Non-obese diabetic (NOD) mice display enhanced immune responses and prolonged survival of lymphoid cells

Abstract

We report that lymphoid cells originating from the non-obese diabetic (NOD) autoimmune prone mouse strain are resistant to several signals known to induce programmed cell death. In vitro culturing of lymphoid cells of splenic or lymph node origin showed that B cells and T cells of both CD4+ and CD8+ phenotypes from NOD mice display extended survival in vitro. By cytofluorimetric analysis, immature CD4+ CD8+ NOD thymocytes were shown to partially resist in vivo treatment with corticosteroids. Finally, immunization with protein antigens induced enhanced and prolonged immune responses in NOD mice compared with normal C57BL/6, BALB/c, and C3H/Tif control mice. We conclude that the NOD mouse displays a defect in the mechanism(s) mediating programmed cell death in T and B lymphocytes. These findings provide a novel explanation for the B cell aberrations observed in the NOD mouse and may have implications for the understanding of the autoimmune pathogenesis in this mouse strain.

Resistance of T-cells to apoptosis in autoimmune diabetic (NOD) mice is increased early in life and is associated with dysregulated expression of Bcl-x

“…Conceivably, therefore, increased resistance of NOD lymphocytes to PCD induced by growth factor withdrawal could facilitate the survival of emerging autoreactive clones. Our finding that peripheral T cells and also single positive mature thymocytes but not double positive thymocytes exhibit an increased resistance to induction of apoptosis is at variance with that of Leijon et al [9]. However, in their study, apoptosis was induced in vivo by injection of glucocorticoids.…”

“…Multiple loci influencing disease susceptibility at various stages have now been mapped in the mouse genome [7]. In this context, apoptosis has been shown to be decreased in NOD mouse lymphocytes compared to those from non-autoimmune strains [8,9]. The actual contribution of this trait to the autoimmune process now needs to be determined.…”

1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes

“…It has already been shown that NOD lymphocytes are highly resistant to various apoptotic signals, such as CY and dexamethasone [20][21][22][23]. A resistance and/or earlier recovery of effectors after CY in the NOD model probably explains the diabetogenic potential of CY.…”

“…Transgenic mice expressing bcl-2, an apoptosisinhibiting gene, have impaired apoptosis which leads to the development of an autoimmune phenomenon depending on their genetic background [15][16][17][18][19]. Also, NOD lymphocytes appear to be resistant to apoptotic signals, such as CY and dexamethasone [20][21][22][23], and it might be hypothesized that this mechanism is involved in the accumulation of autoimmune effector cells in NOD mice. Since it is known that 1,25(OH) 2 D 3 can induce apoptosis in phytohaemagglutinin (PHA)-stimulated lymphocytes, HL60 leukaemic cells and MCF 7 breast cancer cells [24][25][26], the protection against diabetes in NOD mice by 1,25(OH) 2 D 3 might also involve a better elimination of autoimmune effector cells by increasing their sensitivity to apoptosis.…”

Distinct immune responses to transgene products from rAAV1 and rAAV8 vectors

“…However, NOD mice are an exception and provide an excellent opportunity for studies of the immune response. In addition to high susceptibility for autoimmune disease such as type 1 diabetes and Sorgen's syndrome, NOD mice also display elevated immune responsiveness against foreign antigens and transgene products (16,21,22). The lack of immune response to transgene products from rAAV8 in the NOD mouse model strongly suggests that rAAV8 vector could be used in human clinical studies where immune response to transgene product must be avoided.…”