SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4−CD8− T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

Construction of Functional Renal Targeting Nano Drug Liposome and Its Effect on Lupus Nephritis

The main purpose of this study was to explore treatment effect of hydroxychloroquine-loaded OX7 nanoliposomes in murine systemic lupus erythematosus (SLE) disease model. Modification of OX7 monoclonal antibody conferred hydroxychloroquine-loaded OX7 nanoliposomes targeting to renal mesangial cells. The SLE mice models were treated with functional nano liposome via tail vein injection, and then the therapeutic effects on lupus nephritis and complicated pneumonia were evaluated. Our research showed that chronic graft versus host disease lupus nephritis mice model has similar characteristic features of renal pathological damage with human SLE, and is reliable for related study. The symptoms and incidence of pneumonia in model mice were significantly alleviated and reduced after treatment with functional nano liposomes prepared in this experiment.

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells, such as myeloid cells, B cells, and T cells. It controls intracellular signaling pathways, including Syk and Src. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model.Methods: For the lupus model, we used Faslpr/lpr mice (C57BL/6 background). Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed in 35-week-old mice. Serum levels of anti-dsDNA antibody and rheumatoid factor were determined using ELISA. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were generated and analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody and rheumatoid factor, and increased splenic B220+CD4-CD8- T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice.Conclusions: SH3BP2 deficiency ameliorated clinical and immunological manifestations in lupus-prone mice, possibly via targeting dendritic cell differentiation. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

Amiselimod (MT-1303), a Novel Sphingosine 1-Phosphate Receptor-1 Modulator, Potently Inhibits the Progression of Lupus Nephritis in Two Murine SLE Models

Amiselimod (MT-1303) is a novel and selective sphingosine 1-phosphate receptor-1 (S1P1) modulator with a more favorable cardiac safety profile than other S1P1 receptor modulators. In this study, we evaluated the effects of MT-1303 on the progression of lupus nephritis in two well-known murine systemic lupus erythematosus (SLE) models, MRL/lpr and NZBWF1 mice, compared with those of FK506. Daily oral doses of 0.1 and 0.3 mg/kg MT-1303 not only inhibited the development of lupus nephritis when administered before onset in MRL/lpr and NZBWF1 mice but also improved symptoms of lupus nephritis when administered after onset in MRL/lpr mice. Its efficacy in these models was more potent or comparable to that of FK506 (1 and 3 mg/kg). In histological analysis, treatment with MT-1303 inhibited infiltration of T cells into the kidneys, mesangial expansion, and glomerular sclerosis. MT-1303 treatment resulted in a marked reduction in T cells and B cells in the peripheral blood and significantly inhibited increases in the number of plasma cells in the spleen and T cells in the kidneys. In addition, administration of MT-1303 suppressed elevations in serum anti-dsDNA antibody levels in MRL/lpr mice, but not in NZBWF1 mice. Our findings show that MT-1303 exhibits marked therapeutic effects on lupus nephritis in two SLE models, likely by reducing the infiltration of autoreactive T cells into the kidneys. These results suggest that MT-1303 has the potential to be used as a therapeutic agent for patients suffering from SLE, including lupus nephritis.

Central Nervous System Delivery and Biodistribution Analysis of an Antibody-Enzyme Fusion for the Treatment of Lafora Disease

Lafora disease is a fatal juvenile epilepsy, characterized by the malignant accumulation of aberrant glucan inclusions called Lafora Bodies (LBs). Cerebral delivery of protein-based therapeutics for the clearance of Lafora Bodies remain a unique challenge in the field. Recently, a humanized antigen-binding fragment (hFab) derived from a murine systemic lupus erythematosus DNA autoantibody (3E10) has been shown to mediate cell penetration and been proposed as a broadly applicable carrier to mediate cellular targeting and uptake. We report studies on cerebral delivery of VAL-0417, an antibody-enzyme fusion composed of the 3E10 hFab and human pancreatic α-amylase for the clearance of LBs in a mouse model of lafora disease. Herein, we report development of an enzyme-linked immunosorbant-based bioassay to detect VAL-0417 post treatment as a measure of delivery efficacy. We demonstrate the robust and sensitive detection of the fusion protein in multiple tissue types. Using our method, we measured biodistribution in different methods of delivery. We found intracerebroventricular administration provided the most robust delivery, while intrathecal administration only showed modest biodistribution. These data define critical steps in the translational pipeline of VAL-0417for the treatment of Lafora disease.