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Mechanisms of Graft Acceptance: Evidence That Plasminogen Activator Controls Donor-Reactive Delayed-Type Hypersensitivity Responses in Cardiac Allograft Acceptor Mice¹

Alice A. Bickerstaff^2,*, Dongyuan Xia^*, Ronald P. Pelletier^* and Charles G. Orosz^*,,,§

Departments of ^* Surgery, Pathology, and Molecular Virology, Immunology, and Medical Genetics, and ^§ Comprehensive Cancer Center, Ohio State University College of Medicine, Columbus, OH 43210

We have used delayed-type hypersensitivity (DTH) responses to probe the mechanisms of drug-induced cardiac allograft acceptance in mice. DBA/2C57BL/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-ß 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-ß mRNA at DTH challenge sites. This suggests that DTH regulation in allograft acceptor mice may involve TGF-ß activation, rather than TGF-ß production. The protease, plasmin, can activate TGF-ß, 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-ß 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-ß, whereas accepted cardiac isografts express only tPA, but not uPA or activated TGF-ß. 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.

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