Shimada A, Rohane P, Fathman C G, Charlton B
Department of Medicine, Stanford University School of Medicine, California, USA.
Diabetes. 1996 Jan;45(1):71-8. doi: 10.2337/diab.45.1.71.
The adoptive transfer of splenocytes from diabetic NOD mice to NOD-scid/scid (NOD-scid) recipients results in diabetes. This model was used to test the effect of cotransfer of splenocyte subsets from young nondiabetic NOD mice. As shown previously in other NOD models, the CD4+ subset from young nondiabetic mice significantly delayed the onset of diabetes in splenocyte cotransfers (P < 0.001). The data presented here showed that the development of diabetes in NOD-scid recipients correlated with a rapid increase in peripheral CD45RB(low) CD4+ cells. However, the CD45RB(low) subset of CD4+ cells from young nondiabetic mice protected from diabetes transfer in this model. We therefore examined whether CD45RB(low) CD4+ cells from diabetic mice were pathogenic rather than protective. CD45RB(low) CD4+ splenocytes from diabetic NOD mice were transferred along with CD8+ splenocytes from diabetic mice into NOD-scid recipients, and all of the recipients became diabetic within 5 weeks posttransfer. In contrast, no recipients (0 of 10) of CD45RB(high) CD4+ cells along with CD8+ splenocytes from diabetic mice became diabetic within 5 weeks posttransfer (P < 0.001). A correlate for the difference between CD45RB(low) CD4+ cells from diabetic NOD mice and CD45RB(low) CD4+ cells from nondiabetic mice, which showed protective effect in splenocyte cotransfers, was found in cytokine production after stimulation with anti-CD3 antibodies in vitro. CD45RB(low) CD4+ cells from diabetic mice showed a significantly higher ratio (approximately fivefold) of gamma-interferon (IFN-gamma) to interleukin (IL)-4 when compared with CD45RB(low) CD4+ cells from nondiabetic mice (P < 0.001). In conclusion, the function of the CD45RB(low) population of CD4+ cells changes from a protective to a pathogenic one during the development of disease in the NOD mouse. This change in function correlates with cytokine production in vitro; increased IFN-gamma-to-IL-4 ratio is associated with pathogenic potential and occurs coincident with (or after) the onset of diabetes.
将糖尿病NOD小鼠的脾细胞过继转移至NOD-scid/scid（NOD-scid）受体小鼠会导致糖尿病。该模型用于测试共转移来自年轻非糖尿病NOD小鼠的脾细胞亚群的效果。如先前在其他NOD模型中所示，来自年轻非糖尿病小鼠的CD4 +亚群在脾细胞共转移中显著延迟了糖尿病的发病（P <0.001）。此处呈现的数据表明，NOD-scid受体小鼠中糖尿病的发展与外周CD45RB(low) CD4 +细胞的快速增加相关。然而，来自年轻非糖尿病小鼠的CD4 +细胞的CD45RB(low)亚群在该模型中可防止糖尿病转移。因此，我们研究了来自糖尿病小鼠的CD45RB(low) CD4 +细胞是否具有致病性而非保护性。将来自糖尿病NOD小鼠的CD45RB(low) CD4 +脾细胞与来自糖尿病小鼠的CD8 +脾细胞一起转移至NOD-scid受体小鼠，所有受体在转移后5周内均患上糖尿病。相比之下，将来自糖尿病小鼠的CD45RB(high) CD4 +细胞与CD8 +脾细胞一起转移的受体中，没有一只（10只中的0只）在转移后5周内患上糖尿病（P <0.001）。在体外经抗CD3抗体刺激后的细胞因子产生中，发现了来自糖尿病NOD小鼠的CD45RB(low) CD4 +细胞与来自非糖尿病小鼠的CD45RB(low) CD4 +细胞之间的差异相关性，后者在脾细胞共转移中显示出保护作用。与来自非糖尿病小鼠的CD45RB(low) CD4 +细胞相比，来自糖尿病小鼠的CD45RB(low) CD4 +细胞在γ-干扰素（IFN-γ）与白细胞介素（IL）-4的比例上显著更高（约五倍）（P <0.001）。总之，在NOD小鼠疾病发展过程中，CD4 +细胞的CD45RB(low)群体的功能从保护性转变为致病性。这种功能变化与体外细胞因子产生相关；IFN-γ与IL-4比例的增加与致病潜力相关，且与糖尿病的发病同时（或之后）发生。
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