Human peripheral blood lymphocyte reconstituted severe combined immunodeficient (hu-PBL-SCID) mice. A model for human islet allograft rejection.
Severe combined immunodeficient (SCID) mice have become a promising tool for the development of models of human immunologic process. We report the development of a reproducible technique for engrafting SCID mice with human PBL (hu-PBL-SCID). Our results show that a booster injection of anti-CD3 antibody stimulated human lymphocytes given 2 days after the initial injection of lymphocytes will improve the efficiency of chimera establishment to 86.7% (13 out of 15). There was also good correlation among detection of human Ig, human CD3+ cells, and human DNA by polymerase chain reaction amplification in the circulation of hu-PBL-SCID mice. Questions remain concerning the immune function of the human lymphoid cells in the SCID mouse. In this study, we analyzed the ability of human T cells in SCID mice to reject human islet allografts transplanted under the kidney capsule. Human islet allograft function assessed by human C-peptide levels demonstrated failure of islet allografts within 21 days after transplantation in hu-PBL-SCID. In contrast, human islets grafted in unreconstituted SCID mice continued to function for greater than 60 days. Recovered human T cells from rejected islets of hu-PBL-SCID mice displayed specific cytolytic activity against HLA class I-matched islets, while the recovered cells from spleen of hu-PBL-SCID mice showed minimal specific cytotoxicity against islets. These results suggest that graft-infiltrating lymphocytes were activated by the engrafted islets within the hu-PBL-SCID, causing the eventual rejection of the human islet allograft. Thus, engraftment of the anti-CD3 antibody-primed human PBL results in a mouse-human chimera with a functionally competent human immune system that is capable of rejecting a human islet allograft.
Shiroki
R
R
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110.
Poindexter
N J
NJ
Woodle
E S
ES
Hussain
M S
MS
Mohanakumar
T
T
Scharp
D W
DW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001483:Base Sequence; D002096:C-Peptide / Q000032:analysis; D017252:CD3 Complex / Q000276:immunology; D002678:Chimera / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D002096:C-Peptide; D017252:CD3 Complex