Characterization of pancreatic islet cell infiltrates in NOD mice: effect of cell transfer and transgene expression

Abstract

Insulin-dependent diabetes mellitus can be transferred into young irradiated non-obese diabetic (NOD) mice by spleen cells from a diabetic NOD donor. T cells (both L3T4+ and Ly-2+) enter the pancreas 2 weeks following transfer. They are present initially at peri-islet locations but progressively infiltrate the islet with accompanying beta cell destruction. The infiltrate is heterogeneous with respect to V beta usage. Inflammatory macrophages (Mac-1+, F4/80+) can be detected at peri-islet locations at 1 week after transfer and continue to be recruited during the disease process. Their presence at the initiation of disease suggests that their primary function may be autoantigen presentation. Increased expression of major histocompatibility complex (MHC) class I molecules is observed on both endocrine and exocrine tissue in areas of intra-islet infiltration. MHC class II and ICAM-1 expression was restricted to the cells constituting the inflammatory infiltrate. Expression of these molecules was not observed on beta cells implying that presentation of autoantigen by the beta cell itself does not play a role in the beta cell destruction in NOD mice.

Prevention of autoimmune insulitis in nonobese diabetic mice by expression of major histocompatibility complex class I Ld molecules.

“…It is possible that these antigens may bind to NOD-type class I molecules followed by the presentation of these antigens to cytotoxic T cells. In accordance with this, increased expression of class I molecules is observed in both endocrine and exocrine tissues in the vicinity of intraislet infiltration (22,55). But, in NOD-Ld+ transgenic mice, these antigens may not be recognized by these T cells although they may bind to Ld molecules, possibly because they mimic self-peptides to which tolerance may have been induced.…”

Pancreatic NOD beta cells express MHC class II protein and the frequency of I-Ag7 mRNA-expressing beta cells strongly increases during progression to autoimmune diabetes

“…Hence, MHC class II molecules should be expressed by beta cells. However, these findings notwithstanding, the failure to detect surface MHC class II molecules on NOD beta cells [14,21] had led to the generally accepted notion that NOD beta cells do not express MHC class II and, therefore, could not be a direct target of CD4+ T cells. The study revisited this question by analysing pancreatic beta cells by single-cell multiplex RT PCR and single-cell immunofluorescence.…”

Proteome Analysis of Interleukin-1β–Induced Changes in Protein Expression in Rat Islets of Langerhans

“…elective ␤-cell destruction accompanied by mononuclear cell infiltration of the islets of Langerhans (insulitis) is the hallmark of recent-onset type 1 diabetes in humans (1,2) and animal models of type 1 diabetes (e.g., the NOD mouse [3] and the BB rat [4]). Cytokines and cytotoxic T-cells are likely to be the most important mediators of selective ␤-cell destruction (rev.…”