Mechanisms of graft acceptance: evidence that plasminogen activator controls donor-reactive delayed-type hypersensitivity responses in cardiac allograft acceptor mice.
We have used delayed-type hypersensitivity (DTH) responses to probe the mechanisms of drug-induced cardiac allograft acceptance in mice. DBA/2-->C57BL/6 cardiac allograft recipients treated transiently with gallium nitrate accept their grafts for >90 days and fail to display DBA/2-reactive DTH responses. These DTH responses are restored when anti-TGF-beta Abs are included at the challenge site, and cell depletion studies showed that this DTH inhibition is mediated by CD4+ cells. Real-time PCR analysis revealed that allograft acceptor mice produce no more than background levels of TGF-beta mRNA at DTH challenge sites. This suggests that DTH regulation in allograft acceptor mice may involve TGF-beta activation, rather than TGF-beta production. The protease, plasmin, can activate TGF-beta, and activated T cells can express a receptor for the plasmin-producing enzyme urokinase-type plasminogen activator (uPA), and can also produce both uPA and tissue-type plasminogen activator (tPA). We observed that Abs to tPA or uPA can replace anti-TGF-beta mAb for the restoration of donor-reactive DTH responses in allograft acceptor mice. Histologic analysis revealed that accepted cardiac allografts express uPA, tPA, and active TGF-beta, whereas accepted cardiac isografts express only tPA, but not uPA or activated TGF-beta. These data demonstrate that local tPA and uPA contribute to DTH regulation in allograft acceptor mice and suggest that these elements of the fibrinolytic pathway are used to control donor-reactive cell-mediated immunity in allograft acceptor mice.
Bickerstaff
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Department of Surgery, Comprehensive Cancer Center, Ohio State University College of Medicine, Columbus, OH 43210, USA. bickerstaff-1@medctr.osu.edu
Xia
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Pelletier
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Orosz
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CG
D000818:Animals; D005341:Fibrinolysin / Q000502:physiology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006968:Hypersensitivity, Delayed / Q000276:immunology* / Q000378:metabolism; D007519:Isoantigens / Q000008:administration & dosage; D008212:Lymphocyte Depletion; D017710:Lymphocyte Transfusion; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010960:Plasminogen Activators / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D013347:Subcellular Fractions / Q000276:immunology; D010959:Tissue Plasminogen Activator / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D007519:Isoantigens; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin