Murine antithymocyte globulin therapy alters disease progression in NOD mice by a time-dependent induction of immunoregulation

Greg Simon, Matthew Parker, Vijayakumar Ramiya, Clive Wasserfall, Yanfei Huang, Damien Bresson, R. Fletcher Schwartz, Martha Campbell-Thompson, Lauren Tenace, Todd Brusko, Song Xue, Abraham Scaria, Michael Lukason, Scott Eisenbeis, John Williams, Michael Clare-Salzler, Desmond Schatz, Bruce Kaplan, Matthias Von Herrath, Karl WomerMark A. Atkinson

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE-Antilymphocyte serum can reverse overt type 1 diabetes in NOD mice; yet, the therapeutic parameters and immunological mechanisms underlying the ability for this agent to modulate autoimmune responses against β-cells are unclear, forming the rationale for this investigation. RESEARCH DESIGN AND METHODS-A form of antilym-phocyte serum, rabbit anti-mouse thymocyte globulin (mATG), was utilized in a variety of in vivo and in vitro settings, each for the purpose of defining the physiological, immunological, and metabolic activities of this agent, with particular focus on actions influencing development of type 1 diabetes. RESULTS-We observed that mATG attenuates type 1 diabetes development in an age-dependent fashion, only proving efficacious at disease onset or in the late pre-diabetic phase (12 weeks of age). When provided at 12 weeks of age, mATG reversed pancreatic insulitis, improved metabolic responses to glucose challenge, and rapidly increased frequency of antigen-presenting cells in spleen and pancreatic lymph nodes. Surprisingly, mATG therapy dramatically increased, in an age-dependent fashion, the frequency and the functional activity of CD4 +CD25 + regulatory T-cells. Adoptive transfer/cotransfer studies of type 1 diabetes also support the concept that mATG treatment induces a stable and transferable immunomodulatory repertoire in vivo. CONCLUSIONS-These findings indicate that an induction of immunoregulation, rather than simple lymphocyte depletion, contributes to the therapeutic efficacy of antithymocyte globulin and suggest that time-dependent windows for the ability to delay or reverse type 1 diabetes exist based on the capacity to enhance the functional activity of regulatory T-cells.

Original languageEnglish (US)
Pages (from-to)405-414
Number of pages10
JournalDiabetes
Volume57
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

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Inbred NOD Mouse
Antilymphocyte Serum
Type 1 Diabetes Mellitus
Disease Progression
Regulatory T-Lymphocytes
Lymphocyte Depletion
Therapeutics
Adoptive Transfer
Antigen-Presenting Cells
Autoimmunity
Research Design
Spleen
Lymph Nodes
Rabbits
Glucose
Serum

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Simon, G., Parker, M., Ramiya, V., Wasserfall, C., Huang, Y., Bresson, D., ... Atkinson, M. A. (2008). Murine antithymocyte globulin therapy alters disease progression in NOD mice by a time-dependent induction of immunoregulation. Diabetes, 57(2), 405-414. https://doi.org/10.2337/db06-1384

Murine antithymocyte globulin therapy alters disease progression in NOD mice by a time-dependent induction of immunoregulation. / Simon, Greg; Parker, Matthew; Ramiya, Vijayakumar; Wasserfall, Clive; Huang, Yanfei; Bresson, Damien; Schwartz, R. Fletcher; Campbell-Thompson, Martha; Tenace, Lauren; Brusko, Todd; Xue, Song; Scaria, Abraham; Lukason, Michael; Eisenbeis, Scott; Williams, John; Clare-Salzler, Michael; Schatz, Desmond; Kaplan, Bruce; Von Herrath, Matthias; Womer, Karl; Atkinson, Mark A.

In: Diabetes, Vol. 57, No. 2, 02.2008, p. 405-414.

