Differential kinetics of plasma CD105 and transforming growth factor beta expression early in human acute pancreatitis.

OBJECTIVES: The interaction of transforming growth factor beta (TGF-beta) with CD105 (endoglin) is an essential step in the maintenance of endothelial cell quiescence. The importance of this interaction during the critical early phases of acute pancreatitis is unknown. This study explores patterns of expression of CD105 and TGF-beta in plasma during human acute pancreatitis. METHODS: Forty-one patients with a clinical diagnosis of acute pancreatitis constitute the study population. Venous blood samples were taken at admission and on the fifth day. Enzyme-linked immunosorbent assay was performed for CD105, TGF-beta1, TGF-beta3, CD105/TGF-beta1, and CD105/TGF-beta3 complexes. RESULTS: TGF-beta1 levels were significantly elevated on admission in the acute pancreatitis group compared with controls and were further elevated in delayed samples. In contrast, admission CD105 levels were similar to those in controls, but in delayed samples, there was a significant reduction in CD105. Levels of TGF-beta3, CD105/TGF-beta1, and CD105/TGF-beta3 did not differ between groups. CONCLUSIONS: This is the first report to investigate the interplay between plasma expression of CD105, TGF-beta1, TGF-beta3, and ligand complexes in acute pancreatitis. The results of this study confirm previous findings that increased expression of TGF-beta1 is a feature of severe acute pancreatitis. The absence of a parallel elevation in CD105 or CD105/TGF-beta ligand complexes is previously unreported and may suggest that angiogenesis mediated by the interaction between CD105 and TGF-beta is not an early feature of this disease.

Perfusion of 99Tcm-labeled CD105 Mab into kidneys from patients with renal carcinoma suggests that CD105 is a promising vascular target.

There is strong published and unpublished evidence that our CD105 Mab E9, which is highly reactive with angiogenic endothelial cells, could be a useful reagent to target the vasculature of solid tumors in man. Since Mab E9 does not cross-react with animal tissues, we undertook here to evaluate its localization using human kidney as an ex vivo model. Perfusion was performed through the renal artery of 99Tcm-labeled purified CD105 Mab in freshly excised kidneys from 7 patients with renal carcinoma. In all 7 cases, immunoscintigraphs showed the presence of well-defined radioactive hot spots, which matched the positions of the tumors as identified by presurgery MRI scans and subsequent histopathologic examination. Importantly, in one instance, where a presurgery MRI scan had identified only one tumor, immunoscintigraphs showed 2 distinct hot spots of radioactivity. The pathology report confirmed that the additional hot spot corresponded to a small secondary well-vascularized tumor. The implication of this finding is that the radiolabeled Mab, E9, may be of use in the detection of metastatic disease. That the labeling of tumors was specific was confirmed when prior perfusion of unlabeled mab E9 in 2 kidneys completely blocked the localization of 99Tcm-conjugated Mab E9. Radioactivity in samples of tumor and normal tissue taken from 7 kidneys was counted in a gamma counter. In all cases, there was a greater uptake of radioactivity in tumors compared with the corresponding normal kidneys. The median values, adjusted per gram wet weight, for 99Tcm were 14.8 times (range, 4.8-113.0) greater in kidney tumors than in normal kidney tissue (p < 0.007). Immunofluorescent staining of cryostat sections of tumor tissues in each of the 7 cases showed strong and uniform localization of Mab E9 in tumor microvessels. Interestingly, chimeric staining of endothelial cells (ECs) was seen in an occasional microvessel segment. That is, while most of the ECs lining a microvessel were strongly stained, an occasional EC was negative. This was not an artifact of staining. Unstained ECs may be nonangiogenic or apoptotic since CD105 is a proliferation/activation-associated antigen. Further investigations are warranted to establish the pharmacokinetics of 99Tcm-labeled CD105 antibody in vivo. This would enable us to determine whether an apparently highly successful ex vivo study has the potential for tumor imaging/therapeutic vascular targeting in patients with cancer.