A5015756622- Chemokine receptors and signaling
- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- Monoclonal and Polyclonal Antibodies Research
- Immune cells in cancer
- Psoriasis: Treatment and Pathogenesis
- Renal Diseases and Glomerulopathies
- Complement system in diseases
- T-cell and B-cell Immunology
- Inflammatory Bowel Disease
- Cytokine Signaling Pathways and Interactions
- Chronic Kidney Disease and Diabetes
- Liver Disease Diagnosis and Treatment
- Dermatology and Skin Diseases
- Glycosylation and Glycoproteins Research
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Liver Diseases and Immunity
- Cancer, Stress, Anesthesia, and Immune Response
- Nanoplatforms for cancer theranostics
- Urticaria and Related Conditions
- Pancreatic and Hepatic Oncology Research
- HIV/AIDS oral health manifestations
- Mast cells and histamine
- CAR-T cell therapy research
ChemoCentryx (United States)
2015-2024
Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) proteinase 3. In manner that requires activation the alternative complement pathway, passive transfer antibodies to mouse MPO (anti-MPO) induces model NCGN closely mimics human disease. Here, we confirm importance C5aR/CD88 in mediation anti-MPO-induced report C6 not required. We further demonstrate deficiency C5a-like...
The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. Chemokine receptor 9 (CCR9) is known to be central migration immune cells into the intestine. Its only ligand, CCL25, expressed at mucosal surface intestine elevated in intestinal inflammation. To date, there are no reports small-molecule antagonists targeting CCR9. We report, first time, discovery small molecule,...
The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective potent C5aR antagonist challenging. Here we describe the characterization CCX168 (avacopan), orally administered inhibitor. blocked C5a binding, C5a-mediated migration, calcium mobilization, CD11b upregulation in U937 cells as well freshly isolated human neutrophils. retains high potency when present blood. A transgenic knock-in mouse model...
Chemokine (C-C motif) receptor 2 (CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which currently in two separate phase clinical trials diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels type diabetics. In this report, we describe effects compound on glycemic renal function parameters mice. Since CCX140-B a low affinity mouse CCR2, transgenic human knockin mice were generated...
Significance Pancreatic ductal adenocarcinoma cancer (PDAC) cells have an exceptional propensity to invade nerves via pronounced crosstalk between and cells, but the mechanisms of this early neural invasion are yet unknown. By using genetically engineered mouse models, we show that in precursor stage PDAC induces generation ready-to-use for dissemination by secreting chemokine CXCL12 attracts glia (Schwann) nerves. This migration cancerous at very intriguingly attenuates cancer-associated...
Nonalcoholic fatty liver disease (NAFLD) is a common disease, closely associated with obesity and insulin resistance. We investigated the presence of subset myeloid cells metabolic disturbance in patients NAFLD murine model obesity-induced disease. Gene protein expression serum was RT-PCR or ELISA correlated to clinical Liver-infiltrating immune were isolated from normal diseased human for flow cytometric analysis. In animal experiments, mice fed high-fat diet (60% calories fat) 16 wk, 30%...
Abstract mAbs that neutralize IL-17 or its receptor have proven efficacious in treating moderate-to-severe psoriasis, confirming as an important driver of this disease. In mice, a rare population T cells, γδT17 appears to be dominant source experimental psoriasis. These cells traffic between lymph nodes and the skin, are identified by their coexpression TCR variable regions γ4 δ4. homologous Vγ9Vδ2 cell human psoriatic plaques. study we report potent specific small molecule antagonist CCR6...
The anaphylatoxin C5a and its receptor C5aR (CD88) are complement pathway effectors implicated in renal diseases, including ANCA-associated vasculitis. We investigated the kidney expression of a second C5L2 by using immunohistochemistry, situ hybridization, spatial gene on formalin-fixed, paraffin-embedded human mouse kidney. was detected interstitial macrophages multiple tubular regions, distal proximal; had similar pattern. 5/6 nephrectomy model chronic injury exhibited increased...
Abstract Several types of psoriasiform dermatitis are associated with increased IL-36 cytokine activity in the skin. A rare, but severe, psoriasis-like disorder, generalized pustular psoriasis (GPP), is linked to loss-of-function mutations gene encoding IL-36RA, an important negative regulator signaling. To understand effects dysregulation a mouse model, we studied skin inflammation induced by intradermal injections preactivated IL-36α. We found immune cells infiltrating IL-36α–injected be...
C-C chemokine receptor 2 (CCR2) is a key driver of monocyte/macrophage trafficking to sites inflammation and has long been considered target for intervention in autoimmune disease. However, systemic administration CCR2 antagonists associated with marked increases CCL2, ligand, the blood. This heretofore unexplained phenomenon complicates interpretation vivo responses antagonism. We report that CCL2 elevation after pharmacological blockade due interruption balance between secretion by variety...
