Abstract
The autoimmune disease type 1 diabetes in humans and NOD mice is determined by multiple genetic factors, among the strongest of which is the inheritance of diabetes-permissive MHC class II alleles associated with susceptibility to disease. Here we examined whether expression of MHC class II alleles associated with resistance to disease could be used to prevent the occurrence of diabetes. Expression of diabetes-resistant MHC class II I-Abeta chain molecules in NOD mice following retroviral transduction of autologous bone marrow hematopoietic stem cells prevented the development of autoreactive T cells by intrathymic deletion and protected the mice from the development of insulitis and diabetes. These data suggest that type 1 diabetes could be prevented in individuals expressing MHC alleles associated with susceptibility to disease by restoration of protective MHC class II expression through genetic engineering of hematopoietic stem cells.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blood Glucose / metabolism
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Cell Differentiation
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Cell Lineage
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Cells, Cultured
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Diabetes Mellitus, Experimental / genetics
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Diabetes Mellitus, Experimental / immunology
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Diabetes Mellitus, Experimental / prevention & control
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Diabetes Mellitus, Type 1 / genetics*
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Diabetes Mellitus, Type 1 / immunology
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Diabetes Mellitus, Type 1 / prevention & control*
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Disease Susceptibility
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Female
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Genes, MHC Class II
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Genetic Therapy*
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / physiology
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / immunology
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Humans
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Mice
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Mice, Inbred BALB C
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Mice, Inbred NOD
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Mice, Transgenic
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Retroviridae / genetics
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Retroviridae / metabolism
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T-Lymphocytes / immunology
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T-Lymphocytes / physiology
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Transduction, Genetic*
Substances
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Blood Glucose
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Histocompatibility Antigens Class II
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Recombinant Fusion Proteins