A Novel Locus Regulates Both Retroviral Glycoprotein 70 and Anti-Glycoprotein 70 Antibody Production in New Zealand Mice When Crossed with BALB/c

Rigby, Robert J.; Rozzo, Stephen J.; Gill, Herpreet; Fernandez-Hart, Tim J; Morley, Bernard J; Izui, Shozo; Kotzin, Brian L.; Vyse, Timothy J.

doi:10.4049/jimmunol.172.8.5078

Cited by 15 publications

(23 citation statements)

References 29 publications

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“…In addition, when individual glomeruli were evaluated histologically, abnormities were observed in 26% of the glomeruli from the ZSJ-0228-treated mice, which is close to the frequency (21.6%) found in the NZW mice (healthy control, which do develop anti-dsDNA antibodies, high serum levels of retroviral gp70 antigen, and nephritis later in life). 23 Compared to this observation, 40% and 52% of the glomeruli in the Dex and saline groups were found to be abnormal, respectively. Though these differences are not statistically significant ( P = 0.19), the apparent trend further supports the superior efficacy of ZSJ-0228 in treating LN (Figure 4F).…”

Section: Resultsmentioning

confidence: 57%

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

et al. 2018

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Nephritis is one of the major complications of systemic lupus erythematosus. While glucocorticoids (GCs) are frequently used as the first-line treatment for lupus nephritis (LN), long-term GC usage is often complicated by severe adverse effects. To address this challenge, we have developed a polyethylene glycol-based macromolecular prodrug (ZSJ-0228) of dexamethasone, which self-assembles into micelles in aqueous media. When compared to the dose equivalent daily dexamethasone 21-phosphate disodium (Dex) treatment, monthly intravenous administration of ZSJ-0228 for two months significantly improved the survival of lupus-prone NZB/W F1 mice and was much more effective in normalizing proteinuria, with clear histological evidence of nephritis resolution. Different from the dose equivalent daily Dex treatment, monthly ZSJ-0228 administration has no impact on the serum anti-double-stranded DNA (anti-dsDNA) antibody level but can significantly reduce renal immune complex deposition. No significant systemic toxicities of GCs (e.g., total IgG reduction, adrenal gland atrophy, and osteopenia) were found to be associated with ZSJ-0228 treatment. In vivo imaging and flow cytometry studies revealed that the fluorescent-labeled ZSJ-0228 primarily distributed to the inflamed kidney after systemic administration, with renal myeloid cells and proximal tubular epithelial cells mainly responsible for its kidney retention. Collectively, these data suggest that the ZSJ-0228’s potent local anti-inflammatory/immunosuppressive effects and improved safety may be attributed to its nephrotropicity and cellular sequestration at the inflamed kidney tissues. Pending further optimization, it may be developed into an effective and safe therapy for improved clinical management of LN.

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Section: Resultsmentioning

confidence: 57%

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

et al. 2018

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“…In contrast to earlier studies (29), genome-wide linkage analyses involving NZB, NZW, and BXSB mice had failed to show linkage of serum gp70 levels with the H2 locus (7, 11, 28). In contrast, we recently noted the linkage of serum gp70 levels with a locus on distal chromosome 4 of both NZB and NZW mice (28,30). Preliminary studies have shown that B6 mice bearing the NZB-derived Nba1 interval on distal chromosome 4 have significantly increased concentrations of serum gp70.…”

Section: Discussionmentioning

confidence: 94%

Differential Role of Three Major New Zealand Black-Derived Loci Linked with Yaa-Induced Murine Lupus Nephritis

Kikuchi¹,

Fossati-Jimack

Moll³

et al. 2005

The Journal of Immunology

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By assessing the development of Y-linked autoimmune acceleration (Yaa) gene-induced systemic lupus erythematosus in C57BL/6 (B6) × (New Zealand Black (NZB) × B6.Yaa)F1 backcross male mice, we mapped three major susceptibility loci derived from the NZB strain. These three quantitative trait loci (QTL) on NZB chromosomes 1, 7, and 13 differentially regulated three different autoimmune traits: anti-nuclear autoantibody production, gp70-anti-gp70 immune complex (gp70 IC) formation, and glomerulonephritis. Contributions to the disease traits were further confirmed by generating and analyzing three different B6.Yaa congenic mice, each carrying one individual NZB QTL. The chromosome 1 locus that overlapped with the previously identified Nba2 (NZB autoimmunity 2) locus regulated all three traits. A newly identified chromosome 7 locus, designated Nba5, selectively promoted anti-gp70 autoantibody production, hence the formation of gp70 IC and glomerulonephritis. B6.Yaa mice bearing the NZB chromosome 13 locus displayed increased serum gp70 production, but not gp70 IC formation and glomerulonephritis. This locus, called Sgp3 (serum gp70 production 3), selectively regulated the production of serum gp70, thereby contributing to the formation of nephritogenic gp70 IC and glomerulonephritis, in combination with Nba2 and Nba5 in NZB mice. Among these three loci, a major role of Nba2 was demonstrated, because B6.Yaa Nba2 congenic male mice developed the most severe disease. Finally, our analysis revealed the presence in B6 mice of an H2-linked QTL, which regulated autoantibody production. This locus had no apparent individual effect, but most likely modulated disease severity through interaction with NZB-derived susceptibility loci.

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“…In crosses with the NZB and New Zealand White (NZW) parental strains of the autoimmune (NZB ϫ NZW)F 1 strain, gp70IC levels were linked to the MHC on chromosome 17 (8,12) and to a locus on chromosome 7 (13). Crosses with these strains have also shown linkage of gp70 levels to chromosome 4 (14,15). Furthermore, in crosses with the NZB strain, both gp70 and gp70IC levels were linked to chromosome 13 (8,16).…”

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confidence: 86%

The Bxs6 Locus of BXSB Mice Is Sufficient for High-Level Expression of gp70 and the Production of gp70 Immune Complexes

Rankin¹,

Boyle

Rose³

et al. 2007

The Journal of Immunology

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High levels of the retroviral envelope protein gp70 and gp70 immune complexes have been linked to a single locus on chromosome 13 (Bxs6) in the BXSB model, to which linkage of nephritis was also seen. Congenic lines containing the BXSB Bxs6 interval on a non-autoimmune C57BL/10 background were bred in the presence or absence of the BXSB Y chromosome autoimmune accelerator gene (Yaa), which accelerates disease in male mice. In these mice, we have shown that Bxs6 is sufficient to cause high-level expression of gp70 and the production of gp70 autoantibodies, independently of Yaa, with gp70 immune complex levels enhanced by Yaa. In the presence of Yaa, Bxs6 also causes mild nephritis, and interestingly the sporadic production of high levels of anti-DNA Abs in some mice. Fine mapping using rare recombinant mice suggested that Bxs6 lies between 59.7 and 74.8 megabases (Mb), although the interval of 0.6 Mb between 73.6 and 78.6 Mb on chromosome 13 cannot be excluded in this study.

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A Novel Locus Regulates Both Retroviral Glycoprotein 70 and Anti-Glycoprotein 70 Antibody Production in New Zealand Mice When Crossed with BALB/c

Cited by 15 publications

References 29 publications

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

Differential Role of Three Major New Zealand Black-Derived Loci Linked with Yaa-Induced Murine Lupus Nephritis

The Bxs6 Locus of BXSB Mice Is Sufficient for High-Level Expression of gp70 and the Production of gp70 Immune Complexes

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