone mice.

METHODS

MRL/lpr mice were treated with high- and low-dose irinotecan beginning at 8 weeks of age. Treatment was repeated every fourth week. In vitro, DNA was relaxed by recombinant topo I, and altered anti-dsDNA antibody binding was measured by enzyme-linked immunosorbent assay.

RESULTS

Administration of both high- and low-dose irinotecan prevented proteinuria and prolonged survival in MRL/lpr mice. Moreover, both concentrations of irinotecan significantly improved histopathology of the skin at 18 weeks of age. While only high-dose irinotecan diminished the numbers of plasmablasts and double-negative T cells, no changes in IgG-secreting cells or anti-dsDNA IgG were observed. In vitro, relaxation of DNA by topo I increased the binding of anti-dsDNA IgG but not the binding of anti-dsDNA IgM derived from the plasma of MRL/lpr mice.

CONCLUSION

The beneficial effects of topo I inhibition in a second, genetically different strain of lupus-prone mice strongly implicate irinotecan as a new therapeutic option for human SLE.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Keil, Andreas; Hall, Sean; Schmid, Ralph and Frese, Steffen R.

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1478-6354

Publisher:

BioMed Central

Language:

English

Submitter:

Thomas Michael Marti

Date Deposited:

25 Jan 2017 10:20

Last Modified:

29 Jan 2017 02:13

Publisher DOI:

10.1186/s13075-016-1144-5

PubMed ID:

27770825

Uncontrolled Keywords:

Alternative treatment for SLE; Anti-dsDNA binding; DNA relaxation; Inhibitors of topoisomerase I; Lupus nephritis; Lupus-like skin lesions; Systemic lupus erythematosus (SLE)

BORIS DOI:

10.7892/boris.93733

URI:

https://boris.unibe.ch/id/eprint/93733

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