Rejection of human islets and human HLA-A2.1 transgenic mouse islets by alloreactive human lymphocytes in immunodeficient NOD-scid and NOD-Rag1nullPrf1null 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-RagInullPrf1null 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-RagInullPrf1null 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-RagInullPrf1null mice co-engrafted with HLA-A2 mouse transgenic islets and allogeneic human PBMC provide an effective in vivo model of human islet allograft rejection.