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

Background. We have previously shown that >75% of LEW cardiac allografts su rvive indefinitely in BUF rats pretreated at Day -21 intrathymically (IT) w ith 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 ev ents contributing to the "infectious" tolerance pathway in this model. Methods. Spleen cells (25 x 10(6)) harvested from BUF recipients bearing lo ng-term cardiac allografts were injected intravenously into lightly irradia ted (450 R) secondary BUF rats, followed 24 h later by transplantation of L EW of ACI hearts. Cardiac allografts were then analyzed serially by reverse transcription polymerase chain reaction for Th1 and Th2 cytokine gene expr ession. Donor-specific IgM and IgG alloantibody responses in host serum wer e screened by how cytometry. Results. Transfer of regulatory spleen cells harvested between Days 80 and 140 from tolerant hosts induced tolerance to heart grafts in a donor-specif ic manner. In the early posttransplant period, selective sparing of Th2 cyt okines was noted. Adoptively transferred hosts showed overall depression of IgM, but a vigorous IgG1 and IgG2a alloantibody response. Conclusion. IT + ALS-induced tolerance can be transferred in a donor-specif ic "infectious" manner to new cohorts of engrafted recipients. The developm ent of tolerance is nontemporally bound, and associates with an early Th2-t ype immune deviation at the graft site. The elevated levels of T cell-depen dent IgG1 and IgG2 may interfere with the antigen reactivity and allorespon sive effector functions, contributing to graft acceptance in the "infectiou s" tolerance pathway. (C) 1999 Academic Press.