Impact of hyperglycemia on autoimmune pancreatitis and regulatory T-cells.

AIM To evaluate the influence of hyperglycemia on the progression of autoimmune pancreatitis. METHODS We induced hyperglycemia by repetitive intraperitoneal (ip) injection of 50 mg/kg streptozotocin in MRL/MpJ mice, which develop autoimmune pancreatitis due to a genetic predisposition. We compared the extent of inflammation (histological score, CD3+ lymphocytes, CD8+ T-cells, CD4+ T-cells, Foxp3+ T-helper cells) in the pancreas of hyperglycemic and normoglycemic mice. We also analyzed the number of leukocytes, lymphocytes, granulocytes and monocytes in the blood. In addition, we determined the percentage of CD3+ lymphocytes, CD8+ T-cells, CD4+ T-cells, Foxp3+ T-helper cells, Foxp3+ CD25+ T-helper and Foxp3- T-helper cells in the spleen by flow cytometry. RESULTS Treatment with streptozotocin caused a strong induction of hyperglycemia and a reduction in body weight (P < 0.001). Severe hyperglycemia did not, however, lead to an aggravation, but rather to a slight attenuation of autoimmune pancreatitis. In the pancreas, both the histological score of the pancreas as well as the number of CD3+ lymphocytes (P < 0.053) were decreased by hyperglycemia. No major changes in the percentage of CD8+ T-cells, CD4+ T-cells, Foxp3+ T-helper cells were observed between hyperglycemic and normoglycemic mice. Hyperglycemia increased the numbers of leukocytes (P < 0.001), lymphocytes (P = 0.016), granulocytes and monocytes (P = 0.001) in the blood. Hyperglycemia also moderately reduced the percentage of CD3+ lymphocytes (P = 0.057), significantly increased the percentage of Foxp3+ T-helper cells (P = 0.018) and Foxp3+ CD25+ T-helper cells (P = 0.021) and reduced the percentage of Foxp3- T-helper cells (P = 0.034) in the spleen. CONCLUSION Hyperglycemia does not aggravate but moderately attenuates autoimmune pancreatitis, possibly by increasing the percentage of regulatory T-cells in the spleen.

[1]  Ayodeji Oluwarotimi Omiyale.  Autoimmune pancreatitis. , 2016, Gland surgery.

[2]  B. Vollmar,et al.  Diabetes increases pancreatic fibrosis during chronic inflammation , 2014, Experimental biology and medicine.

[3]  P. Hegyi,et al.  Interactions between the Endocrine and Exocrine Pancreas and Their Clinical Relevance , 2009, Pancreatology.

[4]  S. Livadas,et al.  Endocrine Pancreatic Insufficiency in Chronic Pancreatitis , 2005, Pancreatology.

[5]  M. Stolte,et al.  Non-alcoholic duct destructive chronic pancreatitis , 1997, Gut.

[6]  M. Takase,et al.  Amount of CD4+CD25+ Regulatory T Cells in Autoimmune Pancreatitis and Pilonidal Sinus , 2012, Pancreas.

[7]  K. Uchida,et al.  Circulating Naïve and CD4+CD25high Regulatory T Cells in Patients With Autoimmune Pancreatitis , 2008, Pancreas.

[8]  T. Shimosegawa,et al.  Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 III. Treatment and prognosis of autoimmune pancreatitis , 2014, Journal of Gastroenterology.

[9]  K. Momma,et al.  Short and Long-Term Outcomes of Diabetes Mellitus in Patients with Autoimmune Pancreatitis after Steroid Therapy , 2012, Gut and liver.

[10]  T. Shimosegawa,et al.  Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 I. Concept and diagnosis of autoimmune pancreatitis , 2014, Journal of Gastroenterology.

[11]  Myung-Hwan Kim,et al.  International Consensus Diagnostic Criteria for Autoimmune Pancreatitis: Guidelines of the International Association of Pancreatology , 2011, Pancreas.

[12]  A. Tamakoshi,et al.  Influence of Steroid Therapy on the Course of Diabetes Mellitus in Patients with Autoimmune Pancreatitis: Findings from a Nationwide Survey in Japan , 2006, Pancreas.

[13]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2002 .

[14]  S. Giday,et al.  Clinical Profile of Autoimmune Pancreatitis and Its Histological Subtypes: An International Multicenter Survey , 2011, Pancreas.

[15]  R. Jaster,et al.  Adoptive transfer of CD3+ T cells and CD4+ CD44high memory T cells induces autoimmune pancreatitis in MRL/MpJ mice , 2018, Journal of Cellular and Molecular Medicine.

[16]  N. Kamata,et al.  Pancreatic Endocrine and Exocrine Function and Salivary Gland Function in Autoimmune Pancreatitis Before and After Steroid Therapy , 2003, Pancreas.

[17]  V. Deshpande,et al.  Autoimmune pancreatitis-related diabetes: quantitative analysis of endocrine islet cells and inflammatory infiltrate , 2010, Virchows Archiv.

[18]  K. Mizrahi,et al.  Surge in regulatory cells does not prevent onset of hyperglycemia in NOD mice , 2014 .

[19]  T. Nomura,et al.  Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. , 2004, International immunology.

[20]  T. Shimosegawa,et al.  Characteristics of pancreatic diabetes in patients with autoimmune pancreatitis , 2011, Journal of digestive diseases.

[21]  Yong Zhao,et al.  Alterations of peripheral CD4+CD25+Foxp3+ T regulatory cells in mice with STZ-induced diabetes , 2011, Cellular and Molecular Immunology.

[22]  K. Okazaki,et al.  Treatment for autoimmune pancreatitis: consensus on the treatment for patients with autoimmune pancreatitis in Japan , 2007, Journal of Gastroenterology.

[23]  J. Frossard,et al.  Experimental acute pancreatitis: new insights into the pathophysiology. , 2002, Frontiers in bioscience : a journal and virtual library.

[24]  M. Nose,et al.  Spontaneous development of pancreatitis in the MRL/Mp strain of mice in autoimmune mechanism , 1992, Clinical and experimental immunology.

[25]  H. Sarles,et al.  Chronic inflammatory sclerosis of the pancreas—An autonomous pancreatic disease? , 1961, The American Journal of Digestive Diseases.

[26]  T. Shimosegawa,et al.  Standard steroid treatment for autoimmune pancreatitis , 2009, Gut.

[27]  B. Vollmar,et al.  Diabetes aggravates acute pancreatitis and inhibits pancreas regeneration in mice , 2012, Diabetologia.

[28]  J. Mayerle,et al.  Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment , 2013, Gut.

[29]  H. Nizze,et al.  Interferon-Gamma Treatment Accelerates and Aggravates Autoimmune Pancreatitis in the MRL/Mp-Mouse , 2009, Pancreatology.

[30]  J. Kleeff,et al.  Die autoimmune Pankreatitis — eine chirurgische Krankheit? , 2006, Der Chirurg.

[31]  A. Saluja,et al.  Cerulein-induced chronic pancreatitis does not require intra-acinar activation of trypsinogen in mice. , 2013, Gastroenterology.