VEGF-A isoform modulation in an preclinical TNBS model of ulcerative colitis: protective effects of a VEGF164b therapy.

BACKGROUND: Ulcerative colitis (UC) is the most common form of inflammatory bowel disease in the USA. A key component of UC is the increase in inflammatory angiogenesis of the colon during active disease. This increase is driven to a great extent by the over expression of VEGF-A. Recently, VEGF165(b) (VEGF164(b) in mouse), an anti-angiogenic form of VEGF-A was described and its regulation was determined to be disturbed in many pathologies such as cancer and pre-eclampsia. RESULTS: The aims of this study were to examine the role of this inhibitory VEGF by expressing this molecule in a model of intestinal inflammation, and to evaluate its expression as a potential new therapeutic approach for treating UC. A modified model of TNBS colitis was used to determine the effects of rVEGF164(b) expression on colon inflammation. Expansion of the vascular system was assessed by immunhistochemical methods and macro- and microscopic measurements of inflammation in the colon were measured. Leukocyte invasion of the tissue was measured by myeloperoxidase assay and identification and counting of lymphoid follicles. Both angio- and lymphangiogenesis were reduced by expression of rVEGF164(b), which correlated with reduction in both gross and microscopic inflammatory scores. Leukocyte invasion of the tissue was also reduced by rVEGF164(b) expression. CONCLUSIONS: This is the first report using an endogenous inhibitory VEGF-A isoform for therapy in a model of experimental colitis. Inhibitory VEGF molecules play an important role in maintenance of gut homeostasis and may be dysregulated in UC. The results of this study suggest that restoration of rVEGF164(b) expression has anti-inflammatory activity in a TNBS model and warrants further examination as a possible therapeutic for UC.

The effects of high dose interferon-ß1a on plasma microparticles: correlation with MRI parameters.

OBJECTIVES: We previously reported a correlation between levels of micro particles carrying CD31 (PMP(CD31+)) and disease activity in MS. However, the effects of long term (12 month) treatment with high dose, high frequency interferon-ß1a (Rebif™) on plasma levels of PMP(CD31+), PMP(CD146+), and PMP(CD54+) and MRI measures of disease activity have not yet been assessed. METHODS: During this prospective 1-year study, we used flow cytometry to measure changes in plasma micro particles (PMP) bearing CD31 (PMP(CD31+)), CD146 (PMP(CD146+)), and CD54/ICAM-1 (PMP(CD54+)) in 16 consecutive patients with relapsing-remitting MS (RRMS) before and after 3, 6, and 12 months of subcutaneous therapy with interferon-beta1a (44 micrograms, 3X weekly). At each visit, clinical exams and expanded disability status scale (EDSS) scores were recorded. RESULTS: Plasma levels of PMP(CD31+), and PMP(CD54+) were significantly reduced by treatment with IFN-ß1a. PMP(CD146+) appeared to decrease only at 3 months and did not persist at 6 and 12 months (p = 0.0511). In addition, the decrease in plasma levels of PMP(CD31+) and PMP(CD54+) levels at 12 months were associated with a significant decrease in the number and volume of contrast enhancing T1-weigthed lesions. CONCLUSION: Our data suggest that serial measurement of plasma micro particles (PMP), particularly in the initial stages of MS (when neuro-inflammatory cascades are more intense), may serve as reliable and reproducible surrogate markers of response to IFN-ß1a therapy for MS. In addition, the progressive decline in plasma levels of PMP(CD31+) and PMP(CD54+) further supports the concept that IFN-ß1a exerts stabilizing effect on the cerebral endothelial cells during pathogenesis of MS.