Research output: Contribution to journalArticle

Simon, G, Parker, M, Ramiya, V, Wasserfall, C, Huang, Y, Bresson, D, Schwartz, RF, Campbell-Thompson, M, Tenace, L, Brusko, T, Xue, S, Scaria, A, Lukason, M, Eisenbeis, S, Williams, J, Clare-Salzler, M, Schatz, D, Kaplan, B, Von Herrath, M, Womer, K & Atkinson, MA 2008, 'Murine antithymocyte globulin therapy alters disease progression in NOD mice by a time-dependent induction of immunoregulation', Diabetes, vol. 57, no. 2, pp. 405-414. https://doi.org/10.2337/db06-1384
Simon, Greg ; Parker, Matthew ; Ramiya, Vijayakumar ; Wasserfall, Clive ; Huang, Yanfei ; Bresson, Damien ; Schwartz, R. Fletcher ; Campbell-Thompson, Martha ; Tenace, Lauren ; Brusko, Todd ; Xue, Song ; Scaria, Abraham ; Lukason, Michael ; Eisenbeis, Scott ; Williams, John ; Clare-Salzler, Michael ; Schatz, Desmond ; Kaplan, Bruce ; Von Herrath, Matthias ; Womer, Karl ; Atkinson, Mark A. / Murine antithymocyte globulin therapy alters disease progression in NOD mice by a time-dependent induction of immunoregulation. In: Diabetes. 2008 ; Vol. 57, No. 2. pp. 405-414.
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T1 - Murine antithymocyte globulin therapy alters disease progression in NOD mice by a time-dependent induction of immunoregulation

AU - Simon, Greg

AU - Parker, Matthew

AU - Ramiya, Vijayakumar

AU - Wasserfall, Clive

AU - Huang, Yanfei

AU - Bresson, Damien

AU - Schwartz, R. Fletcher

AU - Campbell-Thompson, Martha

AU - Tenace, Lauren

AU - Brusko, Todd

AU - Xue, Song

AU - Scaria, Abraham

AU - Lukason, Michael

AU - Eisenbeis, Scott

AU - Williams, John

AU - Clare-Salzler, Michael

AU - Schatz, Desmond

AU - Kaplan, Bruce

AU - Von Herrath, Matthias

AU - Womer, Karl

AU - Atkinson, Mark A.

PY - 2008/2

Y1 - 2008/2

N2 - OBJECTIVE-Antilymphocyte serum can reverse overt type 1 diabetes in NOD mice; yet, the therapeutic parameters and immunological mechanisms underlying the ability for this agent to modulate autoimmune responses against β-cells are unclear, forming the rationale for this investigation. RESEARCH DESIGN AND METHODS-A form of antilym-phocyte serum, rabbit anti-mouse thymocyte globulin (mATG), was utilized in a variety of in vivo and in vitro settings, each for the purpose of defining the physiological, immunological, and metabolic activities of this agent, with particular focus on actions influencing development of type 1 diabetes. RESULTS-We observed that mATG attenuates type 1 diabetes development in an age-dependent fashion, only proving efficacious at disease onset or in the late pre-diabetic phase (12 weeks of age). When provided at 12 weeks of age, mATG reversed pancreatic insulitis, improved metabolic responses to glucose challenge, and rapidly increased frequency of antigen-presenting cells in spleen and pancreatic lymph nodes. Surprisingly, mATG therapy dramatically increased, in an age-dependent fashion, the frequency and the functional activity of CD4 +CD25 + regulatory T-cells. Adoptive transfer/cotransfer studies of type 1 diabetes also support the concept that mATG treatment induces a stable and transferable immunomodulatory repertoire in vivo. CONCLUSIONS-These findings indicate that an induction of immunoregulation, rather than simple lymphocyte depletion, contributes to the therapeutic efficacy of antithymocyte globulin and suggest that time-dependent windows for the ability to delay or reverse type 1 diabetes exist based on the capacity to enhance the functional activity of regulatory T-cells.

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