While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for movement of leukocytes into small intestine development small-intestinal inflammation, role this chemokine-receptor pair in colonic inflammation is not clear. Toward end, we compared protein levels healthy individuals to those patients with ulcerative colitis. In addition, determined effect pharmacological inhibition mdr1a(-/-) mouse model Colon samples from colitis had significantly...
Meeting abstracts Trafficking and expansion of myeloid derived suppressor cells (MDSCs) plays a major role in immune suppression tumor. MDSCs express chemokine receptors which likely mediate their recruitment to the tumor microenvironment. Suppression T is also mediated by
Focal segmental glomerulosclerosis (FSGS) comprises a group of uncommon disorders that present with marked proteinuria, nephrotic syndrome, progressive renal failure and characteristic glomerular lesions on histopathology. The current standard care for patients FSGS include immunosuppressive drugs such as glucocorticoids followed by calcineurin inhibitors, if needed intolerance or inadequate response to glucocorticoids. Renin-angiotensin-aldosterone (RAAS) blockers are also used control an...
Abstract Pancreatic cancer is an aggressive malignancy with 5 year survival rate of less than percent. The predominant immune cells infiltrating the tumor microenvironment are monocytes/macrophages, which reported to support growth by suppressing host responses tumor. Recruitment monocytes various tissues, including tumors, dependent upon activation chemokine receptor CCR2 one or more chemokines CCL2, CCL8 and CCL13. In preclinical clinical studies, inhibition in pancreatic has shown...
The following manuscript was published as a Fast Forward article on February 29, 2012: Sullivan TJ, Dairaghi DJ, Krasinski A, Miao Z, Wang Y, Zhao BN, Baumgart T, Berahovich R, Ertl LS, Pennell Seitz L, S, Ungashe Wei Johnson D, Boring Tsou C-L, Charo IF, Bekker P, Schall and Jaen JC, Characterization of CCX140-B, an orally bioavailable antagonist the CCR2 chemokine receptor, for treatment type 2 diabetes associated complications. J Pharmacol Exp Ther jpet.111.190918;...
Abstract Pancreatic cancer is an aggressive malignancy with a 5 year survival rate of less than five percent. The predominant immune cells infiltrating the tumor microenvironment are monocytes/macrophages, which reported to support growth by suppressing host responses tumor. Recruitment monocytes various tissues, including tumors, dependent upon activation chemokine receptor CCR2 one or more chemokines CCL2, CCL8 and CCL13. In preclinical clinical studies, inhibition in pancreatic has shown...
The interaction of PD-L1 with PD-1 is a major immune checkpoint that limits effector T cell function against cancer cells; monoclonal antibodies block this pathway have been approved in multiple tumor indications. As next generation therapy, small molecule inhibitors inherent drug properties may be advantageous for certain patient populations compared to antibody therapies. In report we present the pharmacology orally-available, inhibitor CCX559 immunotherapy. potently and selectively...
Background: In recent years, antibody-based therapies targeting the Programmed cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) immune checkpoint axis have gained tremendous success in cancer immunotherapy. We embarked on an effort to identify and develop small molecules capable of this checkpoint, with aim provide new therapeutic options improved anticancer responses, increased tumor penetration, shorter half-life better managing related adverse events, lower cost goods. Methods:...
PurposeWhile CCR9-mediated migration of immune cells from the circulation into inflamed small intestine has been well documented, role this chemokine receptor in colonic inflammation remained largely uninvestigated. This study describes presence CCR9 ligand (TECK) human colon samples healthy and IBD subjects. It also key played by CCR9/TECK spontaneous development colitis a genetic mouse model effective treatment condition with antagonists.
e13580 Background: Glioblastoma (GBM) is the most common form of malignant brain cancer. Despite aggressive therapy, consisting radiotherapy, surgical resection, and chemotherapeutic treatment, mean survival from time diagnosis remains little more than one year. The chemokine receptor CXCR7 highly expressed on both human glioma cells tumor-associated vasculature, may play a key role in tumor growth survival. Methods: vitro activity antagonist CCX662 was determined using radioligand binding...
Abstract Introduction: FDA-approved antibody-based therapies targeting the Programmed cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) immune checkpoint axis have gained considerable attention and success in cancer immunotherapy recently. As a next-generation therapy, small-molecule PD-1/PD-L1 inhibitors may provide potential for increased tumor penetration, shorter half-life (to better manage related adverse events), lower cost of goods. We embarked on an effort to identify develop small...