Topo-proteomic in situ analysis of psoriatic plaque under efalizumab treatment.

Abstract

In a pilot study 6 psoriasis patients were treated over 12 weeks with efalizumab targeting the CD11a subunit of LFA-1. The treatment was well tolerated. Five of these patients proved to be responders with an average decrease in psoriasis area and severity index (PASI) from 21.3 +/- 5.4 (day 0) to 3.9 +/- 0.6 (week 12). The nonresponder was subsequently successfully treated with cyclosporin. Skin biopsies were taken before and after efalizumab treatment and subjected to Multi-Epitope Ligand Cartography (MELC) robot microscopy. A MELC library of 46 antibodies including FITC-labeled efalizumab was chosen focusing upon inflammatory epitopes. Quantification of marker expression was performed using a special adaptation to the needs of skin tissue in terms of pixel events normalized to a standardized horizontal skin width of 100 mum. The before-versus-after comparison for the responders revealed at the 'single epitope level' of MELC analysis a significant decrease (p < 0.05) in epidermal thickness (represented by pan-cytokeratin, CD71, CD138), of the expression of common leukocyte antigen (CD45), T-cell markers (CD2, CD4, CD8, CD45R0), CD11a, efalizumab binding site (EfaBS), and CD58. At the 'EfaBS-centered, double colocation level' a corresponding decrease was observed for CD2, CD3, CD4, CD8, CD11a, CD13, CD26, CD44, CD45, CD45R0, CD54, CD62L, HLA-DR, and TIA-1. MELC analysis at the 'multicombinatorial level' revealed predominant combinatorial molecular phenotype (CMP) motifs, which showed an efalizumab treatment-dependent significant decrease. These CMP motifs were defined as toponomic combinations of lead markers for (i) leukocytes in general (CD45), (ii) T cells (CD2, CD3, CD4, CD45R0, CD45RA), (iii) macrophages (CD68), (iv) cell activation (CD13, CD26, HLA-DR), and (v) cell adhesion (CD11a, EfaBS). Thirty-five of the most relevant 50 CMP motifs were directly related to the T-cell type. A descriptive statistical analysis of the nonresponder before treatment showed a below-responder range degree of expression for CD4, CD8, CD44 (H-CAM), CD56, CD62L, HLA-DQ, and also for these epitopes in colocation with EfaBS. In the nonresponder and before treatment we observed an above-responder range degree of expression for CD54 (ICAM-1) as LFA-1 ligand. In conclusion, the topo-proteomic data provide new diversified insights into the pleiotropic cellular dynamics in psoriatic skin lesions under effective efalizumab treatment. Moreover, the data may be relevant to the future development of possible strategies for individual prediction of efalizumab treatment response or nonresponse.

• Authors: B Bonnekoh, A J Pommer, R Böckelmann, H Hofmeister, L Philipsen, H Gollnick
• Journal: Skin pharmacology and physiology (Skin Pharmacol Physiol) Vol. 20 Issue 5 Pg. 237-52 ( 2007) ISSN: 1660-5527 [Print] Switzerland
• PMID: 17587888 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2007 S. Karger AG, Basel.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• CD11a Antigen
• Epitopes
• Immunosuppressive Agents
• Ligands
• Lymphocyte Function-Associated Antigen-1
• Proteome
• efalizumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• CD11a Antigen (immunology)
• Epitopes
• Female
• Humans
• Immunosuppressive Agents (therapeutic use)
• Ligands
• Lymphocyte Function-Associated Antigen-1 (immunology)
• Male
• Middle Aged
• Pilot Projects
• Protein Array Analysis
• Proteome (analysis)
• Proteomics
• Psoriasis (drug therapy, metabolism)
• Robotics
• Severity of Illness Index
• Treatment Outcome