Rejection of human islets and human HLA-A2.1 transgenic mouse islets by alloreactive human lymphocytes in immunodeficient NOD-scid and NOD-Rag1(null)Prf1(null) mice.
Immunodeficient NOD mice engrafted with human peripheral blood mononuclear cells (PBMCs) were used in two models of human islet allograft rejection. Model one: human PBMCs were engrafted into chemically diabetic NOD-scid mice bearing established subrenal human islet allografts. Inflammation and often complete islet allograft rejection were observed. Model 2 incorporated three key advances. First, we developed a new immunodeficient recipient, NOD-RagI(null)Prf1(null) mice. Second, graft-lymphocyte interactions were optimized by intrasplenic co-transplantation of islets and human PBMC. Third, NOD-scid islets expressing human HLA-A2.1 were used as allograft targets. Diabetic NOD-RagI(null)Prf1(null) recipients of HLA-A2.1 transgenic mouse islets, alone or co-engrafted with HLA-A2-positive human PBMC, exhibited durable graft survival and euglycemia. Contrastingly, co-transplantation with HLA-A2-negative human PBMC led to islet graft rejection without evidence of graft-vs.-host disease (GVHD). We propose that diabetic NOD-RagI(null)Prf1(null) mice co-engrafted with HLA-A2 mouse transgenic islets and allogeneic human PBMC provide an effective in vivo model of human islet allograft rejection.
Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Scott J
SJ
Banuelos
Leonard D
LD
Shultz
Dale L
DL
Greiner
Lisa M
LM
Burzenski
Bruce
B
Gott
Bonnie L
BL
Lyons
Aldo A
AA
Rossini
Michael C
MC
Appel
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003920:Diabetes Mellitus / Q000097:blood / Q000139:chemically induced / Q000276:immunology / Q000601:surgery; D017353:Gene Deletion; D016654:Genes, RAG-1 / Q000235:genetics*; D006084:Graft Rejection / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D016511:Severe Combined Immunodeficiency / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
D001786:Blood Glucose; D015789:HLA-A2 Antigen; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin