The evidence that the development of IDDM in the NOD mouse requires macrophages is contradictory. Although macrophage depletion using silica completely prevents diabetes (29), liposome depletion does not (30). However, the importance of CD4+ T cells is uniformly accepted. Transgenic mice with an Ap null phenotype, which leads to an absence of class II MHC expression and the CD4+ T-cell subset, crossed onto a NOD mice background have no insulitis and no diabetes (31). Histological analysis of the development of insulitis in NOD mice shows that in the early infiltrate, CD4+ T-cells predominate, and that CD8+
T cells become more common only in late insulitis (32). The same sort of longitudinal studies are clearly not possible in human IDDM, but as IDDM is a chronic disease, different areas of the pancreas at a single point in time appear to show that early and late stages of infiltration can be distinguished in the same patient. Some studies have proposed that macrophages or Langerhans cells are the earliest type of infiltrating cell in human IDDM (33), although this remains controversial.
The interaction between autoreactive CD4+ T cells and professional antigen-presenting cells, presumed to be macrophages and/or Langerhans cells, requires that the autoantigen is first available for presentation. In the case of hsp 60, it is not clear whether spontaneous release from the normal location in the p cell of the insulin secretory granule occurs or presentation follows an initial p-cell insult, although redistribution of hsp 60 into the cytoplasm has been observed (34).
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