scholarly journals An inhibitor of spleen tyrosine kinase suppresses experimental crescentic glomerulonephritis

2018 ◽  
Vol 32 ◽  
pp. 205873841878340 ◽  
Author(s):  
Yingjie Han ◽  
Frank Y Ma ◽  
Julie Di Paolo ◽  
David J Nikolic-Paterson
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Crescentic Glomerulonephritis ◽  
Mesangial Cells ◽  
Therapeutic Potential ◽  
Myeloid Cells ◽  
Tubular Damage ◽  
Spleen Tyrosine Kinase ◽  
Markers Of Inflammation ◽  
Syk Inhibitor

Non-selective inhibitors of spleen tyrosine kinase (SYK) efficiently suppress disease in T cell-dependent models of crescentic glomerulonephritis. However, the therapeutic potential of selective SYK inhibitors in this disease has not been established. In addition, we lack knowledge regarding SYK expression in non-myeloid cells in glomerulonephritis. We addressed these two issues in a rat model of nephrotoxic serum nephritis (NTN) using a SYK inhibitor, GS-492429. Disease was induced in Sprague-Dawley rats (Study 1) or Wistar-Kyoto (WKY) rats (Study 2) by immunization with sheep IgG and administration of sheep anti-rat nephrotoxic serum. Animals were untreated or received GS-492429 (30 mg/kg/bid) or vehicle treatment from 2 h before nephrotoxic serum injection until being killed 3 or 24 h later (Study 1) or 14 days later (Study 2). Two-colour confocal microscopy found that SYK expression in NTN kidney was restricted to myeloid cells and platelets, with no evidence of SYK expression by T cells, mesangial cells, podocytes or tubular epithelial cells. In Study 1, GS-492429 treatment significantly reduced glomerular neutrophil and macrophage infiltration, with protection from glomerular thrombosis and proteinuria. In Study 2, GS-492429 treatment reduced glomerular crescent formation by 70% on day 14 NTN in conjunction with reduced glomerular thrombosis, glomerulosclerosis and tubular damage. This was accompanied by a marked reduction in markers of inflammation (CCL2, TNF-α, NOS2, MMP-12). Importantly, the protective effects of GS-492429 were independent of T cell infiltration and activation and independent of JAK/STAT3 signalling. In conclusion, this study demonstrates that a SYK inhibitor can suppress the development of crescentic glomerulonephritis through effects upon myeloid cells and platelets.

scholarly journals Spleen Tyrosine Kinase Inhibition Ameliorates Tubular Inflammation in IgA Nephropathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Wai Han Yiu ◽  
Kam Wa Chan ◽  
Loretta Y. Y. Chan ◽  
Joseph C. K. Leung ◽  
Kar Neng Lai ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Iga Nephropathy ◽  
Conditioned Medium ◽  
Mesangial Cells ◽  
Mapk Signaling ◽  
Tubular Damage ◽  
Renal Tubules ◽  
Spleen Tyrosine Kinase ◽  
Human Mesangial Cells ◽  
Healthy Control

Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase involved in signal transduction in a variety of immune responses. It has been demonstrated that Syk plays a pathogenic role in orchestrating inflammatory responses and cell proliferation in human mesangial cells (HMC) in IgA nephropathy (IgAN). However, whether Syk is involved in tubular damage in IgAN remains unknown. Using human kidney biopsy specimens, we found that Syk was activated in renal tubules of biopsy-proven IgAN patients with an increase in total and phosphorylated levels compared to that from healthy control subjects. In vitro, cultured proximal tubular epithelial cells (PTECs) were stimulated with conditioned medium prepared from human mesangial cells incubated with polymeric IgA (IgA-HMC) from patients with IgAN or healthy control. Induction of IL-6, IL-8, and ICAM-1 synthesis from cultured PTECs incubated with IgA-HMC conditioned medium was significantly suppressed by treatment with the Syk inhibitor R406 compared to that from healthy control. Furthermore, R406 downregulated expression of phosphorylated p65 NF-κB and p-42/p-44 MAPK, and attenuated TNF-α-induced cytokine production in PTECs. Taken together, our findings suggest that Syk mediates IgA-HMC conditioned medium-induced inflammation in tubular cells via activation of NF-κB and p-42/p-44 MAPK signaling. Inhibition of Syk may be a potential therapeutic approach for tubulointerstitial injury in IgAN.

