טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentSapir Yair
SubjectExploring the Involvement of CCR5 Chemokines in
Autoimmune Processes by a Novel Recombinant
Soluble Receptor
DepartmentDepartment of Medicine
Supervisor Professor Nathan Karin
Full Thesis textFull thesis text - English Version


Abstract

Chemokines are small structurally related proteins that regulate cell trafficking via interactions with a subset of seven-transmembrane, G protein-coupled receptors. Accumulating evidence supports the involvement of chemokines in inflammatory processes and autoimmune diseases. CCR5 is a key CC chemokine receptor that is highly expressed on CD4+ T cells and monocytes. It binds three different ligands CCL3 (MIP-1a), CCL4 (MIP-1b), and CCL5 (RANTES) and its involvement in various diseases such as MS, RA, AIDS and transplantations has been suggested. Recent studies implied that the interaction between CCR5 and its ligands is essential not only for attracting these CCR5+ cells, but also is substantial for their activation. We initiated our study by exploring the imoprtance of CCR5 ligands in activation of T cells. We show redundant compensatory functionality between CCR5 ligands not only in chemo-attractive properties, but also in their ability to induced stimulatory signals via CCR5. We then show that combined neutralization of all CCR5 ligands is essential to control autoimmune cell activation. This motivated us to explore the role of CCR5 ligands in autoimmune diseases, and evaluate the effects of their selective or combined neutralization in vivo. A novel strategy for efficient neutralization of chemokines has been developed in our lab by generating a unique soluble receptor construct, composed of the extracellular domains of the seven TM receptor fused to the FC domain of IgG. We have constructed a panel of fusion proteins encoding the various extra cellular domains of CCR5. Our results indicate that only one of the fusion receptors comprised from 30 amino acids from the E2 domain stabilized by the IgG heavy chain FC fragment, selectively binds and neutralized all CCR5 ligands and effectively skews target cells toward a noninflammatory state. Our soluble receptor when administered during ongoing experimental autoimmune encephalomyelitis (EAE) rapidly suppressed the disease while arresting antigen specific effector T cell functions. 

Our work demonstrates the ability to restrain the autoimmune process by combined chemokine neutralization, and provide a novel therapeutic approach to treat various inflammatory conditions.