Murine insulin-dependent diabetes mellitus : a model for disease development and protection

Detta är en avhandling från Stockholm : Stockholms universitet

Sammanfattning: Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease caused by destruction of the insulin-producing beta cells in the pancreatic Langerhans' islets. This destruction is preceded by an infiltration of mononuclear leukocytes called insulitis. This study aims at determining the cellular mechanisms for the autoimmune reaction associated with diabetes development by using transgenic animal models as well as the spontaneously diabetic non-obese diabetic (NOD) mice.MHC class II expression on beta cells has been proposed to be a mechanism for the development of insulitis and diabetes. Transgenic mice expressing physiological levels of allogeneic MHC class II on beta cells do not display any sign of neither insulitis nor diabetes, although they are functionally intolerant to the allogeneic MHC. We demonstrate that this inability to react to the allogeneic MHC class II on beta cells is due to a functional inability of the beta cells to act as antigen-presenting cells. The MHC class II transgenic mice were mated to mice expressing the costimulatory molecule B7-1 on beta cells. Mice expressing both MHC class II and B7-1 on beta cells develop a severe insulitis and diabetes, while mice lacking either transgene reveal no sign of autoimmunity. This demonstrates that expression of costimulatory molecules can overcome immunological non-recognition.E alpha-transgenic NOD mice are almost completely protected against insulitis and diabetes. This effect can be modulated by mutating the Ea promoter to give a restricted expression of the transgene. These mice are only partially protected against the development of insulitis. By comparing the different degrees of insulitis in three promoter-mutated transgenic lines, and relating them to the different patterns of I-E expression, we demonstrate the requirements for I-E expression on primary antigen-presenting cells in order to alleviate NOD insulitis. By mating the promoter-mutated lines to one another we got double-transgenic lines with an expression pattern very close to normal wildtype expression. In spite of this, none out of three double-transgenic lines were completely protected from insulitis.We therefore conclude that minute differences in I-E expression account for the susceptibility to insulitis seen in the double-transgenic lines.By intracellular immunofluorescence staining for eight different cytokines we demonstrate a biphasic cytokine pattern with early monokine production correlated to an increasing infiltration of the Langerhans' islets, and Th1 lymphokines produced prior to the development of diabetes, thus characterising the effector phase with beta-cell destruction. In addition, we could find abundant production of IL-6 by endocrine cells, probably as a stress response to the ongoing tissue damage

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