title: HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/γc(null)/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.
  
  
  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/γc(null)/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/γc(null)/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/γc(null)/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/γc(null)/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/γc(null)/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.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Fatima
authors.initials: F
authors.lastname: Whitfield-Larry
authors.forename: Ellen F
authors.initials: EF
authors.lastname: Young
authors.forename: Garrick
authors.initials: G
authors.lastname: Talmage
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fudge
authors.forename: Anita
authors.initials: A
authors.lastname: Azam
authors.forename: Shipra
authors.initials: S
authors.lastname: Patel
authors.forename: Joseph
authors.initials: J
authors.lastname: Largay
authors.forename: Warren
authors.initials: W
authors.lastname: Byrd
authors.forename: John
authors.initials: J
authors.lastname: Buse
authors.forename: Ali S
authors.initials: AS
authors.lastname: Calikoglu
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Frelinger
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006239:Haplotypes; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D051379:Mice; D008822:Mice, Transgenic; D013154:Spleen / Q000166:cytology
chemical_list: D015789:HLA-A2 Antigen