Analysis of inflammatory changes in human pancreatic islet cells.

Jackson, Andrew M.

Analysis of inflammatory changes in human pancreatic islet cells.

dc.contributor.advisor	Naziruddin, Bashoo.
dc.contributor.author	Jackson, Andrew M.
dc.contributor.department	Biomedical Studies.	en
dc.contributor.other	Baylor University. Institute of Biomedical Studies.	en
dc.date.accessioned	2009-07-01T16:56:51Z
dc.date.available	2009-07-01T16:56:51Z
dc.date.copyright	2009-05
dc.date.issued	2009-02-27
dc.description	Includes bibliographical references (p. 126-143).	en
dc.description.abstract	Pancreatic islet cell transplantation is a promising investigational research treatment for labile type 1 diabetes mellitus. However, several obstacles still exist to the implementation of clinical islet cell transplantation as a standard therapy. These obstacles include a shortage of donor pancreata, an imperfect islet isolation procedure, significant loss of islets during the peri-transplant period, and islet toxicity of immunosuppressive drugs. The present study is focused on addressing two of these major hurdles; namely, identification of factors affecting the islet isolation, and understanding the mechanism involved in the peri-transplant loss of islets. Initial analysis was centered on the effect of cold ischemia time (CIT) on the islet isolation outcome. Comparison of varying CIT and several factors that determine the quantity and quality of islets obtained from 52 isolations was performed. This analysis showed that CIT of less than four hours significantly improved islet isolation results. This finding could help improve the current strategy used in clinical islet transplantation. We hypothesized that following transplantation, the inflammatory environment will specifically alter gene expression in transplanted islets, and also will induce surface expression of HLA-class II molecules. This, in turn, could cause anti-donor response resulting in islet destruction. To test the above hypotheses, two studies were performed. Islet cells were treated with control or type 1 diabetic serum. Gene expression was then analyzed using micro array and confirmed by real-time PCR. Islets treated with diabetic serum demonstrated specific induction of multiple genes reported to have secondary roles in angiogenesis while inhibiting transcription of genes with protective attributes against environmental stresses. Islet cells were treated with IFNγ and TNFα and analyzed for HLA class II induction by real-time PCR analysis, flow cytometry, and immunofluorescent imaging.Cytokine treated islets demonstrated significantly upregulated HLA class II gene transcription and surface expression. Importantly, islet transplant recipient serum showed increased binding and cytotoxicity specifically directed against cytokine treated islets. Together these data suggest that in the context of hepatic portal vein transplantation, islet cells contribute to the innate and adaptive immune response during the peri-transplant period resulting in islet destruction.	en
dc.description.degree	Ph.D.	en
dc.description.statementofresponsibility	by Andrew M. Jackson.	en
dc.format.extent	xvii, 143 p. : ill.	en
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dc.format.mimetype	application/pdf
dc.format.mimetype	application/pdf
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dc.identifier.citation	Jackson, Andrew M., John E. Connolly, Shinichi Matsumoto, Hirofumi Noguchi, Nicholas Onaca, Marlon F. Levy, and Bashoo Naziruddin. "Evidence for induced expression of HLA class II on human islets : possible mechanism for HLA sensitization in transplant recipients." Transplantation 87, no. 4 (2009): 500-506.	en
dc.identifier.uri	http://hdl.handle.net/2104/5344
dc.language.iso	en_US	en
dc.rights	Baylor University theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. Contact librarywebmaster@baylor.edu for inquiries about permission.	en
dc.rights.accessrights	Worldwide access	en
dc.rights.accessrights	Access changed 8/1/11
dc.subject	Islands of Langerhans -- Transplantations.	en
dc.subject	Diabetes -- Treatment -- Complications.	en
dc.subject	Pancreas -- Cryopreservation.	en
dc.subject	Genetic expression -- Analysis.	en
dc.subject	HLA class II antigens -- Analysis.	en
dc.title	Analysis of inflammatory changes in human pancreatic islet cells.	en
dc.type	Thesis	en