2005 Abstracts: Anti-Reg I and III Antibodies Worsen Pancreatitis In Vivo
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Anti-Reg I and III Antibodies Worsen Pancreatitis In Vivo
Domenico Viterbo, Martin Bluth, Cathy M. Mueller, Gordon Callender, Yin-yao Lin, Shirley Murray, Victor Ocasio, Theresa DiMaio, Michael Zenilman, SUNY Downstate Medical Center, Brooklyn, NY
Background:. The regeneration (Reg) family of proteins, which include RegI (pancreatic stone protein) and Reg III (pancreatitis-associated protein - PAP) is a family of proteins minimally expressed in normal pancreas but strongly induced in acute pancreatitis. This suggests a protective effect. We have previously demonstrated that antisense mediated gene knockdown of Reg/PAP in vivo worsens pancreatitis. Here we examined the effect of anti-Reg antibodies on pancreatitis severity.
Methods: Acute pancreatitis was induced in Wistar rats by retrograde infusion of 4% sodium taurocholate (NaT) into the pancreatic duct with subsequent administration of anti-Reg I, anti Reg III antibody, or non specific antibody (IgG). Sham rats consisted of open laparotomy with subsequent installation of anti-Reg or IgG antibodies in saline. After 24-48 hr, pancreata were harvested and assessed for worsening pancreatitis by histopathology (edema, hemorrhage/necrosis, leukocytic infiltration) and pancreatic wet weight(% of pancreas to total body weight, mg/g); serum was analyzed for amylase and C-reactive protein (CRP). Results: When anti Reg antibodies alone were administered to healthy rats no evidence of pancreatitis was observed. Induced pancreatitis increased organ edema, serum amylase and CRP. Addition of anti-Reg I or anti RegIII worsened pancreatitis as demonstrated by increased fat necrosis and leukocytic infiltration when compared with control (p<0.05 Student's t-test). Pancreatic wet weight and serum CRP and amylase levels also increased with anti-Reg antibody treatment compared with controls. Administration of both anti-Reg I and anti Reg III antibodies into NaT induced pancreatitic rats demonstrated even worsened pancreatitis and increased mortality. Conclusions: Neutralization of Reg proteins with anti-Reg antibodies worsens pancreatitis as demonstrated by an increased inflammatory response indicating a protective effect. Immunotherapy based investigation provides a unique approach to study Reg protein function in vivo.
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