Cholera toxin, mucosal immunity and development of mucosal vaccines and immunotherapies
Members: Stephen Attridge (Associate professor, Ph.D.), Carl-Fredrik Flach (postdoc, Ph.D.), Michael Lebens (scientist, Ph.D.), Anna Lundgren (shared postdoc, Ph.D.), Jia-Bin Sun (scientist, Ph.D.), Sukanya Raghavan (postdoc, Ph.D.), Erik Nygren (Ph.D. student), Johan Wiman (Ph.D. student), Margareta Blomquist (research technician), Bin-Ling Li (research technician, M.D.), Gun Wallerström (research technician)
The mucosal immune system comprises ca 80% of all immunocytes and has developed effective, as yet 
incompletely understood means for protecting both against mucosal infections and harmful immune responses to ingested or inhaled antigens. There is currently great interest internationally in developing mucosal vaccines against many important microbial pathogens. Mucosally induced tolerance also is a promising form of immunomodulation for treating certain autoimmune diseases and allergies. Our research addresses these closely interlinked areas by studies in which cholera toxin or cholera toxin derivatives are often used as antigens, vectors or immunomodulating agents:
1. Mucosal immunity research aiming at improved ways of mucosal vaccination and immune response steering. We will continue animal research to further define mucosal regulatory mechanisms determining the outcome -- immunity or tolerance -- of local antigen exposure and to develop ways of steering and maximizing the immune response in the desired direction. Specifically, we will continue our efforts to define the role of different subsets of mucosally induced antigen presenting cells (APC) for induction of immunity or tolerance, compare immunization by different mucosal routes focusing on oral and sublingual antigen delivery, and continue our development of mucosal adjuvants including the recently described promising CTB-CpG conjugate.
2. Continued research towards the development of oral vaccines against gastrointestinal infections. We have developed an internationally widely registered oral vaccine (Dukoral®) against cholera with efficacy also against diarrhea caused by enterotoxigenic E.coli (ETEC); this is the only original vaccine ever developed in Scandinavia. The further specific vaccine development objectives are: (1) To develop an oral vaccine against Vibrio cholerae O139, a new cholera serotype with potential to cause another pandemic; (2) To contribute to the development of a specific vaccine against ETEC diarrhea, the most common cause of diarrheal illness in both children in developing countries and in travelers – joint project with A-M Svennerholm et al. and SBL Vaccin; and (3) to advance the understanding and develop means of steering the balance between immune protection and immunopathology in experimental H. pylori infection and immunization as a basis for vaccine development.
3. Research to develop therapeutic vaccines based on oral tolerance induction, including the further development of a promising “vaccine” in the treatment of Behcet’s disease. We have developed a novel concept for mucosal tolerance induction based on the use of recombinantly produced CTB fused chemically or genetically to a relevant antigen/tolerogen. This has given very promising results in the prevention and treatment in animal models of autoimmune diseases (e.g. MS-like encephalomyelitis, RA-like arthritis, diabetes and uveitis); IgE- and DTH-mediated allergies; and infection immunopathology (e.g. schistosomiasis). An important breakthrough is that this novel treatment principle now for the first time has been tested clinically with very promising results in patients with Behcet’s disease! Based on this we will now (1) Further develop selected CTB-based fusion proteins for potential immune therapy in Behcet’s disease, diabetes and arteriosclerosis; (2) In animals and humans further define immunological correlates to positive treatment effects; and (3) Further develop the promising initial clinical studies in Behcet’s disease.
Important review papers:
Holmgren J, Czerkinsky C. (2005). Mucosal immunity and vaccines. Nature Med 11: S45-53.
Sanchez J and Holmgren J. (2005) Virulence factors, pathogenesis and vaccine protection in cholera and ETEC diarrhea. Curr Opin in Immunol 17:388-398.
Raghavan S and Holmgren J. (2005) CD4+CD25+ suppressor T cells regulate pathogen induced inflammation and disease. FEMS Immunol Med Microbiol 44:121-127.