Scientific Abstract
Proposal No. IBD-0088
Principal Investigator: Maria-Anna Ortner, M.D.
Applicant Organization: Hospitalier Universitaire Vaudois (Lausanne, Switzerland)
Project Title: Photodynamic therapy in Crohn's disease
Period of Award: February 1, 2004 – June 30, 2006
Photodynamic therapy could be a multidimensional treatment option for Cohn’s disease, since it has immunomodulatory properties and is also able to inactivate several enteric bacteria. Photosensitizers have been shown to accumulate in activated T-cells and macrophages, leading to apoptosis of these cells and, in surviving cells, to a reduction of pro-inflammatory cytokine production after light activation. Furthermore, photosensitizers can accumulate in some bacteria that are killed when exposed to visible light. Therefore, it seems reasonable to evaluate local photodynamic therapy as a new treatment option.
The immediate goal of this project is to investigate the effect and safety of photodynamic therapy on healing of colitis in a SCID mouse model and to identify the optimal photosensitizer as well as the dose of drug and energy. Furthermore, the basic mechanisms of the immunomodulatory properties of photodynamic therapy on colitis and the effect on the bacterial flora will be evaluated.
In order to test our hypotheses, we propose the following specific aims:
(1) In series of in vitro experiments, we will evaluate the optimal photosensitizer, the doses of drug and energy, as well as the optimal type of illumination. Jurkat cell lines, mice and human T-cells from Crohn’s patients and healthy human controls will be used. Drug uptake in activated T-cells and apoptosis will be evaluated.
(2) The safety of photodynamic therapy will be determined in normal mice. Fibrosis, inflammation, and ulcerations of the mucosa, as well as systemic side effects will be assessed.
(3) A SCID mouse mode will be used, in which the transfer of subpopulation of CD4+CD45RBhigh leads to a Th1-mediated Crohn’s-like colitis. Healing of colitis will be evaluated.
(4) If this goal can be achieved, the local and systemic immunomodulatory effect of PDT and the effect on the microflora will also be investigated.
In conclusion, the information gained could lead to a new therapeutic approach with a mild side effect profile and the possibility of easy retreatment, whenever necessary. If, as expected, colitis in a mouse model can be adequately controlled, a second major project evaluating photodynamic therapy in humans will be undertaken.