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.
Banuelos
Scott J
SJ
Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Shultz
Leonard D
LD
Greiner
Dale L
DL
Burzenski
Lisa M
LM
Gott
Bruce
B
Lyons
Bonnie L
BL
Rossini
Aldo A
AA
Appel
Michael C
MC
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