Article

An immunosuppressive and anti-inflammatory HLA class I-derived peptide binds vascular cell adhesion molecule-1

Department of Cardiothoracic Surgery, Stanford University, Palo Alto, California, United States
Transplantation (Impact Factor: 3.78). 09/2000; 70(4):662-7. DOI: 10.1097/00007890-200008270-00021
Source: PubMed

ABSTRACT A synthetic peptide corresponding to residues 75-84 of HLA-B2702 modulates immune responses in rodents and humans both in vitro and in vivo.
We used a yeast two-hybrid screening, an in vitro biochemical method, and an in vivo animal model.
Two cellular receptors for this novel immunomodulatory peptide were identified using a yeast two-hybrid screen: immunoglobulin binding protein (BiP), a member of the heat shock protein 70 family, and vascular cell adhesion molecule (VCAM)-1. Identification of BiP as a ligand for this peptide confirms earlier biochemical findings, while the interaction with VCAM-1 suggests an alternative mechanism of action. Binding to the B2702 peptide but not to closely related variants was confirmed by ligand Western blot analysis and correlated with immunomodulatory activity of each peptide. In mice, an ovalbumin-induced allergic pulmonary response was blocked by in vivo administration of either the B2702 peptide or anti-VLA-4 antibody.
We propose that the immunomodulatory effect of the B2702 peptide is caused, in part, by binding to VCAM-1, which then prevents the normal interaction of VCAM-1 with VLA-4.

Download full-text

Full-text

Available from: Xianlong Ling, Jul 03, 2015
0 Followers
 · 
74 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pathogenic hypotheses for spondyloarthropathies are evolving. Several candidates have been added to the list of inciting microorganisms, and genes other than HLA-B27 are under scrutiny. Above all, the chiefly “immunological” theory of spondyloarthropathies incriminating a cross-reaction between self proteins and bacterial peptides is giving way to a more “microbiological” concept in which latent bacteria residing within macrophagic or dendritic cells undergo reactivation through a process facilitated by HLA-B27. This molecule is prone to misfolding, which decreases the presentation of bacterial peptides to the immune system and stimulates the Nf-KB inflammation pathway within infected macrophages and/or dendritic cells. Migration of these infected cells from the mucous membranes to the tissues targeted by spondyloarthropathies, particularly the bone marrow located near entheses, may facilitate transient reactivation of dormant intracellular bacteria by creating a favorable cytokine environment. This environment may include high levels of TGF-β and IL-10, noted also at other sites that enjoy immune privilege, such as the eye. The reactivation may be stopped by a local response of CD4+ and/or CD8+ T cells at the expense of local inflammation responsible for clinical manifestations. This scenario seems consistent with results from studies of murine models transgenic for the HLA-B27 antigen: exposure to bacteria is necessary to the development of spondyloarthropathy, but the disease occurs even when only the heavy chain of HLA-B27 is present (i.e., beta2-microgloblin is not indispensable). Improved understanding of the mechanisms that confer to some bacterial strains a strong potential for persisting within cells, including macrophagic cells, may open the way toward new treatment approaches capable of complementing antagonists of TNF-α and other monokines, which merely suspend the disease process, and antibiotic therapy, which fails to kill dormant bacteria located within cells.
    Revue du Rhumatisme 03/2002; 69(3):197-206. DOI:10.1016/S1169-8330(02)00282-X
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pathogenic hypotheses for spondyloarthropathies are evolving. Several candidates have been added to the list of inciting microorganisms, and genes other than HLA-B27 are under scrutiny. Above all, the chiefly 'immunological' theory of spondyloarthropathies incriminating a cross-reaction between self-proteins and bacterial peptides is giving way to a more 'microbiological' concept in which latent bacteria residing within macrophagic or dendritic cells undergo reactivation through a process facilitated by HLA-B27. This molecule is prone to misfolding, which decreases the presentation of bacterial peptides to the immune system and stimulates the Nf-KB inflammation pathway within infected macrophages and/or dendritic cells. Migration of these infected cells from the mucous membranes to the tissues targeted by spondyloarthropathies, particularly the bone marrow located near entheses, may facilitate transient reactivation of dormant intracellular bacteria by creating a favorable cytokine environment. This environment may include high levels of TGFbeta and IL-10, noted also at other sites that enjoy immune privilege, such as the eye. The reactivation may be stopped by a local response of CD4+ and/or CD8+ T cells at the expense of local inflammation responsible for clinical manifestations. This scenario seems consistent with results from studies of murine models transgenic for the HLA-B27 antigen: exposure to bacteria is necessary to the development of spondyloarthropathy, but the disease occurs even when only the heavy chain of HLA-B27 is present (i.e., beta2-microgloblin is not indispensable). Improved understanding of the mechanisms that confer to some bacterial strains a strong potential for persisting within cells, including macrophagic cells, may open the way toward new treatment approaches capable of complementing antagonists of TNF-alpha and other monokines, which merely suspend the disease process, and antibiotic therapy, which fails to kill dormant bacteria located within cells. Pathogenic hypotheses for spondyloarthropathies are evolving. This review presents the most recent concepts. These concepts have not all received confirmation from experimental data. However, the high degree of consistency among them prompted us to consolidate them into a single picture. Although this approach may yield a motley composite of fact and speculation, it may open up new avenues of thought for rheumatologists interested in the links between chronic intracellular infections and inflammatory joint disease.
    Joint Bone Spine 04/2002; 69(2):114-22. DOI:10.1016/S1297-319X(02)00371-8 · 3.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: VCAM-1 plays a major role in the chronic inflammatory processes present in vulnerable atherosclerotic plaques. The residues 75-84 (B2702-p) and 84-75/75-84 (B2702-rp) of the major histocompatibility complex-1 (MHC-1) molecule B2702 were previously shown to bind specifically to VCAM-1. We hypothesised that radiolabelled B2702-p and B2702-rp might have potential for the molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) expression in atherosclerotic plaques. Preliminary biodistribution studies indicated that 125I-B2702-rp was unsuitable for in vivo imaging owing to extremely high lung uptake. 123I- or 99mTc-labelled B2702-p was injected intravenously to Watanabe heritable hyperlipidaemic rabbits (WHHL, n=6) and control animals (n=6). After 180 min, aortas were harvested for ex vivo autoradiographic imaging, gamma-well counting, VCAM-1 immunohistology and Sudan IV lipid staining. Robust VCAM-1 immunostaining was observed in Sudan IV-positive and to a lesser extent in Sudan IV-negative areas of WHHL animals, whereas no expression was detected in control animals. Significant 2.9-fold and 1.9-fold increases in 123I-B2702-p and 99mTc-B2702-p aortic-to-blood ratios, respectively, were observed between WHHL and control animals (p<0.05). Tracer uptake on ex vivo images co-localised with atherosclerotic plaques. Image quantification indicated a graded increase in 123I-B2702-p and 99mTc-B2702-p activities from control to Sudan IV-negative and to Sudan IV-positive areas, consistent with the observed pattern of VCAM-1 expression. Sudan IV-positive to control area tracer activity ratios were 17.0+/-9.0 and 5.9+/-1.8 for 123I-B2702-p and 99mTc-B2702-p, respectively. Radiolabelled B2702-p is a potentially useful radiotracer for the molecular imaging of VCAM-1 in atherosclerosis.
    European journal of nuclear medicine and molecular imaging 06/2007; 34(6):830-40. DOI:10.1007/s00259-006-0310-4 · 5.22 Impact Factor