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Immunology and Transplantation

Long-Term Remission of Diabetes in NOD Mice Is Induced by Nondepleting Anti-CD4 and Anti-CD8 Antibodies

  1. Zuoan Yi1,
  2. Ramiro Diz1,
  3. Aaron J. Martin1,
  4. Yves Maurice Morillon1,
  5. Douglas E. Kline1,
  6. Li Li1,
  7. Bo Wang1 and
  8. Roland Tisch1,2⇓
  1. 1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  2. 2UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  1. Corresponding author: Roland Tisch, rmtisch{at}med.unc.edu.
Diabetes 2012 Nov; 61(11): 2871-2880. https://doi.org/10.2337/db12-0098
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  • FIG. 1.
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    FIG. 1.

    Short-course treatment with YTS177 and YTS105 rapidly induces remission in recent-onset diabetic NOD mice that is maintained long-term. A: Recent-onset diabetic NOD female mice were treated with YTS177 and YTS105 (n = 24; top panel) or control 2A3 (n = 5; bottom panel) and blood glucose was monitored. B: Blood glucose levels of individual recent-onset diabetic NOD mice prior to and 72 h after YTS treatment. *P < 10−3. C: Recent-onset diabetic NOD female mice were treated with only YTS105 (n = 5; top panel) or YTS177 (n = 8; bottom panel) and blood glucose was monitored. D: Blood glucose levels were measured in individual 12–14-week-old prediabetic (n = 17) or YTS-treated, long-term remission (≥250 days; n = 18) NOD female mice (left panel) *P < 10−3. Tolerance to injected glucose was assessed in groups of three to six animals (right panel); YTS-treated NOD female mice remaining free of recurrent diabetes ≥150 days were tested.

  • FIG. 2.
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    FIG. 2.

    YTS177 and YTS105 treatment induces T-cell loss in the pancreas and PLN. A: IL-2 and IFN-γ were measured via ELISA in pancreatic homogenates prepared from groups of recent-onset diabetic NOD mice treated with YTS177 and YTS105 (YTS), control 2A3 (Ctrl), or left untreated (Diabetic). Data are the average of eight individual mice. *P ≤ 0.008. The number of CD4+ and CD8+ T cells in the pancreas (Pan), PLN, and spleen (Spl) of NOD (*P ≤ 0.02) (B), NOD.BDC.2.5 (*P < 10−3) (C), and NOD.8.3 (*P ≤ 0.037) (D) was determined via FACS 6 days post-YTS or control 2A3 treatment. Data are the average of 8–15 individual mice. E: The number (left panel) and frequency (right panel) of Foxp3+ Treg in the respective tissues was determined in groups of six NOD.BDC.Foxp3.GFP female mice. *P ≤ 0.01.

  • FIG. 3.
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    FIG. 3.

    YTS177- and YTS105-induced T-cell loss in the pancreas and PLN is not due to apoptosis. A: Representative FACS histograms for TUNEL staining of CD8+ thymocytes in NOD mice 12 h postdexamethasone (Dex) treatment and CD4+ and CD8+ T cells in the PLN of NOD.BDC2.5 and NOD.8.3 mice, respectively, treated with YTS or control 2A3. B: The frequency of TUNEL staining T cells in PLN of individual YTS and isotype control mAb-treated NOD.BDC2.5 and NOD.8.3 mice over time. C: Representative immunofluorescence of thymic sections from control and Dex-treated NOD mice or pancreatic sections from YTS versus control 2A3-treated NOD.BDC2.5 (36 h) and NOD.8.3 (24 h) mice stained with TUNEL (FITC), anti-CD90.2 (PE), and anti-insulin (Alexa 647). (A high-quality color representation of this figure is available in the online issue.)

  • FIG. 4.
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    FIG. 4.

