Mechanistic Studies in the Inflammatory Response of Pancreatitis and Pancreatric Cancer - Role of Myeloid Derived Suppressor Cells

Persistent Link:
http://hdl.handle.net/10150/594648
Title:
Mechanistic Studies in the Inflammatory Response of Pancreatitis and Pancreatric Cancer - Role of Myeloid Derived Suppressor Cells
Author:
Cieza Rubio, Napoleon Eduardo
Issue Date:
2015
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Tumor-infiltrating myeloid-derived suppressor cells (MDSCs), are important mediators of a tumor-permissive microenvironment that contributes to tumor growth and could account for the limited success of immunotherapeutic strategies. MDSCs suppress adaptive immunity by blocking T cell activation, inducing Treg accumulation, and inhibiting natural killer cell cytotoxicity against tumor cells. We investigated the roles of MDSCs in the regeneration of the exocrine pancreas associated with acute pancreatitis and the progression of acinar to ductal metaplasia. Acute pancreatitis was induced in wild type and P48+/Cre;LSL-KRASG12D mice using caerulein and an early influx of MDSCs into the pancreas was observed flow cytometry and immunocytochemistry. Numbers of Gr1(+)CD11b(+) MDSCs increased over 20-fold in pancreata of mice with acute pancreatitis to account for nearly 15% of intrapancreatic leukocytes and have T cell suppressive properties. This marked accumulation of MDSCs returned to normal values within 24 hours of the insult in wild type mice; however, in the oncogenic KRAS mice, MDSCs levels remained elevated. When intrapancreatic MDSCs were depleted by administration of a CXCR2 antagonist (SB265610) in wild type mice the severity of acinar damage was increased. This was also accompanied by a delayed regeneration determined morphologically and with the mitotic immunomarker phospho-histone H3. Isolated intrapancreatic MDSCs from treated mice induce naïve acinar cells to undergo acinar ductal metaplasia when co-cultured in collagen 3D cultures. Purified splenic MDSCs failed to induce the phenotypic transdifferentiation. We conclude that MDSCs are required for adequate pancreatic regeneration in wild type mice with acute pancreatitis and their persistent elevation in oncogenic KRAS mice is not only associated with immune-evasion, but may also function as direct enhancer of malignant proliferation.
Type:
text; Electronic Thesis
Keywords:
Oncogenic Kras; Pancreas regeneration; Pancreatic adenocarcinoma; Pancreatitis; Medical Sciences; Myeloid Derived Suppressor Cells
Degree Name:
M.S.
Degree Level:
masters
Degree Program:
Graduate College; Medical Sciences
Degree Grantor:
University of Arizona
Advisor:
Heimark, Ronald L.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleMechanistic Studies in the Inflammatory Response of Pancreatitis and Pancreatric Cancer - Role of Myeloid Derived Suppressor Cellsen_US
dc.creatorCieza Rubio, Napoleon Eduardoen
dc.contributor.authorCieza Rubio, Napoleon Eduardoen
dc.date.issued2015en
dc.publisherThe University of Arizona.en
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en
dc.description.abstractTumor-infiltrating myeloid-derived suppressor cells (MDSCs), are important mediators of a tumor-permissive microenvironment that contributes to tumor growth and could account for the limited success of immunotherapeutic strategies. MDSCs suppress adaptive immunity by blocking T cell activation, inducing Treg accumulation, and inhibiting natural killer cell cytotoxicity against tumor cells. We investigated the roles of MDSCs in the regeneration of the exocrine pancreas associated with acute pancreatitis and the progression of acinar to ductal metaplasia. Acute pancreatitis was induced in wild type and P48+/Cre;LSL-KRASG12D mice using caerulein and an early influx of MDSCs into the pancreas was observed flow cytometry and immunocytochemistry. Numbers of Gr1(+)CD11b(+) MDSCs increased over 20-fold in pancreata of mice with acute pancreatitis to account for nearly 15% of intrapancreatic leukocytes and have T cell suppressive properties. This marked accumulation of MDSCs returned to normal values within 24 hours of the insult in wild type mice; however, in the oncogenic KRAS mice, MDSCs levels remained elevated. When intrapancreatic MDSCs were depleted by administration of a CXCR2 antagonist (SB265610) in wild type mice the severity of acinar damage was increased. This was also accompanied by a delayed regeneration determined morphologically and with the mitotic immunomarker phospho-histone H3. Isolated intrapancreatic MDSCs from treated mice induce naïve acinar cells to undergo acinar ductal metaplasia when co-cultured in collagen 3D cultures. Purified splenic MDSCs failed to induce the phenotypic transdifferentiation. We conclude that MDSCs are required for adequate pancreatic regeneration in wild type mice with acute pancreatitis and their persistent elevation in oncogenic KRAS mice is not only associated with immune-evasion, but may also function as direct enhancer of malignant proliferation.en
dc.typetexten
dc.typeElectronic Thesisen
dc.subjectOncogenic Krasen
dc.subjectPancreas regenerationen
dc.subjectPancreatic adenocarcinomaen
dc.subjectPancreatitisen
dc.subjectMedical Sciencesen
dc.subjectMyeloid Derived Suppressor Cellsen
thesis.degree.nameM.S.en
thesis.degree.levelmastersen
thesis.degree.disciplineGraduate Collegeen
thesis.degree.disciplineMedical Sciencesen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorHeimark, Ronald L.en
dc.contributor.committeememberHeimark, Ronald L.en
dc.contributor.committeememberJie, Tunen
dc.contributor.committeememberNfonsam, Valentine N.en
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