An Oral Spleen Tyrosine Kinase (Syk) Inhibitor for Rheumatoid Arthritis

2010 ◽  
Vol 363 (14) ◽  
pp. 1303-1312 ◽  
Author(s):  
Michael E. Weinblatt ◽  
Arthur Kavanaugh ◽  
Mark C. Genovese ◽  
Theresa K. Musser ◽  
Elliott B. Grossbard ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tyrosine Kinase ◽  
Spleen Tyrosine Kinase ◽  
Syk Inhibitor

scholarly journals A Novel Spleen Tyrosine Kinase Inhibitor Suppresses Invasiveness of Rheumatoid Arthritis Fibroblast Like Synoviocytes and Improves Collagen Induced Arthritis

2020 ◽  
Author(s):  
Seon Uk Kim ◽  
Hyun Jung Yoo ◽  
Jung Ho Kim ◽  
Hae Jun Hwang ◽  
Jin Kyun Park ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Spleen Tyrosine Kinase ◽  
Collagen Induced Arthritis ◽  
Tnf Α ◽  
Clinical Arthritis ◽  
Syk Inhibitor ◽  
Fibroblast Like Synoviocytes

Abstract Background/PurposeRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by bone and cartilage destruction with leukocyte infiltration and activation at synovial tissue. The fibroblast-like synoviocytes (FLS) have a central role in disease pathogenesis and their invasiveness correlates with articular damage in RA patients. Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase known to have a crucial role in immune receptor signaling. This study aimed to evaluate the inhibitory effect of a novel small-molecule SYK inhibitor, SKI-O-592, on the invasiveness of RA FLS and inflammation of monocytes in vitro and in a mouse collagen-induced arthritis (CIA) model in vivo.MethodsFLS were isolated from synovial tissues of RA patients. FLS were treated with SKI-O-592 for 1 hr and then stimulated with tumor necrosis factor-alpha (TNF-α) for 48 hr. After stimulation, cell viability was measured using cell counting kit-8 (CCK-8) assay. The levels of IL-6, IL-8, CXCL10, MMP-3, and TNF-α were measured in culture supernatant of RA FLS and the monocytic cell line THP-1 cells by ELISA. Wound healing assay transwell migration and invasion assay using RA FLS was performed to evaluate cell migration ability. The adhesion ability of FLS was evaluated by co-culture with calcein-AM labeled THP-1 cells, and the expression of VCAM-1, ICAM-1, α-tubulin, β-actin, total and phosphorylated SYK, c-Jun N-terminal kinase (JNK), p38, ERK, phosphorylated c-Jun, mitogen-activated protein kinase kinase 4 (MKK4), and MKK3/6 was determined by Western blotting. CIA was developed in DBA/1J mice. Clinical arthritis score and histological scores were evaluated after treatment with SKI-O-592.ResultsSKI-O-592 reduced the secretion of chemokine, CXCL10 in RA FLS. Migration of cells to the wound region and through membrane pores and matrigel were decreased by SKI-O-592. Phosphorylation of JNK and p38 was reduced by SKI-O-592 after TNF-α stimulation. SKI-O-592 decreased secretion of TNF-α levels dose-dependently in THP-1 cells with IgG stimulation. The viability and proliferation of FLS and THP-1 were not affected by SKI-O-592. In the CIA model, scores for clinical arthritis and histology were decreased following SKI-O-592 treatment.ConclusionSKI-O-592 inhibited the invasiveness of RA FLS and had an anti-inflammatory effect on monocytes. SKI-O-592 exhibited therapeutic effects in the mouse CIA model by improving clinical and histological scores with amelioration of joint destruction. In conclusion, a novel SYK inhibitor, SKI-O-592, may provide a new therapeutic option for RA patients.