    TGF-β is necessary for YTS177- and YTS105-induced diabetes reversal. A: TGF-β was measured in individual pancreases from groups of three recent-onset diabetic NOD mice treated with YTS, control 2A3, or left untreated and from unmanipulated B6 mice (left panel; *P ≤ 0.0017) and serum at the time of onset and post-YTS treatment in five remission NOD female mice (right panel). The data are representative of at least three experiments. B: Recent-onset diabetic NOD female mice were treated with YTS177 and YTS105 plus anti–TGF-β (n = 9; left panel) or isotype control mAb (n = 10; right panel) and blood glucose was monitored. C: Recent-onset diabetic NOD (n = 7; left panel) and NOD.IL4null (n = 8; right panel) female mice were treated with YTS plus anti–IL-10 receptor mAb or YTS alone, respectively, and blood glucose was monitored. D: NOD.BDC2.5/Cα−/− mice were treated with YTS177 plus anti–TGF-β or isotype control mAb, and 6 days later, the number of CD4+ T cells in the pancreas determined via FACS. *P < 10−3. E: Fold increase in TGF-β1 mRNA in DC, macrophages (MΦ), and T cells sorted from handpicked islets and PLN of individual NOD.BDC2.5 mice (n = 4 to 5/group) 6 days after treatment with YTS or isotype control. DC: *P = 0.004; MΦ: *P = 0.048.

  • FIG. 5.
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    FIG. 5.

    Long-term remission NOD mice have altered β-cell–specific T-cell reactivity in the PLN. Cytokine production by β-cell–specific T cells was measured in the spleen (A) and PLN (B) (*P ≤ 0.04) of YTS-treated animals in remission for >200 days and control recent-onset diabetic NOD mice. Shown is the average of two to four experiments. In medium-only controls, ≤10 IFN-γ or IL-4 spot-forming units (SFU) (left and middle panels) and ≤50 pg/mL of TGF-β (right panel) were detected in enzyme-linked immunospot and ELISA, respectively. C: The frequency (left panel) and number (right panel) of Foxp3+CD25+CD4+ T cells in the spleen (Spl) and PLN of diabetic (Ctrl; n = 6–10) and YTS-treated long-term remission (YTS; >200 days; n = 7–10) NOD female mice as determined by FACS. *P = 0.01.

  • FIG. 6.
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    FIG. 6.

    PLN but not the spleen (Spl) of YTS-treated long-term remission NOD mice contains Treg. Groups of 5–10 NOD.scid mice received diabetogenic splenocytes plus splenocytes (A, left panel) or splenic CD25+CD4+ T cells (A, right panel) and PLN cells (B, left panel) or PLN-derived CD25+CD4+ T cells (B, right panel) isolated from YTS-treated long-term remission (>200 days) or control 2A3-treated diabetic NOD female mice. *P ≤ 0.002. C: Proliferation of CFSE-labeled BDC2.5 CD4+ T cells was measured via FACS (representative histograms provided) in the PLN of YTS Ab-treated long-term remission (>150 days) and nondiabetic 16-week-old NOD female mice. Data are the average of six mice/group. *P = 10−4.

  • FIG. 7.
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    FIG. 7.

    Immunity to foreign antigens is unaffected by YTS Ab treatment. A: Representative FACS plots (left panel) of in vivo CTL activity specific for HA512–520-pulsed targets in nondiabetic untreated (Naive) or peptide-immunized (Ctrl) NOD female mice and YTS Ab-treated long-term remission NOD mice (>150 days) immunized with HA512–520 average specific lysis for groups of eight mice (right panel). B: KLH-specific serum IgM (left panel) and IgG (right panel) were measured in untreated or KLH-immunized NOD female mice or YTS Ab-treated long-term remission NOD mice (>150 days) immunized with KLH.

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Long-Term Remission of Diabetes in NOD Mice Is Induced by Nondepleting Anti-CD4 and Anti-CD8 Antibodies
Zuoan Yi, Ramiro Diz, Aaron J. Martin, Yves Maurice Morillon, Douglas E. Kline, Li Li, Bo Wang, Roland Tisch
Diabetes Nov 2012, 61 (11) 2871-2880; DOI: 10.2337/db12-0098

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Long-Term Remission of Diabetes in NOD Mice Is Induced by Nondepleting Anti-CD4 and Anti-CD8 Antibodies
Zuoan Yi, Ramiro Diz, Aaron J. Martin, Yves Maurice Morillon, Douglas E. Kline, Li Li, Bo Wang, Roland Tisch
Diabetes Nov 2012, 61 (11) 2871-2880; DOI: 10.2337/db12-0098
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