期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 98, 期 1, 页码 235-240出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.98.1.235
关键词
diabetes; cytokines; free radicals; pancreatic islets; T cells
资金
- NCI NIH HHS [CA-34196, P30 CA034196] Funding Source: Medline
- NIAID NIH HHS [AI41469] Funding Source: Medline
- NIDDK NIH HHS [DK51090, R01 DK027722, R01 DK046266, R37 DK027722, R01 DK051090, R29 DK046266, F32 DK009865, DK36175, DK27722, DK46266, R01 DK036175] Funding Source: Medline
Genetic analysis of autoimmune insulin-dependent diabetes mellitus (IDDM) has focused on genes controlling immune functions, with little investigation of innate susceptibility determinants expressed at the level of target beta cells. The Alloxan (AL) Resistant (R) Leiter (Lt) mouse strain, closely related to the IDDM-prone nonobese diabetic (NOD)/Lt strain, demonstrates the importance of such determinants, ALR mice are unusual in their high constitutive expression of molecules associated with dissipation of free-radical stress systemically and at the beta -cell level. ALR islets were found to be remarkably resistant to two different combinations of beta -cytotoxic cytokines (IL-1 beta, tumor necrosis factor alpha, and IfN-gamma) that destroyed islets from the related NOD and alloxan-susceptible strains. The dose MHC relatedness between the NOD and ALR strains (H2-K-d and H2-Ap(g7) identical) allowed us to examine whether ALR islet cells could survive autoimmune destruction by NOD-derived K-d-restricted diabetogenic cytotoxic T lymphocyte clones (A14 and the insulin-reactive G9C8 clones). Both clones killed islet cells from all K-d-expressing strains except ALR, ALR resistance to diabetogenic immune systems was determined in vivo by means of adoptive transfer of the G9C8 clone or by chimerizing lethally irradiated ALR or reciprocal (ALR x NOD)F-1 recipients with NOD bone marrow. In all in vivo systems, ALR and F-1 female recipients of NOD marrow remained IDDM free; in contrast, all of the NOD recipients became diabetic. In conclusion, the ALR mouse presents a unique opportunity to identify dominant IDDM resistance determinants expressed at the beta cell level.
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