In Crohn’s disease (CD), one of the major forms of idiopathic, chronic inflammatory bowel disorders, inflammation is thought to result from an overwhelming and ongoing activation of the mucosal immune system, induced by the normal luminal flora in genetically susceptible individuals.Therefore, drug treatment is mainly directed at modification of the immunological response or manipulation of the enteric flora. Despite development of biological cures, therapy in CD is still unsatisfactory.
Therefore, new treatment modalities are desirable. Desired characteristics would include an inhibition of the overwhelming proinflammatory immune response, an effect on bacterial mucosal colonization, a good safety profile and the possibility to readminister treatment as often as needed.
We postulate that photodynamic therapy (PDT) fulfills these goals. PDT uses photo-physical properties of light-absorbing drugs, which accumulate in activated cells (for example activated inflammatory cells). After exposure to light, these drugs induce a variety of reactions like cell death, inhibition of proinflammatory immune messengers, and inactivation or death of several strains of bacteria. In a mouse colitis model resembling CD we were able to demonstrate that even a single «low dose » of PDT exerts a favorable effect on colitis and induces a downregulation of the proinflammatory immune response. In this model, the PDT effect correlates positively with the severity of inflammation. Furthermore PDT is safe, neither inducing local or systemic side effects.
The immediate goal of this project is to evaluate «low dose » PDT in patients with CD (specific aim 1: clinical improvement, healing of colitis, safety) and to investigate the pathophysiological mechanism of «low dose » PDT in humans (specific aim 2: downregulation of the proinflammatory immune response, decrease of mucosal bacterial colonization).
In order to evaluate the response to PDT, a multicenter, randomized, double-blind, placebo-controlled trial in patients with known CD involving the colon will be performed. Patients with moderately active disease and stable medication will be eligible for this study. Crohn’s Activity Index, Quality of Life, Endosocpic Severity Index, histological scores and adverse effects will be assessed. In order to investigate the local immunomodulatory effects and the effects on bacterial colonization, local (cytokines, apoptosis, metalloproteinases in colonic tissue) and systemic (whole blood cell synthesis of cytokines), immunological markers will be assessed.
The information gained could lead to a new therapeutic approach in CD that favorably modifies the immunologic response and inhibits mucosal bacterial colonization. Furthermore, in contrast to available drug treatment that blocks only isolated cytokines, PDT could lead to a comprehensive control of the immune response. If systemic side effects turn out to be negligible in man, PDT could be repeated as often as needed.