Journal Article

Unusual Resistance of ALR/Lt Mouse β Cells to Autoimmune Destruction: Role for β Cell-Expressed Resistance Determinants

Savinov, Alexei, Graser, Robert T., Mathews, Clayton E., Serreze, David V., Leiter, Edward H.

2001

Overview

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 β 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 β-cell level. ALR islets were found to be remarkably resistant to two different combinations of β-cytotoxic cytokines (IL-1β, tumor necrosis factor α, and IFN-γ) that destroyed islets from the related NOD and alloxan-susceptible strains. The close MHC relatedness between the NOD and ALR strains (H2-Kdand H2-Ag7identical) allowed us to examine whether ALR islet cells could survive autoimmune destruction by NOD-derived Kd-restricted diabetogenic cytotoxic T lymphocyte clones (AI4 and the insulin-reactive G9C8 clones). Both clones killed islet cells from all Kd-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)F1recipients with NOD bone marrow. In all in vivo systems, ALR and F1female 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 β cell level.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adoptive Transfer / Alloxan - pharmacology / Animals / Autoimmunity - genetics / Autoimmunity - immunology / Biological Sciences / Bone marrow / Bone Marrow Transplantation - immunology / Cell Death - drug effects / Cells / Chimera - genetics / Chimera - immunology / Clone Cells - immunology / Clone Cells - metabolism / Cyclophosphamide - pharmacology / Cytokines / Diabetes / Diabetes complications / Diabetes mellitus / Diabetes Mellitus, Experimental - chemically induced / Diabetes Mellitus, Experimental - genetics / Diabetes Mellitus, Experimental - immunology / Diabetes Mellitus, Experimental - pathology / Diabetes Mellitus, Type 1 - chemically induced / Diabetes Mellitus, Type 1 - genetics / Diabetes Mellitus, Type 1 - immunology / Diabetes Mellitus, Type 1 - pathology / Female / g-Interferon / Genetic Predisposition to Disease / Genetics / histocompatibility antigen H-2 / Histocompatibility Antigens Class I - analysis / Histocompatibility Antigens Class I - immunology / Immune system / Immunology / Insulin / Insulin - metabolism / Insulin Secretion / Interferon-gamma - biosynthesis / Interferon-gamma - pharmacology / Interferon-gamma - toxicity / interleukin 1^b / Interleukin-1 - pharmacology / Interleukin-1 - toxicity / Islet cells / Islets of Langerhans / Islets of Langerhans - drug effects / Islets of Langerhans - immunology / Islets of Langerhans - metabolism / Islets of Langerhans - pathology / Lymphocyte Activation / Mice / Mice, Inbred NOD / Mice, Inbred Strains / Mutation / T lymphocytes / T-Lymphocytes, Cytotoxic - immunology / T-Lymphocytes, Cytotoxic - metabolism / Tumor Necrosis Factor-alpha - pharmacology / Tumor Necrosis Factor-alpha - toxicity / Type 1 diabetes mellitus