The HLA class II molecules play a pivotal role in most immune responses. Thus, while the HLA class II molecules are critical for protection against infection and cancer, they are also implicated in susceptibility to various autoimmune diseases and immune deficiencies. Considerable knowledge has been generated on the MHC class II molecules through studies with the mouse as well as the human system. During the past few years, transgenic mice expressing HLA-DQ and -DR genes have provided us with an additional tool to dissect the role of class II molecules in various human immune responses. As part of this research proposal, the available transgenic mice will be generated to fill the gaps in the information and to complement studies. The genes are introduced into mice lacking endogenous class II such that human class II antigens are the sole restricting element for CD4. In selected mice, human CD4 gene will replace the deleted mouse CD4 gene to further humanize these mice. HLA-DQ and -DR restricted epitopes on known human allergens, house dust mite and ragweed will be identified, and antagonist peptides will be generated to test their efficacy in desensitization in an in vivo model of allergy. An HLA-DR/DQ restricted experimental autoimmune encephalomyelitis disease model for Multiple Sclerosis will be studied to identify epitopes on potential human autoantigens such as MBP, PLP, and MOG, and to understand how the gene complementation between the HLA-DQ and -DR genes determine predisposition, onset, and the severity of the disease. A spontaneous insulitis model in the HLA-DQ/DR transgenic mice would be utilized to understand the events which lead from insulitis to full-blown diabetes. This model can also be used to understand the role of potential autoantigens such as GAD and insulin in human diabetes. Finally, this set of transgenic mice will be a resource for investigators studying various aspects of the role of HLA class II molecules in human immune responses and to generate DQ/DR restricted mouse models for human diseases.
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