Modulation of autoantibody production by mycophenolate mofetil: effects on the development of SLE in (NZBxNZW)F1 mice

Ramos, María Ángeles; Piñera, Celestino; Setién, Maria Angeles; Buelta, Luis; Cossío, María Ángeles de Cos; Francisco, Angel-Luis M de; Merino, Ramón; Arias, Manuel

doi:10.1093/ndt/gfg034

Cited by 30 publications

(22 citation statements)

References 17 publications

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“…Equivalent dosing of free MPA at 0.625 mpk did not extend survival, nor did 16-fold more of free drug at 10 mpk. These results demonstrate the therapeutic advantage of using nanoparticles, as published reports have shown that much larger and more frequent free MPA regimens of 30 to 100 mpk every day are used for treating murine lupus (34,35).…”

Section: Figuresupporting

confidence: 70%

Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice

Look

Stern²,

Wang³

et al. 2013

J. Clin. Invest.

110

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The ability to selectively inactivate immune cells with immunosuppressants is a much sought-after modality for the treatment of systemic lupus erythematosus and autoimmunity in general. Here, we designed and tested a novel nanogel drug delivery vehicle for the immunosuppressant mycophenolic acid (MPA). Treatment with MPA-loaded nanogels increased the median survival time (MST) of lupus-prone NZB/W F1 mice by 3 months with prophylactic use (MST was 50 weeks versus 38 weeks without treatment), and by 2 months when administered after the development of severe renal damage (MST after proteinuria onset was 12.5 weeks versus 4 weeks without treatment). Equivalent and greater doses of MPA administered in buffer were not efficacious. Nanogels had enhanced biodistribution to organs and association with immune cells. CD4-targeted nanogels yielded similar therapeutic results compared with nontargeted formulations, with protection from glomerulonephritis and decreases in IFN-γ-positive CD4 T cells. DCs that internalized nanogels helped mediate immunosuppression, as they had reduced production of inflammatory cytokines such as IFN-γ and IL-12. Our results demonstrate efficacy of nanogel-based lupus therapy and implicate a mechanism by which immunosuppression is enhanced, in part, by the targeting of antigen-presenting cells.

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Section: Figuresupporting

confidence: 70%

Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice

Look

Stern²,

Wang³

et al. 2013

J. Clin. Invest.

110

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“…Moreover, (NZBϫNZW)F 1 female mice treated with sirolimus showed a moderate, but nonsignificant, increase in serum IgG1 antibodies at the end of 27 weeks of age; a similar effect had previously been described after treatment of (NZBϫNZW)F 1 female mice with low doses of mycophenolate mofetil. 15 This moderate increase in IgG1 could be related to their protective effect against SLE development in (NZBϫNZW)F 1 female mice. In this sense, the role of T-cells in the pathogenesis of SLE in (NZBϫNZW)F 1 mice has been underlined in several studies.…”

Section: Discussionmentioning

confidence: 94%

Prevention of murine lupus disease in (NZB×NZW)F1 mice by sirolimus treatment

Ramos-Barron

Piñera-Haces

Gómez-Alamillo

et al. 2007

Lupus

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Sirolimus is a new immunosuppressive drug used to avoid allograft rejection. The immunosuppressive effect of sirolimus is due to inhibition of the mammalian target of rapamycin, necessary for the proliferation and clonal expansion of activated T-cells. Because T-cells play a central role in the pathogenesis of autoimmune disease developed in (NZBxNZW)F1 mice, we evaluated the therapeutic use of sirolimus in such mice. (NZBxNZW)F1 female mice received 1mg/kg/day of sirolimus from 12 to 37 weeks of age. The development of autoimmune disease was evaluated by measuring the serum levels of auto-antibodies (autoAbs) and their immunoglobulin isotypes, prevalence of glomerulonephritis and mortality rates. Sirolimus directly inhibited production of autoAbs, glomerular deposits of immunoglobulins and development of proteinuria; also the survival of these mice was prolonged. Our results demonstrate the beneficial effects of sirolimus in preventing the development of lupus disease in (NZBxNZW)F1 female mice.

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“…This suggestion is corroborated by experimental findings in Fas lpr/lpr l upus-prone mice. [41][42][43][44][45] Induction therapy One randomized controlled trial compared mycophenolate mofetil for 12 months with oral cyclophosphamide for 6 months followed by azathioprine for 6 months (both groups also received prednisolone) in 42 Chinese patients with active class IV lupus nephritis. 46 After 12 months, response rates in the two groups were similar, with approximately 80% and 15% of patients achieving complete and partial remission, respectively (Table 1).…”

Section: Mycophenolate Mofetilmentioning

confidence: 99%

Treatment of severe lupus nephritis: the new horizon

Chan

2014

Nat Rev Nephrol

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Lupus nephritis is a common and severe manifestation of systemic lupus erythematosus, and an important cause of both acute kidney injury and end-stage renal disease. Despite its aggressive course, lupus nephritis is amenable to treatment in the majority of patients. The paradigm of immunosuppressive treatment for lupus nephritis has evolved over the past few decades from corticosteroids alone to corticosteroids combined with cyclophosphamide. Sequential treatment regimens using various agents have been formulated for induction and long-term maintenance therapy, and mycophenolate mofetil has emerged as a standard of care option for both induction and maintenance immunosuppressive treatment. The current era has witnessed the emergence of multiple novel therapeutic options, such as calcineurin inhibitors and biologic agents that target key pathogenetic mechanisms of lupus nephritis. Clinical outcomes have improved in parallel with these therapeutic advances. This Review discusses the evidence in support of current standard of care immunosuppressive treatments and emerging therapies, and describes their roles and relative merits in the management of patients with lupus nephritis.

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Modulation of autoantibody production by mycophenolate mofetil: effects on the development of SLE in (NZBxNZW)F1 mice

Abstract: The mechanisms through which MMF controls the development of SLE in (NZB x NZW)F(1) females is highly dependent upon immunosuppressor dose. Interestingly, lower dose MMF selectively reduced IgG2a antibody levels, suggesting that this dose may modulate T(H1) CD4+ activity.

Cited by 30 publications

References 17 publications

Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice

Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice

Prevention of murine lupus disease in (NZB×NZW)F1 mice by sirolimus treatment

Treatment of severe lupus nephritis: the new horizon

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