Indirect recognition of porcine swine leukocyte Ag class I molecules expressed on islets by human CD4+ T lymphocytes.
Xenotransplantation of porcine islets is considered a viable alternative treatment for type 1 diabetes mellitus. Therefore, we characterized human PBL responding to porcine islets both in vitro by coculture and in vivo using SCID mice reconstituted with human PBLs (HuPBL-SCID) and transplanted with porcine islets. T cell lines generated in vitro and graft-infiltrating T cells obtained from HuPBL-SCID mice were CD4+-proliferated specifically to porcine islets cultured with autologous APC. This proliferation was abrogated by an anti-human class II Ab. These T cell lines also proliferated to purified swine leukocyte Ag (SLA) class I molecules in the presence of self-APC, indicating that the primary xenoantigens recognized are peptides derived from SLA. This CD4+ T cell line lysed porcine islets but not splenocytes. CD4+ T cell clones with Th0, Th1, and Th2 cytokine profiles were isolated. The Th0 and Th1 clones lysed porcine islets, whereas the Th2 clone that secreted a large amount of IL-4 was not lytic. These results demonstrate that human T cells responding to porcine islets are primarily CD4+ and recognize porcine xenoantigens by the indirect Ag pathway presentation. These activated T cells produce cytokines that lyse islets. Furthermore, we demonstrate that the major porcine xenoantigens recognized are SLA class I molecules.
Olack
B
B
Departments ofSurgery and Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Manna
P
P
Jaramillo
A
A
Steward
N
N
Swanson
C
C
Kaesberg
D
D
Poindexter
N
N
Howard
T
T
Mohanakumar
T
T
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002469:Cell Separation; D002999:Clone Cells; D016207:Cytokines / Q000633:toxicity; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D017710:Lymphocyte Transfusion; D051379:Mice; D016513:Mice, SCID; D013045:Species Specificity; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology
D016207:Cytokines; D015395:Histocompatibility Antigens Class I