HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/ γcnull/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells

Fatima Whitfield-Larry, Ellen F. Young, Garrick Talmage, Elizabeth Fudge, Anita Azam, Shipra Patel, Joseph Largay, Warren Byrd, John Buse, Ali S. Calikoglu, Leonard D. Shultz, Jeffrey A Frelinger

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

OBJECTIVE - Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing β-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes. RESEARCH DESIGN AND METHODS - We adoptively transferred HLA-A2-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/γc null/HLA-A*0201 (NOD-scid/γcnull/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/γcnull/A2 mice after transfer. RESULTS - Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/γcnull/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/γcnull/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2-matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8+ T cells among the islet infiltrates. CONCLUSIONS - We show that insulitis is transferred to NOD-scid/γc null/A2 mice that received HLA-A2-matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8+ T cells are epitope-specific and produce interferon-γ after in vitro peptide stimulation. This indicates that NOD-scid/γcnull/A2 mice transferred with HLA-A2-matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell-mediated responses in patients with type 1 diabetes.

Original languageEnglish (US)
Pages (from-to)1726-1733
Number of pages8
JournalDiabetes
Volume60
Issue number6
DOIs
StatePublished - Jun 2011

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HLA-A2 Antigen
Transgenic Mice
Blood Cells
varespladib methyl
Tissue Donors
T-Lymphocytes
Type 1 Diabetes Mellitus
Inbred NOD Mouse
T-Lymphocyte Epitopes
Lymphocytes
Spleen
Lymph Nodes
Adoptive Transfer
Interferons
Autoimmune Diseases
Disease Progression
Epitopes
B-Lymphocytes
Research Design
Animal Models

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/ γcnull/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells. / Whitfield-Larry, Fatima; Young, Ellen F.; Talmage, Garrick; Fudge, Elizabeth; Azam, Anita; Patel, Shipra; Largay, Joseph; Byrd, Warren; Buse, John; Calikoglu, Ali S.; Shultz, Leonard D.; Frelinger, Jeffrey A.

In: Diabetes, Vol. 60, No. 6, 06.2011, p. 1726-1733.

Research output: Contribution to journalArticle

Whitfield-Larry, Fatima ; Young, Ellen F. ; Talmage, Garrick ; Fudge, Elizabeth ; Azam, Anita ; Patel, Shipra ; Largay, Joseph ; Byrd, Warren ; Buse, John ; Calikoglu, Ali S. ; Shultz, Leonard D. ; Frelinger, Jeffrey A. / HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/ γcnull/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells. In: Diabetes. 2011 ; Vol. 60, No. 6. pp. 1726-1733.
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title = "HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/ γcnull/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells",
abstract = "OBJECTIVE - Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing β-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes. RESEARCH DESIGN AND METHODS - We adoptively transferred HLA-A2-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/γc null/HLA-A*0201 (NOD-scid/γcnull/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/γcnull/A2 mice after transfer. RESULTS - Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/γcnull/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/γcnull/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2-matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8+ T cells among the islet infiltrates. CONCLUSIONS - We show that insulitis is transferred to NOD-scid/γc null/A2 mice that received HLA-A2-matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8+ T cells are epitope-specific and produce interferon-γ after in vitro peptide stimulation. This indicates that NOD-scid/γcnull/A2 mice transferred with HLA-A2-matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell-mediated responses in patients with type 1 diabetes.",
author = "Fatima Whitfield-Larry and Young, {Ellen F.} and Garrick Talmage and Elizabeth Fudge and Anita Azam and Shipra Patel and Joseph Largay and Warren Byrd and John Buse and Calikoglu, {Ali S.} and Shultz, {Leonard D.} and Frelinger, {Jeffrey A}",
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T1 - HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/ γcnull/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells

AU - Whitfield-Larry, Fatima

AU - Young, Ellen F.

AU - Talmage, Garrick

AU - Fudge, Elizabeth

AU - Azam, Anita

AU - Patel, Shipra

AU - Largay, Joseph

AU - Byrd, Warren

AU - Buse, John

AU - Calikoglu, Ali S.

AU - Shultz, Leonard D.

AU - Frelinger, Jeffrey A

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N2 - OBJECTIVE - Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing β-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes. RESEARCH DESIGN AND METHODS - We adoptively transferred HLA-A2-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/γc null/HLA-A*0201 (NOD-scid/γcnull/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/γcnull/A2 mice after transfer. RESULTS - Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/γcnull/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/γcnull/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2-matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8+ T cells among the islet infiltrates. CONCLUSIONS - We show that insulitis is transferred to NOD-scid/γc null/A2 mice that received HLA-A2-matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8+ T cells are epitope-specific and produce interferon-γ after in vitro peptide stimulation. This indicates that NOD-scid/γcnull/A2 mice transferred with HLA-A2-matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell-mediated responses in patients with type 1 diabetes.

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