scholarly journals Anti-CD27 Enhances Lymphoma Immunotherapy through Profound Myeloid Cell Recruitment

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3024-3024
Author(s):  
Anna H Turaj ◽  
Vikki L Field ◽  
Claude H.T. Chan ◽  
Christine A. Penfold ◽  
Jinny H. Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Nk Cells ◽  
Research Funding ◽  
Therapeutic Potential ◽  
Cell Lymphoma ◽  
Myeloid Cells ◽  
B Cell Lymphoma ◽  
Anti Cd20

Abstract Direct-targeting monoclonal antibodies (mAb) such as anti-CD20 mAb are thought to elicit their anti-tumor function through antibody-dependent cellular phagocytosis (ADCP) mediated by myeloid cells (monocytes and macrophages), with little involvement of T cells. In contrast, immunomodulatory mAbs to TNFR superfamily members, CD27, OX40 and CD137, function by augmenting T-cell responses. We examined the therapeutic potential of combining anti-CD20 mAb with a panel of immunomodulatory mAbs (OX40, CD137, CD27, TIGIT, GITR, CTLA4, PD-1). In the syngeneic BCL1 B-cell lymphoma mouse model only an agonistic mAb to CD27, provided a synergistic effect when combined with anti-CD20. Anti-CD20 and anti-CD27 mAb individually provided modest therapeutic benefit (median survival 33 days and 62 days, respectively), but mice treated with the combination survived beyond 100 days. Similar synergistic survival benefit was observed in another B-cell lymphoma model, A31, and in BCL1-bearing human CD27 transgenic mice, when anti-CD20 was combined with varlilumab, an anti-human CD27 mAb currently under clinical investigation. We observed that in mice treated with anti-CD27, there was an early and substantial increase in intra-tumoral monocyte, neutrophil and macrophage infiltration. CD27 is expressed constitutively on T and NK cells but not myeloid cells or the tumor itself. To investigate whether CD27 agonism promotes intra-tumoral myeloid cell infiltration through T cells, we depleted T cells in the BCL1model. Surprisingly, CD4 or CD8 T-cell depletion had no effect on the survival of anti-CD20 and anti-CD27-treated mice, suggesting that the remaining CD27+ immune effector cells, NK cells, are required. To further probe the relative importance of these two sub-sets, we performed experiments in γ chain knockout mice, where activatory FcγR are not expressed. Here, anti-CD27 mediated T-cell activation can still occur via crosslinking from the inhibitory FcγRII, but effector function through NK cells, mediated through activatory FcγR, is abrogated. In this model, the therapeutic benefit of anti-CD27 was completely abolished, thereby supporting the requirement for NK cells. We hypothesize that anti-CD27 stimulates CD27+ NK cells to release chemokines that draw myeloid cells into the tumor, where they subsequently perform augmented anti-CD20 mediated ADCP. These data demonstrate the clear therapeutic potential of combining direct targeting and immunomodulatory mAb but that the therapeutic mechanism of action may differ to that expected; here involving a previously unheralded effect of anti-CD27 on myeloid infiltration. Based upon these data, we have implemented a phase II clinical trial examining rituximab and varlilumab in B-cell lymphoma, which will commence recruitment shortly. Disclosures Keler: Celldex Therapeutics: Employment, Equity Ownership. Johnson:Celldex Therapeutics: Research Funding. Al-Shamkhani:Celldex Therapeutics: Patents & Royalties: On therapeutic use of antibodies targeting anti-CD27 and another applied for anti-CD20/anti-CD27 use, Research Funding. Glennie:Celldex Therapeutics: Patents & Royalties: Patent on therapeutics use of antibodies targeting human CD27 and patent for anti-CD20+anti-CD27 applied. Cragg:Baxalta: Consultancy; Gilead Sciences: Research Funding; GSK: Research Funding; Roche: Consultancy, Research Funding; Bioinvent International: Consultancy, Research Funding. Lim:Celldex Therapeutics: Patents & Royalties: Patent for anti-CD20+anti-CD27 applied, Research Funding.

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