Leukocyte adhesion and recruitment mediated by various chemokines is a critical step in the pathogenesis of atherosclerosis. We have developed a novel monoclonal antibody (mAb) 4A11 in our laboratory by immunizing mice with cells from inflamed RA synovial tissue lining the joints. MAb 4A11 detects the glycoconjugates H-5-2 (abbreviated H-2) and Lewisy-6 (Ley). H-2 and Ley are collectively termed """"""""the 4A11 antigen"""""""". We have shown that 2-fucosyllactose, a readily available glucose analog of H-5-2, termed H-2g, as a potent mediator of angiogenesis, and upregulates intercellular adhesion molecule-1 in endothelial cells (ECs). We have observed that H-2g is a potent chemoattractant for monocytes (MNs) in vitro and in vivo. To define the mechanistic role of H-2g in MN recruitment at the site of chronic inflammatory diseases, we will perform in vivo migration assays with MNs transfected with siRNA directed against signaling molecules. We will use a RA synovial tissue (ST)-severe combined immunodeficient (SCID) mouse chimera in which SCID mice will be engrafted with RA ST. We will inject i.v. dye-tagged human MNs in each mouse after injecting H- 2g or its control in the grafts. Cryosections will be examined to evaluate MN migration in response to H-2g. We will neutralize H-2g with 4A11 mAb and examine the effect on cell migration. We have data showing that H-2g induces interleukin-8, a potent mediator of angiogenesis, in MNs. We will determine if H-2g induces the production of other cytokines and the signaling mechanism involved in the production of these cytokines in MNs. We will evaluate the role of H-2g and mAb 4A11 in EC homing/angiogenesis using the ST-SCID chimera model. In the same model, we will inject transfected Ecs with antisense oligodeoxynucleotides and siRNA directed against signaling molecules to define the mechanisms involved in H-2g-induced EC homing/angiogenesis. Finally, we will examine the role of 4A11 mAb in inflammation and angiogenesis using rat adjuvant induced arthritis model. In this model, we will determine the decrease in production of cytokines, MN recruitment and angiogenesis in rats treated with mAb 4A11 compared to nontreated rats. After the completion of this proposal, we will be able to define the signaling mechanisms involved in H-2g-induced cytokine production in MNs, as well as the role of H-2g in chronic inflammatory diseases. 4A11 antigen is angiogenic and plays an important role in MN recruitment in vitro and in vivo. Targeting this antigen may provide a potential therapeutic to RA. ? ? ? ? ? ? ? ?
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