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.

0 Followers
 · 
72 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Vascular cell adhesion molecule 1 (VCAM-1) plays a major role in the chronic inflammatory processes involved in vulnerable atherosclerotic plaque development. We previously showed that the (99m)Tc-labeled major histocompatibility complex 1-derived peptide B2702p bound specifically to VCAM-1 and allowed the ex vivo imaging of atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits. However, B2702p target-to-background ratio was suboptimal for the in vivo imaging of VCAM-1 expression in atherosclerotic lesions. To improve the target-to-background ratio, 20 derivatives of B2702p (B2702p1-B2702p20) were synthesized using the alanine scan methodology. We hypothesized that (99m)Tc-radiolabeled B2702p derivatives might allow the molecular imaging of VCAM-1 expression in an experimental model of atherosclerosis. METHODS: A mouse model of focal atherosclerotic plaque development induced by left carotid artery ligation in apolipoprotein E double-knockout (ApoE(-/-)) mice was used (n = 82). (99m)Tc-B2702p and (99m)Tc-B2702p1-(99m)Tc-B2702p20 were injected intravenously in anesthetized animals 3 wk after the ligation. Whole-body planar imaging was performed for 3 h. SPECT imaging of 6 additional ligated ApoE(-/-) mice was also performed with (99m)Tc-B2702p1. The animals were then euthanized, and the biodistribution of (99m)Tc-labeled peptides was evaluated by γ-well counting of excised organs. Expression of VCAM-1 in the ligated and contralateral carotid arteries was evaluated by immunohistology. RESULTS: Robust VCAM-1 immunostaining was observed in the left carotid atherosclerotic lesions as a consequence of artery ligation, whereas no VCAM-1 expression was detected in the contralateral carotid artery. Among all evaluated peptides, (99m)Tc-B2702p1 exhibited the most favorable properties. By γ-well counting, there was a significant 2.0-fold increase in the (99m)Tc-B2702p1 left-to-right carotid artery activity ratio (2.6 ± 0.6) and a 3.4-fold increase in the left carotid-to-blood activity ratio (1.4 ± 0.4) in comparison to (99m)Tc-B2702p (1.3 ± 0.2 and 0.4 ± 0.1, respectively, P < 0.05 for both comparisons). Similarly, planar image quantification indicated a higher left-to-right carotid activity ratio in (99m)Tc-B2702p1- than in (99m)Tc-B2702p-injected mice (1.2 ± 0.1 vs. 1.0 ± 0.0, respectively, P < 0.05). Finally, a significantly higher (99m)Tc-B2702p1 activity in the left than in the right carotid artery was observed by SPECT imaging (2.2 ± 0.4 vs. 1.4 ± 0.3 cpm/mm(2)/injected dose, respectively, P < 0.05). CONCLUSION: (99m)Tc-B2702p1 is a potentially useful radiotracer for the in vivo molecular imaging of VCAM-1 expression in atherosclerotic plaques.
    Journal of Nuclear Medicine 05/2013; 54(8). DOI:10.2967/jnumed.112.115675 · 5.56 Impact Factor
  • [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: Atherosclerotic cardiovascular diseases (CVD) are the leading cause of mortality worldwide, accounting for greater than 19.106 deaths annually. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. Indeed, an acute heart attack is the first symptom of atherosclerosis in as much as 50% of individuals with severe disease. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerosis in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could potentially allow the identification of vulnerable patients by non-invasive scintigraphic imaging following administration of a radiolabeled tracer. The development of radiolabeled probes that specifically bind to and allow the in vivo imaging of vulnerable atherosclerotic plaques is therefore the subject of intense ongoing experimental and clinical research. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET imaging. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable atherosclerotic plaques in the carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of the coronary arteries remains a challenging issue because of the small size of atherosclerotic lesions and of their vicinity with blood and the circulating tracer activity.
    Medecine Nucleaire 03/2009; DOI:10.1016/j.mednuc.2009.01.004 · 0.16 Impact Factor

Full-text (2 Sources)

Download
24 Downloads
Available from
May 31, 2014