Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice

Matthew J. Parker, Song Xue, John J. Alexander, Clive H. Wasserfall, Martha L. Campbell-Thompson, Manuela Battaglia, Silvia Gregori, Clayton E. Mathews, Sihong Song, Misty Troutt, Scott Eisenbeis, John Williams, Desmond A. Schatz, Michael J. Haller, Mark A. Atkinson

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Abstract

OBJECTIVE - The autoimmune destruction of β-cells in type 1 diabetes results in a loss of insulin production and glucose homeostasis. As such, an immense interest exists for the development of therapies capable of attenuating this destructive process through restoration of proper immune recognition. Therefore, we investigated the ability of the immune-depleting agent antithymocyte globulin (ATG), as well as the mobilization agent granulocyte colony-stimulating factor (GCSF), to reverse overt hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes. RESEARCH DESIGN AND METHODS - Effects of each therapy were tested in pre-diabetic and diabetic female NOD mice using measurements of glycemia, regulatory T-cell (CD4+CD25+Foxp3+) frequency, insulitis, and/or β-cell area. RESULTS - Here, we show that combination therapy of murine ATG and GCSF was remarkably effective at reversing new-onset diabetes in NOD mice and more efficacious than either agent alone. This combination also afforded durable reversal from disease (>180 days postonset) in animals having pronounced hyperglycemia (i.e., up to 500 mg/dl). Additionally, glucose control improved over time in mice subject to remission from type 1 diabetes. Mechanistically, this combination therapy resulted in both immunological (increases in CD4-to-CD8 ratios and splenic regulatory T-cell frequencies) and physiological (increase in the pancreatic β-cell area, attenuation of pancreatic inflammation) benefits. CONCLUSIONS - In addition to lending further credence to the notion that combination therapies can enhance efficacy in addressing autoimmune disease, these studies also support the concept for utilizing agents designed for other clinical applications as a means to expedite efforts involving therapeutic translation.

Original languageEnglish
Pages (from-to)2277-2284
Number of pages8
JournalDiabetes
Volume58
Issue number10
DOIs
Publication statusPublished - Oct 2009

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Inbred NOD Mouse
Type 1 Diabetes Mellitus
Antilymphocyte Serum
Granulocyte Colony-Stimulating Factor
Regulatory T-Lymphocytes
Hyperglycemia
Therapeutics
Glucose
CD4-CD8 Ratio
Autoimmune Diseases
Homeostasis
Research Design
Insulin
Inflammation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Parker, M. J., Xue, S., Alexander, J. J., Wasserfall, C. H., Campbell-Thompson, M. L., Battaglia, M., ... Atkinson, M. A. (2009). Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice. Diabetes, 58(10), 2277-2284. https://doi.org/10.2337/db09-0557

Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice. / Parker, Matthew J.; Xue, Song; Alexander, John J.; Wasserfall, Clive H.; Campbell-Thompson, Martha L.; Battaglia, Manuela; Gregori, Silvia; Mathews, Clayton E.; Song, Sihong; Troutt, Misty; Eisenbeis, Scott; Williams, John; Schatz, Desmond A.; Haller, Michael J.; Atkinson, Mark A.

In: Diabetes, Vol. 58, No. 10, 10.2009, p. 2277-2284.

Research output: Contribution to journalArticle

Parker, MJ, Xue, S, Alexander, JJ, Wasserfall, CH, Campbell-Thompson, ML, Battaglia, M, Gregori, S, Mathews, CE, Song, S, Troutt, M, Eisenbeis, S, Williams, J, Schatz, DA, Haller, MJ & Atkinson, MA 2009, 'Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice', Diabetes, vol. 58, no. 10, pp. 2277-2284. https://doi.org/10.2337/db09-0557
Parker, Matthew J. ; Xue, Song ; Alexander, John J. ; Wasserfall, Clive H. ; Campbell-Thompson, Martha L. ; Battaglia, Manuela ; Gregori, Silvia ; Mathews, Clayton E. ; Song, Sihong ; Troutt, Misty ; Eisenbeis, Scott ; Williams, John ; Schatz, Desmond A. ; Haller, Michael J. ; Atkinson, Mark A. / Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice. In: Diabetes. 2009 ; Vol. 58, No. 10. pp. 2277-2284.
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AU - Gregori, Silvia

AU - Mathews, Clayton E.

AU - Song, Sihong

AU - Troutt, Misty

AU - Eisenbeis, Scott

AU - Williams, John

AU - Schatz, Desmond A.

AU - Haller, Michael J.

AU - Atkinson, Mark A.

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N2 - OBJECTIVE - The autoimmune destruction of β-cells in type 1 diabetes results in a loss of insulin production and glucose homeostasis. As such, an immense interest exists for the development of therapies capable of attenuating this destructive process through restoration of proper immune recognition. Therefore, we investigated the ability of the immune-depleting agent antithymocyte globulin (ATG), as well as the mobilization agent granulocyte colony-stimulating factor (GCSF), to reverse overt hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes. RESEARCH DESIGN AND METHODS - Effects of each therapy were tested in pre-diabetic and diabetic female NOD mice using measurements of glycemia, regulatory T-cell (CD4+CD25+Foxp3+) frequency, insulitis, and/or β-cell area. RESULTS - Here, we show that combination therapy of murine ATG and GCSF was remarkably effective at reversing new-onset diabetes in NOD mice and more efficacious than either agent alone. This combination also afforded durable reversal from disease (>180 days postonset) in animals having pronounced hyperglycemia (i.e., up to 500 mg/dl). Additionally, glucose control improved over time in mice subject to remission from type 1 diabetes. Mechanistically, this combination therapy resulted in both immunological (increases in CD4-to-CD8 ratios and splenic regulatory T-cell frequencies) and physiological (increase in the pancreatic β-cell area, attenuation of pancreatic inflammation) benefits. CONCLUSIONS - In addition to lending further credence to the notion that combination therapies can enhance efficacy in addressing autoimmune disease, these studies also support the concept for utilizing agents designed for other clinical applications as a means to expedite efforts involving therapeutic translation.

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