IMMUNOHISTOCHEMICAL CHARACTERIZATION OF MONOCYTES-MACROPHAGES AND DENDRITIC CELLS INVOLVED IN THE INITIATION OF THE INSULITIS AND BETA-CELLDESTRUCTION IN NOD MICE

This immunohistochemical study describes the infiltration pattern of m onocytes-macrophages and dendritic cells during the development of ins ulitis and diabetes in the NOD mouse. A panel of monoclonal antibodies (MoAbs) was used to analyze pancreases of nondiabetic (glucosuria neg ative) male and female NOD mice at 3, 7, 10, and 17 weeks of age. BALB /c female mice 17-weeks-old, diabetic NOD female mice 20- to 30-weeks- old, and nondiabetic NOD male mice 22-weeks-old were used as controls. Three MoAbs (viz., FR-MP23, MOMA1, and BM8) were special and appeared to identify macrophage/dendritic cell subsets that either had a chara cteristic infiltration pattern in the initial phases of the autoimmune reaction before T-cell infiltration or were typical for the later bet a-cell destructive insulitis process. 1) Raised numbers of ER-MP23(+) and MORA-1(+) dendritic cells/ macrophages were characteristic for the initial phases of the NOD insulitis in 3-week-old mice. The cells wer e found in and near swollen para-insular vessels. In 7-week-old mice, these ER-MP23(+) and MOMA-1(+) cells had accumulated around the islets and were the first hematopoietic cells detectable at these spots. 2) From 7 weeks of age onward, BM8(+) macrophages could be found in the p ara- and periinsulitis processes. However, only in females were these BM8(+) macrophages found to infiltrate into the islets. In lymphoid ti ssues, ER-MP23 predominantly reacts with macrophages/dendritic cells p resent in the subcapsular and interfollicular sinuses of lymph nodes a nd the T-cell zones of these lymph nodes. ER-MP23 also reacts with tis sue macrophages/dendritic cells. MOMA-1 reacts with the marginal metal lophilic macrophages of the spleen and with sinus macrophages of the l ymph node. Both populations of cells are likely to be involved in anti gen presentation in lymphoid tissues as well as in the NOD peri-insuli tis. BM8 in lymphoid tissues predominantly reacts with the phagocytosi ng macrophages present in the red pulp of the spleen. Because beta-cel l destruction and glucosuria almost exclusively take place in NOD fema les, our findings suggest that BMS(+) macrophage infiltration into the female islets is linked to a beta-cell destructive process, either as a destructive type of infiltration or as an infiltration meant to rem ove the beta-cell debris caused by another immune assault.