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Recombinant fusion proteins based on cholera toxin B subunit for the prevention and treatment of autoimmune disease

Group leader: Michael Lebens (Ph.D.)
Members: Jan Holmgren (Professor, M.D., Ph.D.), Susanne Källgård (Research engineer/BMA), Johan Wiman (Ph.D. student)

Inflammatory autoimmune responses directed against human 60 kDa heat shock protein (HSP60) have been implicated in a number of important autoimmune diseases. For some of these, intervention therapy aimed at tolerance induction or immune deviation from a Th1 to a Th2 dominated response has had positive effects on the progression of the disease. Notably in type 1 diabetes a single HSP60-derived peptide (p277) has been used to immunize patients with early symptoms . A second disease in which a specific HSP60 peptide has been identified as having a role in pathology is Behcet’s syndrome. In this multisystem inflammatory disorder the major manifestation is uveitis. Disease activity is correlated with T cell proliferative responses to the HSP60 peptide p336-351. The same peptide, chemically coupled to cholera toxin B subunit (CTB), could suppress development of experimentally induced disease in Lewis rats and in a limited clinical trial, significantly reduce symptoms in Behcet’s patients.

The aim of our work is therefore to develop CTB fusion proteins for the treatment of autoimmune diseases as we have previously done in schistosomiasis liver inflammation. A number of proteins have been constructed and purified carrying epitopes from proteins implicated in different inflammatory diseases. Among these are HSP60-derived peptides (including p336-351) and two fusion proteins derived from low density lipoprotein (LDL), a protein implicated in development of atherosclerosis . One of these LDL fusion proteins has been shown to be active in reduction of aortic plaque size in ApoE null mice and the proteins serve as good examples of the advantages and disadvantages of this technology. Further work is aimed at developing novel methods for identification of active T cell epitopes from proteins implicated in the development of different autoimmune diseases.

Important publications:
Lebens M, Sun JB, Czerkinsky C, Holmgren J: Current status and future prospects for a vaccine against schistosomiasis. Expert Rev Vaccines 3:315-328, 2004.

Stanford, M., Whittall, T., Bergmeier, L.A., Lindblad, M., Lundin, S., Shinnick, T., Mizushima, Y., Holmgren, J., Lehner, T. 2004. Oral tolerization with peptide 336-351 linked to cholera toxin B subunit in preventing relapses of uveitis in Behcet's disease. Clin Exp Immunol. 137 (1):201-8.

Sidansvarig: Dan Baeckström|Sidan uppdaterades: 2007-03-26
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