Prediction of spontaneous autoimmune diabetes in NOD mice by quantification of autoreactive T cells in peripheral blood - PubMed (original) (raw)

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Prediction of spontaneous autoimmune diabetes in NOD mice by quantification of autoreactive T cells in peripheral blood

Jacqueline D Trudeau et al. J Clin Invest. 2003 Jan.

Abstract

Autoimmune (type 1) diabetes mellitus results from the destruction of insulin-producing pancreatic beta cells by T lymphocytes. Prediction of cell-mediated autoimmune diseases by direct detection of autoreactive T cells in peripheral blood has proved elusive, in part because of their low frequency and reduced avidity for peptide MHC ligands. This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

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Figure 1

Figure 1

High-avidity peptide/MHC class I tetramers detect a higher frequency of autoreactive T cells from freshly isolated islets. All numbers indicate percentage of CD8+ B220– tetramer+ cells. (a) Pancreatic islets derived from 8-week-old female NOD mice were stained with tetramers associated with the indicated peptides. Data are representative of six independent experiments from mice 6–15 weeks of age. Similar results (but approximately tenfold lower) were observed with peripheral blood (data not shown). (b) Representative examples of TUM, NRP-V7, and INS tetramer staining of islets at 4, 9, 12, and 16 weeks of age. (c) Mean percentage (± SEM) of tetramer-positive cells from mice at 4–5 (n = 4), 7–10 (n = 14), 11–14 (n = 17), and 15–18 (n = 14) weeks of age. NRP staining performed only at 4–5 weeks, n = 3; 7–10 weeks, n = 7; 15–18 weeks, n = 10. Data is shown also for nondiabetic mice at 32 weeks of age (n = 5). ND, not determined; PE, phycoerythrin.*P < 0.001 compared with TUM at each age. (d) Islet cells pooled from 4 mice (13–16 weeks of age) were assayed by ELISpot for IFN-γ secretion in response to TUM, NRP-V7, or INS (n = 4). Naive spleen cells from an 8.3-TCR NOD mouse were used as negative control. *P < 0.0001 compared with TUM, #P < 0.05 compared with INS. Inset: representative ELISpot assay: duplicate wells containing 20,000 islet cells from 14-week-old NOD mice.

Figure 2

Figure 2

NRP-V7–reactive T cells detected in peripheral blood indicate their presence in pancreatic islets. The mean (± SEM) percentage of NRP-V7 tetramer-positive CD8+ B220– cells within peripheral blood, pancreatic islets, spleen, and pancreatic draining lymph nodes are shown for individual NOD mice of 9–10 (gray bars; n = 7), 11–14 (black bars; n = 13), and 15–17 (white bars; n = 10) weeks of age. The inset shows a representative staining of each tissue from a single 12-week-old mouse. Numbers indicate the percentage of CD8+ B220– tetramer-positive cells.

Figure 3

Figure 3

NRP-V7–specific T cells in peripheral blood can be used to predict diabetes development. (a) Mean proportion (± SEM) of NRP-V7 tetramer-positive CD8+ B220– cells in peripheral blood of mice that developed diabetes (filled circles; n = 13) versus mice that remained nondiabetic to 32 weeks of age (open squares; n = 5). Mice from different litters were analyzed in two groups, beginning at 6 (n = 6) or 9 weeks of age (n = 12). Most diabetic mice were removed from the study after 21 weeks of age. The difference in NRP-V7 tetramer-positivity between diabetic and nondiabetic mice was significant for every time point from 9 to 16 weeks of age (bar; P < 0.001). For diabetic animals, the differences between NRP-V7 tetramer-positive peaks (*) and the time points before and after the peak were also significant (P < 0.001). (b) Accumulation of NRP-V7 tetramer-positive cells in peripheral blood of diabetic (open circles; n = 13) and nondiabetic (open squares; n = 5) mice from 9 to 16 weeks of age. Weekly measurements of NRP-V7 tetramer-positive cells were summed cumulatively and expressed as a mean ± the 95% confidence interval (shading). (c) Representative data from individual mice showing the proportion of NRP-V7 tetramer-positive cells in peripheral blood (filled circles) along with blood glucose (solid line, no symbols). Glucose normalization following hyperglycemia was due to insulin treatment. Arrows indicate the point at which mice had accumulated 0.75% NRP-V7 tetramer-positive cells, predictive of diabetes development. Time points where NRP-V7 tetramer staining exceeded 0.50% (*) or 1.00% (+) are indicated along with the 0.50% threshold (dashed line).

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