Intrathymic immunomodulation and the "infectious" tolerance pathway in allograft recipients

We have previously shown that >75% of LEW cardiac allografts survive indefinitely in BUF rats pretreated at Day -21 intrathymically (IT) with donor alloantigen in conjunction with a single intravenous dose of ALS. Spleen cells can adoptively transfer the tolerant state to new cohorts of test recipients. This study was designed to analyze cellular and humoral events contributing to the "infectious" tolerance pathway in this model.

Spleen cells (25 x 10(6)) harvested from BUF recipients bearing long-term cardiac allografts were injected intravenously into lightly irradiated (450 R) secondary BUF rats, followed 24 h later by transplantation of LEW of ACl hearts. Cardiac allografts were then analyzed serially by reverse transcription polymerase chain reaction for Th1 and Th2 cytokine gene expression. Donor-specific IgM and IgG alloantibody responses in host serum were screened by flow cytometry.

Transfer of regulatory spleen cells harvested between Days 80 and 140 from tolerant hosts induced tolerance to heart grafts in a donor-specific manner. In the early posttransplant period, selective sparing of Th2 cytokines was noted. Adoptively transferred hosts showed overall depression of IgM, but a vigorous IgG1 and IgG2a alloantibody response.

IT + ALS-induced tolerance can be transferred in a donor-specific "infectious" manner to new cohorts of engrafted recipients. The development of tolerance is nontemporally bound, and associates with an early Th2-type immune deviation at the graft site. The elevated levels of T cell-dependent IgG1 and IgG2 may interfere with the antigen reactivity and alloresponsive effector functions, contributing to graft acceptance in the "infectious" tolerance pathway.