Immunosuppressive treatments of systemic lupus (SLE) remain associated with significant toxicities; hence, compounds with better toxicity profiles are needed. Dihydroorotate dehydrogenase (DHODH) inhibition with leflunomide has proven to be effective in autoimmune diseases including SLE, but leflunomide can cause a variety of side effects. We hypothesized that 4SC-101, a novel DHODH inhibitor with a more favorable toxicity profile, would be as effective as high-dose cyclophosphamide (CYC) in controlling experimental SLE of female MRL(Fas)lpr mice. Daily oral gavage of 30, 100, and 300 mg/kg 4SC-101 from 12 to 22 weeks of age was compared with either vehicle or CYC treatment (30 mg/kg/ week, i.p.) in terms of efficacy and toxicity. Three hundred milligrams per kilogram 4SC-101 was as effective as CYC in depleting spleen autoreactive T cells, B cells, and plasma cells as well as the respective DNA and RNA serum autoantibodies. This was associated with a comparable amelioration of the renal , dermal , and pulmonary SLE manifestations of MRL(Fas)lpr mice. However , even the highest dose of 4SC-101 had no effect on bone marrow neutrophil counts , which were significantly reduced in CYC-treated mice. Together , the novel DHODH inhibitor 4SC-101 is as effective as high dose CYC in controlling SLE without causing myelosuppression. Hence , DHODH inhibition with 4SC-101 might be suitable to treat active SLE with fewer side effects than CYC. (Am J Pathol
Objectives Interleukin-1 receptor-associated kinase (IRAK)-M suppresses Toll-like receptor (TLR)-mediated activation of innate immunity during infection. A similar role was hypothesised for IRAK-M in autoimmunity. Methods Irak-m-defi cient mice were crossed with autoimmune C57BL/6-lpr/lpr mice and detailed phenotype analysis was performed. Results Irak-m defi ciency converted the mild autoimmune phenotype of C57BL/6-lpr/lpr mice into a massive lymphoproliferative syndrome with lethal autoimmune lung disease and lupus nephritis. Irak-m defi ciency induced a number of interferon-related genes, cytokines and plasma cell survival factors in spleen cells of these mice. Irak-m-defi cient C57BL/6-lpr/lpr mice showed expansion of autoreactive T cells, dysfunctional regulatory T cells and plasma cells which was associated with increased lupus autoantibody production. TLR7 antagonism almost completely abrogated this phenotype consistent with IRAK-M-mediated suppression of TLR7 signalling in vitro. Conclusions These data identify a previously unknown function of IRAK-M-namely, suppression of TLR7-mediated autoimmunity-and mutant IRAK-M as a previously unknown genetic risk for murine SLE.
In summary, recombinant Cpn10 selectively prevents cutaneous lupus and suppresses nephritis in MRL-(Fas)lpr mice without affecting the underlying systemic autoimmune process. Hence, Cpn10 might be useful for the treatment of skin and kidney manifestations of SLE.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.