title: Abnormal thymic maturation and lymphoproliferation in MRL-Faslpr/lprmice can be partially reversed by synthetic oligonucleotides: implications for systemic lupus erythematosus and autoimmune lymphoproliferative syndrome.
abstract: MRL-Faslpr/lprmice 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-Faslpr/lprmice 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-Faslpr/lprmice, carry a mutation in the Fas gene.
authors.affiliation: Division of Immunology, Department of Internal Medicine, Carver College of Medicine, Iowa City, IA, USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Ashman
authors.affiliation: Division of Immunology, Department of Internal Medicine, Carver College of Medicine, Iowa City, IA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Singh
authors.affiliation: Division of Immunology, Department of Internal Medicine, Carver College of Medicine, Iowa City, IA, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Lenert
mesh_terms: D000818:Animals; D056735:Autoimmune Lymphoproliferative Syndrome / Q000178:diet therapy* / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D009841:Oligonucleotides; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors
keywords: Thymus; autoimmune lymphoproliferative syndrome; oligonucleotides; systemic lupus erythematosus; toll-like receptors