P050 The influence of anti-TNF therapy on chosen angiogenesis-related processes in patients with Crohn's disease
P. Eder*1, L. Lykowska-Szuber1, K. Korybalska2, A. Wozniak3, I. Krela-Kazmierczak1, K. Stawczyk-Eder1, K. Klimczak1, A. Szymczak1, K. Linke1, J. Witowski2
1Poznan University of Medical Sciences, Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan, Poland, 2Poznan University of Medical Sciences, Department of Pathophysiology, Poznan, Poland, 3Poznan University of Medical Sciences, Department of Clinical Pathomorphology , Poznan, Poland
Immune-mediated angiogenesis seems to be a crucial phenomenon in the pathogenesis of Crohn's disease (CD). Anti-TNF antibodies are believed to be the most powerful drugs in diminishing the inflammatory lesions in the gastrointestinal tract, however direct mechanisms of their action are to be elucidated. In our study we performed a complex analysis of the influence of anti-TNF agents on chosen angiogenesis-related processes in CD patients in relation to clinical efficacy of biological therapy.
The influence of the sera from CD patients on the proliferation of Human Umbilical Vein Endothelial Cells (HUVEC) of the EA.hy926 line was assessed in vitro by using the MTT formazan proliferation test. Concentrations of crucial angiogenesis-related cytokines (Vascular Endothelial Growth Factor - VEGF; Angiopoietin-1 - Ang-1; basic Fibroblast Growth Factor - bFGF; soluble Tumor Necrosis Factor Alpha - TNF) were measured by using the ELISA method. Immunohistochemical expression of VEGF and platelet/endothelial cell adhesion molecule-1 (PECAM-1) was estimated in intestinal biopsies taken from inflamed areas of the colon during colonoscopy.
All aforementioned tests were performed before and after induction phase of anti-TNF therapy (adalimumab, infliximab). Patients who achieved a decrease in the Crohn's Disease Activity Index of 100 or more (CDAI-100 response) were considered as primary responders.
24 CD patients were enrolled into the study, proliferation of HUVEC was assessed in case of 6 patients. We found a significant reduction in proliferating vessels in intestinal biopsies assessed by PECAM-1 expression after anti-TNF therapy, what was accompanied by a significant decrease in VEGF-positive staining. Proliferation of HUVEC decreased when exposed to sera of CD patients who achieved clinical response, and it increased in case of failure of the anti-TNF therapy. Concentration of VEGF and Ang-1 significantly decreased (350.8 ± 578.9 to 300.4 ± 583.3 g/ml, p=0.04 for VEGF; and 55.7 ± 15.5 to 44.9 ± 15.7 ng/ml, p=0.02 for Ang-1) after anti-TNF therapy in the responders group, and it did not change significantly in non-responders group. Moreover, high baseline VEGF concentration was predictive for clinical improvement after anti-TNF therapy. Concentrations of bFGF and TNF did not change in the course of anti-TNF treatment independently on its clinical efficacy.
Clinical efficacy of anti-TNF agents is at least partly dependent on the reduction of the immune-mediated angiogenesis in inflamed intestinal tissues in CD. This could be mediated by a decrease in proliferating endothelial cells after anti-TNF therapy, what is related to a significant change in the concentrations of crucial pro-angiogenic cytokines.
- Posted in: Poster presentations: Basic Science (2015)