Journal article
Abnormal thymic maturation and lymphoproliferation in MRL-Fas(lpr/lpr) mice can be partially reversed by synthetic oligonucleotides: implications for systemic lupus erythematosus and autoimmune lymphoproliferative syndrome
Lupus, Vol.26(7), pp.734-745
06/01/2017
DOI: 10.1177/0961203316676381
PMID: 27837196
Abstract
MRL-Fas (lpr/lpr) mice represent an excellent animal model for studying non-malignant lymphoproliferation, regeneration and systemic autoimmunity. Retro-transposon insertion into the second intron of the pro-apoptotic Fas gene appears to be responsible for both lymphoproliferation and autoimmunity, while other genes are more likely to contribute to the regenerative healing characteristic of this mouse strain. Previous studies have shown that neonatal thymectomy can halt the development of abnormal lymphoproliferation. Whereas at four weeks of age primary and secondary lymphoid organs appear to be grossly intact, vigorous lymphoproliferation and autoantibody production subsequently ensues. This is first noticeable at six weeks of age, at which time lymph nodes, spleens and thymuses, but not the bone marrow, become infiltrated with abnormal B220(+)CD3(+)CD4(-)CD8(-) T cells. Around the same time, thymuses show a significant drop in CD4(+)CD8(+)double-positive T cells generating an abnormal ratio between double-positive and single-positive thymocytes. The objective of current study was to evaluate the effect of synthetic oligonucleotides-toll-like receptor antagonists on early lymphoid development in this strain of mice. Herein, we demonstrate the ability of synthetic oligonucleotides made with the nuclease-resistant phosphorothioate backbone to partially reverse abnormal lymphoproliferation and thymic involution in pre-diseased MRL-Fas (lpr/lpr) mice when administered intraperitoneally starting from week four of age. This curative effect of oligonucleotides was primary sequence/secondary oligonucleotide structure-independent, suggesting an effect through the toll-like receptor 7. A similar approach may potentially benefit patients with autoimmune lymphoproliferative syndrome who, like MRL-Fas (lpr/lpr) mice, carry a mutation in the Fas gene.
Details
- Title: Subtitle
- Abnormal thymic maturation and lymphoproliferation in MRL-Fas(lpr/lpr) mice can be partially reversed by synthetic oligonucleotides: implications for systemic lupus erythematosus and autoimmune lymphoproliferative syndrome
- Creators
- R. F. Ashman - University of IowaN. Singh - University of IowaP. S. Lenert - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Lupus, Vol.26(7), pp.734-745
- Publisher
- Sage
- DOI
- 10.1177/0961203316676381
- PMID
- 27837196
- ISSN
- 0961-2033
- eISSN
- 1477-0962
- Number of pages
- 12
- Grant note
- University of Iowa, Carver College of Medicine
- Language
- English
- Date published
- 06/01/2017
- Academic Unit
- Epidemiology; Immunology; Internal Medicine
- Record Identifier
- 9984359797802771
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