Designing small molecule CXCR3 antagonists

Pease, James E.

doi:10.1080/17460441.2017.1268597

Cited by 17 publications

(16 citation statements)

References 88 publications

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“…Recent studies demonstrated that therapy with potent smallmolecule CXCR3 antagonists showed significant efficacy in animal models of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and in the prevention of transplant rejection. 3,[17][18][19] Cleavage of the transmembrane chemokines CXCL16 and CX3CL1 is associated with the inflammatory cascade and, therefore, the soluble form of the molecules may serve as inflammatory markers.…”

Section: Discussionmentioning

confidence: 99%

Differential CXC and CX3C Chemokine Expression Profiles in Aqueous Humor of Patients With Specific Endogenous Uveitic Entities

El‐Asrar

Berghmans

Al-Obeidan

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine the levels of the neutrophil chemoattractants CXCL1, CXCL2, CXCL5, CXCL6, and CXCL8, the T helper 1 chemoattractants CXCL9, CXCL10 and CXCL11, the lymphoid chemokines CXCL12 and CXCL13 and the soluble form of the transmembrane chemokines CXCL16 and CX3CL1, in aqueous humor samples from patients with specific uveitic entities.METHODS. Aqueous humor samples from patients with active uveitis associated with Behçet's disease (n ¼ 13), sarcoidosis (n ¼ 8), HLA-B27-related inflammation (n ¼ 12), Vogt-KoyanagiHarada (VKH) disease (n ¼ 12), and healthy controls (n ¼ 9) were assayed with the use of a multiplex assay.RESULTS. All chemoattractant levels were significantly higher in all patients than in the controls. The levels of all neutrophil chemoattractants and CXCL10, CXCL16, and CX3CL1 were significantly higher in nongranulomatous uveitis (Behçet's disease and HLA-B27-associated uveitis) than in granulomatous uveitis (sarcoidosis and VKH disease), whereas the levels of the B cell chemoattractant CXCL13 were significantly higher in granulomatous uveitis than in nongranulomatous uveitis. CXCL13 levels were highest in the patients with VKH disease. CXCL9, CXCL11, and CXCL12 levels did not differ significantly.CONCLUSIONS. Inflammation in nongranulomatous uveitis appears to be driven by neutrophils and T helper 1 lymphocytes, whereas B lymphocytes may contribute to the inflammatory process in granulomatous uveitis, particularly in VKH disease.

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Section: Discussionmentioning

confidence: 99%

Differential CXC and CX3C Chemokine Expression Profiles in Aqueous Humor of Patients With Specific Endogenous Uveitic Entities

El‐Asrar

Berghmans

Al-Obeidan

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…Indeed, a CXCL10-antagonist demonstrated clinical efficacy in RA-patients [69]. CXCR3-antagnoists have shown promising results in vitro and in animal models but no clinical efficacy in psoriasis patients [70]. CCR5-inhibition, on the other hand, has been extensively studied in the context of HIV due to CCR5 being the entry receptor for HIV-1 [71,72].…”

Section: Blocking Infiltration To the Inflammatory Tissuementioning

confidence: 99%

Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond

Christophersen

Risnes

Dahal‐Koirala

et al. 2019

Trends in Molecular Medicine

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Few therapeutic and diagnostic tools specifically aim at T cells in autoimmune disorders, but are T cells a narrow target in these diseases? Lessons may be learned from celiac disease (CeD), one of the few autoimmune disorders where the T cell driving antigens are known, i.e. dietary gluten proteins. T cell clonotypes specific to gluten are expanded, persist for decades and express a distinct phenotype in CeD patients. Cells with this phenotype are increased also in other autoimmune conditions. Accordingly, disease-specific CD4 + T cells form an immunological scar in CeD and probably other autoimmune disorders. We discuss approaches how such T cells may be targeted for better treatment and diagnosis via their antigen specificity or via their expression of characteristic phenotypic markers.

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“…CX3CL1, which is expressed on neurons, is pivotal to maintenance of immune quiescence ; the receptor is present in the CNS only on microglia ( 7 ). “Mucosal CKs” encompass CCL25, CCL28, CXCL14, and CXCL17 ( 37 ). “Angiogenic CKs” comprise many of the CXC CK family, such as CXCL1 through CXCL17 ( 38 ).…”

Section: Cks/cytokines and Their Receptorsmentioning

confidence: 99%

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

Pranzatelli

2018

Front. Immunol.

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The concept and recognized components of “neuroinflammation” are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron–glia interactions and other mechanisms affecting neurotransmission. They issue the “help me” cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic). Human cerebrospinal fluid (CSF) studies have been instrumental in revealing soluble immunobiomarkers involved in immune dysregulation, their dichotomous effects, and the cells—often subtype specific—that produce them. CKs/cytokines continue to be attractive targets for the pharmaceutical industry with varying therapeutic success. This review summarizes the developing armamentarium, complexities of not compromising surveillance/physiologic functions, and insights on applicable strategies for neuroinflammatory disorders. The main approach has been using a designer monoclonal antibody to bind directly to the chemo/cytokine. Another approach is soluble receptors to bind the chemo/cytokine molecule (receptor ligand). Recombinant fusion proteins combine a key component of the receptor with IgG1. An additional approach is small molecule antagonists (protein therapeutics, binding proteins, and protein antagonists). CK neutralizing molecules (“neutraligands”) that are not receptor antagonists, high-affinity neuroligands (“decoy molecules”), as well as neutralizing “nanobodies” (single-domain camelid antibody fragment) are being developed. Simultaneous, more precise targeting of more than one cytokine is possible using bispecific agents (fusion antibodies). It is also possible to inhibit part of a signaling cascade to spare protective cytokine effects. “Fusokines” (fusion of two cytokines or a cytokine and CK) allow greater synergistic bioactivity than individual cytokines. Another promising approach is experimental targeting of the NLRP3 inflammasome, amply expressed in the CNS and a key contributor to neuroinflammation. Serendipitous discovery is not to be discounted. Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers.

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Designing small molecule CXCR3 antagonists

Cited by 17 publications

References 88 publications

Differential CXC and CX3C Chemokine Expression Profiles in Aqueous Humor of Patients With Specific Endogenous Uveitic Entities

Differential CXC and CX3C Chemokine Expression Profiles in Aqueous Humor of Patients With Specific Endogenous Uveitic Entities

Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

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