β-Cell Destruction May Be a Late Consequence of the Autoimmune Process in Nonobese Diabetic Mice

The NOD mouse is an animal model of IDDM that shows many of the characteristics of human IDDM. It has been proposed that β-cell destruction in IDDM progresses over time in a linear manner. Recently, we and others have demonstrated that T helper type 1 (Thl) cells have pathogenic roles in the NOD model and proposed that cytokine balances change as the disease progresses. However, it has not been demonstrated how or when the cytokine balances change or how the β-cell destruction progresses. We have recently demonstrated that the cytokine profiles of CD45RB^low CD4⁺ cells correlate either with their pathogenic or with their protective roles in the NOD mouse. To further analyze this apparent correlation between the shift in cytokine level and IDDM, we examined the anti-CD3-induced cytokine profiles of this subset from NOD mice of various ages compared with that from age-matched I-A^k transgenic NOD and BALB/c mice as controls. A significantly higher ratio of anti-CD3–induced interferon-γ/interleukin-4 was found in diabetic NOD mice (P < 0.0001) but not in age-matched nondiabetic NOD mice. This cytokine ratio did not change significantly until the onset of diabetes in NOD mice. Based upon these results, we propose that IDDM in the NOD mouse progresses as a predominant inflammatory β-cell dysfunction without actual β-cell destruction until late in the disease process. This supports the possibility that late-stage immunotherapy may preserve islet β-cell mass.