Shon Roland Pulley

Rapid and recurrent neutrophil mobilization regulated by T134, a CXCR4 peptide antagonist

The CXCR4/stromal cell-derived factor-1 (SDF-1) axis plays important roles in development, leukocyte trafficking, HIV infection, and tumorigenesis. Its critical function in bone marrow stem cell and hematopoietic progenitor cell retention, homing and release has been well-characterized by genetic and pharmacological analyses. However, its role in neutrophil retention and release is still poorly understood. In this study, we demonstrated that T134, a peptide antagonist of human CXCR4, is also a potent antagonist of mouse CXCR4. Treatment of C57BL/6 mice with T134 resulted in a rapid and time-dependent increase of white blood cells (WBC) and neutrophils, as well as hematopoietic stem and progenitor cells in peripheral blood. Interestingly, recurrent WBC and neutrophil mobilization was achieved by repeated T134 treatment, and the T134-mediated increase and subsequent retreat of WBC and neutrophils correlated with T134 activity in the peripheral blood. Kinetic analysis revealed that T134 binding to CXCR4 did not induce any significant cell-surface receptor downregulation, indicating that T134-induced WBC and neutrophil mobilization is likely due to direct blockage of the CXCR4/SDF-1 interaction. The results from this study support an important role of CXCR4/SDF-1 axis in neutrophil retention and release in the marrow.

CCR5 antagonists: from discovery to clinical efficacy

CCR5 is a prototypically inflammatory chemokine receptor belonging to the seven transmembrane G-protein-coupled receptor (GPCR) family. This family is generally considered druggable and well represented in marketed drugs [1]–[6]. The CCR5 receptor is expressed on numerous host defense cells including monocytes, macrophages, T-lymphocytes, dendritic cells and microglia [4, 5]. Interaction of CCR5 with its ligands MIP-1α, MIP-1β (CCL3/CCL4) or RANTES (CCL5) results in a conformational change in the seven transmembrane domain initiating a signaling cascade through heterotrimeric G-proteins ultimately giving rise to migration of immune cells to sites of inflammation [2, 5]. Due to the well documented role of CCR5 in the immune system, it has been implicated in the pathophysiology of rheumatoid arthritis (RA), multiple sclerosis (MS), transplant rejection, gastric disorders, diabetes and myeloma [7]. Perhaps the biggest driver behind the development of CCR5 receptor antagonists was the discovery that CCR5 plays an important role as a co-receptor for macrophage tropic HIV-1 strains to facilitate viral fusion and entry into host cells [5], [8]–[12]. In addition, individuals with a mutation in the CCR5 gene (CCR5Δ32) lacking expression of CCR5 on the cell surface are resistance to HIV-1 infection without notable immune system effects [13, 14], thus validating pharmaceutical intervention with a CCR5 antagonist.