Summary
We have analysed whether infiltration of macrophages and lymphocyte subtypes into pancreatic islets of diabetes prone BB rats occurs at random or whether insulitis requires a specific sequence of events. Serial sections from more than 700 islets of diabetes prone BB rats (70–150 days of age) were analysed for infiltrating immunocytes and expression of major histocompatibility complex antigens by 4–11 different monoclonal antibodies. In parallel, electron microscopy was performed in a fraction of islets. Part of the animals had been treated with macrophage toxic silica particles. A specific non-random sequence of events was identified and 4 stages of islet inflammation were recognised. Stages 1 a and 1 b are defined by macrophage (ED1+, W3/25+. Ox3/6/17+, ED2−) infiltration and concomitant enhanced major histocompatibility complex class I antigen expression initially at one pole or at the periphery of islets. T-, NK- and B-lymphocytes are absent (<1 cell per mean islet section). In stage 2, more macrophages are infiltrating and concomitantly Ox19+-T-lymphocytes and Ox8+-granular (NK-) lymphocytes are observed. In stage 3, additional massive infiltration of Ox12+-B-lymphocytes is noted. Silica treatment of BB rats largely prevented macrophage infiltration. Concomitantly islets were free of lymphocytes. Thus, macrophage infiltration clearly precedes T- and NK-lymphocyte and later B-lymphocyte infiltration. Lymphocytes do not infiltrate islets in the absence of prior macrophage invasion.
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Nakhooda AF, Like AA, Chappel CI, Murray FT, Marliss EB (1977) The spontaneously diabetic Wistar rat. Metabolic and morphologic studies. Diabetes 26: 100–112
Like AA, Kislauskis E, Williams RM, Rossini AA (1982) Neonatal thymectomy prevents spontaneous diabetes mellitus in the BB/W rat. Science 216: 664–666
Like AA, Biron CA, Weringer EJ, Byman K, Sroczynski E, Guberski DL (1986) Prevention of diabetes in BioBreeding/Worcester rats with monoclonal antibodies that recognize T lymphocytes or natural killer cells. J Exp Med 164: 1145–1159
Koevary SB, Williams DE, Williams RM, Chick WL (1985) Passive transfer of diabetes from BB/W to Wistar-Furth rats. J Clin Invest 75: 1904–1907
Oschilewski U, Kiesel U, Kolb H (1985) Administration of silica prevents diabetes in BB-rats. Diabetes 34: 197–199
Kiesel U, Oschilewski M, Kantwerk G, Maruata M, Hanenberg H, Treichel U, Kolb-Bachofen V, Hartung HP, Kolb H (1986) Essential role of macrophages in the development of type I diabetes in BB rats. Transplant Proc 18: 1525–1527
Kolb-Bachofen V, Kolb H (1983) New concept of insulitis and B-islet cell destruction. Diabetes 32 [Suppl 1]: 22A
Kolb H, Kiesel U, Flohr K, Greulich B, Freytag G, Kolb-Bachofen V (1984) Cell mediated immunity to islet cells: lessions from animal studies. Behring Inst Mitt 75: 33–38
McMaster WR, Williams AF (1979) Identification of Ia glycoproteins in rat thymus and purification from rat spleen. Eur J Immunol 9: 426–433
Dallman MJ, Mason DW, Webb M (1982) The role of host and donor cells in the rejection of skin allografts by T-cell-deprived rats injected with synorgeneic T-cells. Eur J Immunol 12: 511–518
Brideau RJ, Carter PB, McMaster WR, Mason DW, Williams AF (1980) Two subsets of rat T lymphocytes defined with monoclonal antibodies. Eur J Immunol 10: 609–615
Cantrell DA, Robins RA, Brooks CG, Baldwin RW (1982) Phenotype of rat natural killer cells defined by monoclonal antibodies marking rat lymphocyte subsets. Immunology 45: 97–103
Hunt S, Fowler MH (1981) A repopulation assay for B and T lymphocyte stem cells employing radiation chimaeras. Cell Tissue Kinet 14: 445–464
Fukumoto T, McMaster WR, Williams AF (1982) Mouse monoclonal antibodies against rat major histocompatibility antigens. Two Ia antigens and expression of Ia and class I antigens in rat thymus. Eur J Immunol 12: 237–243
Dallman MJ, Thomas ML, Green JR (1984) MRC Ox-19: a monoclonal antibody that labels rat T lymphocytes and augments in vitro proliferative responses. Eur J Immunol 14: 260–267
White RA, Mason DW, Williams AF, Galfre G, Milstein CF (1978) T-lymphocyte heterogeneity in the rat: seperation of functional subpopulations using a monoclonal antibody. J Exp Med 148: 664–673
Williams AF, Galfre G, Milstein C (1977) Analysis of cell surfaces by xenogeneic myeloma-hybrid antibodies: Differentiation antigens of rat lymphocytes. Cell 12: 663–669
Barclay AN (1981) The localization of populations of lymphocytes defined by monoclonal antibodies in rat lymphoid tissues. Immunology 42: 593–600
Dijkstra CD, Döpp EA, Joling P, Kraal G (1985) The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology 54: 589–599
Kolb-Bachofen V, Epstein S, Kiesel U, Kolb H (1988) Low-dose streptozocin-induced diabetes in mice. Electron microscopy reveals single-cell insulitis before diabetes onset. Diabetes 37: 21–27
Woda BA, Like AA, Padden C, McFadden ML (1986) Deficiency of phenotypic cytotoxic-suppressor T lymphocytes in the BB/W rat. J Immunol 136: 856–859
In't Veld PA, Pipeleers DG (1988) In situ analysis of pancreatic islets in rats developing diabetes. Appearance of nonendocrine cells with surface MHC class II antigens and cytoplasmic insulin immunoreactivity. J Clin Invest 82: 1123–1128
Dean BM, Walker R, Bone AJ, Baird JD, Cooke A (1985) Prediabetes in the spontaneously diabetic BB/E rat: lymphocyte subpopulations in the pancreatic infiltrate and expression of rat MHC class II molecules in endocrine cells. Diabetologia 28: 464–466
Walker R, Bone AJ, Cooke A, Baird JD (1988) Distinct macrophage subpopulations in pancreas of prediabetic BB/E rats. Possible role for macrophages in pathogenesis of IDDM. Diabetes 37: 1301–1304
Lee KU, Kim MK, Amano K, Pak CY, Jaworski MA, Mehta JG, Yoon J-W (1988) Preferential infiltration of macrophages during early stages of insulitis in diabetes-prone BB rats. Diabetes 37: 1053–1958
Lee KU, Pak CY, Amano K, Yoon J-W (1988) Prevention of lymphocytic thyroiditis and insulitis in diabetes-prone BB rats by the depletion of macrophages. Diabetologia 31: 400–402
Seemayer TA, Colle E, Tannenbaum GS, Oligny LL, Guttmann RD, Goldman H (1983) Spontaneous diabetes mellitus syndrome in the Rat, III. Pancreatic alterations in aglycosuric and untreated diabetic BB Wistar-derived rats. Metabolism 32: 26–31
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Hanenberg, H., Kolb-Bachofen, V., Kantwerk-Funke, G. et al. Macrophage infiltration precedes and is a prerequisite for lymphocytic insulitis in pancreatic islets of pre-diabetic BB rats. Diabetologia 32, 126–134 (1989). https://doi.org/10.1007/BF00505185
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DOI: https://doi.org/10.1007/BF00505185