Xiaojian Huang

Genetic Absence of γ-Interferon Delays but Does Not Prevent Diabetes in NOD Mice

Cytoldnes, particularly interferons, may participate in the development of type I diabetes. This involvement could be from direct cytotoxic actions of the interferons on the pancreatic (β-cells or from an indirect influence on the number, activity, or type of inflammatory cells that invade the islets in type I diabetes. To examine directly the role of interferon (IFN)-γ in a mouse model of type I diabetes, we have introduced an inactivating mutation in the IFN-γ gene (ifg) into NOD mice. The genetic absence of IFN-γ does not prevent either insulitis or diabetes in the NOD mice, but it does increase the time to onset. Although it might have been predicted that the absence of IFN-γ in these mice would lead to an increase in expression of Th2 T-helper cell-related cytoldnes, we found instead a profound decrease in the expression of two of the characteristic Th2 cytoldnes, interleukin (IL)-4 and EL-1O. We also demonstrate that the splenocytes taken from IFN-γ–deficient diabetic mice are fully capable of transferring diabetes to naive recipients.

Interferon Expression in the Pancreases of Patients With Type I Diabetes

We have used a reverse transcriptase–polymerase chain reaction (RT-PCR) protocol to examine the expression of cytokines in the pancreases and islets of patients with type I diabetes. We detect a significant increase in the level of expression of interferon (IFN)-α in the pancreases of the diabetic patients as compared with the control pancreases. In contrast, IFN-β was detected at comparable levels in both groups, while IFN-γ was detected in three of four control pancreases and one of four pancreases from the diabetic individuals. The IFN-α cDNAs generated by the RT-PCR were cloned and sequenced to determine which α-subtypes were being expressed. We found that the repertoire of subtypes was quite limited in any one individual (diabetic or not), although each individual was different with respect to the pattern of subtypes expressed. We also examined these pancreases for the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1α, IL-2, IL-4, and IL-6. We found no detectable expression of TNF-α or IL-2 in any pancreases, and the expression of the other cytokines was variable, with no pattern emerging from the comparison of the diabetic and nondiabetic individuals. We conclude that, of the cytokines examined, only IFN-α was significantly increased in the diabetic patients, a result that is consistent with the possibility that this cytokine is directly involved in the development of type I diabetes.

Islet expression of interferon-α precedes diabetes in both the BB rat and streptozotocin-treated mice

The mechanism(s) leading to beta cell dysfunction in type I diabetes has not been defined. We have investigated whether islet expression of IFN alpha could be a cause of the lesions that are hallmarks of type I diabetes. Streptozotocin induces the expression of interferon-alpha by pancreatic islets prior to the diabetes induced by streptozotocin. Increased IFN alpha, induced by poly I/C or expressed from a transgene will exacerbate the diabetogenic effects of streptozotocin. In another rodent model of type I diabetes (the BB rat), islet expression of IFN alpha precedes lymphocytic infiltration and diabetes. As in the streptozotocin model, in the BB rats poly I/C will induce islet expression of IFN alpha and accelerate the onset of diabetes. These results are consistent with the hypothesis that islet expression of IFN alpha participates in causing type I diabetes.

Control of Islet Intercellular Adhesion Molecule-1 Expression by Interferon-α and Hypoxia

The ability of interferon-α (IFN-α) to induce the adhesion molecules that characterize the islets of patients with type I diabetes has been investigated. We have found that all tested recombinant IFN-as will induce major histocompatibility complex (MHC) class I on arterial endothelial cells. Some but not all IFN-as will induce intercellular adhesion molecule-1 (ICAM-1). However, there is only a transient and modest increase in VCAM on arterial endothelial cells. IFN-α has very little effect on endothelial MHC class II expression but will induce these proteins on monocytes. Thus, there is a close concordance between the biological actions of IFN-α and the appearance of those adhesion molecules induced in the islets of patients with type I diabetes. IFN-α is also produced in normal human islets during short-term cultures, probably as a result of the ischemia present at the center of the islet. This induction of IFN-α by hypoxia may explain the previously reported spontaneous induction of ICAM-1 in human islets and may also be a contributing factor to the failure of islet grafts.

The Role of Interferon-α in the Development of Type I Diabetes

Type I diabetes is an acquired disorder with genetic susceptibility conferred primarily by genes within the human leukocyte antigen (HLA) locus (reviewed in 1–5). Several lines of evidence, including the presence of autoantibodies directed against β-cell components and leukocytic infiltration into the islets, suggest that the disease is predominantly autoimmune. However, the mechanisms by which the disease is initiated and the means by which insulin secretion is lost and the β cells destroyed have not been resolved.