TYPE-2 HELPER - T-CELL-TYPE CYTOKINES AND THE DEVELOPMENT OF INFECTIOUS TOLERANCE IN RAT CARDIAC ALLOGRAFT RECIPIENTS

CD4-targeted therapy with a nondepleting RIB-5/2 mAb abrogates acceler ated (<36 h) rejection in presensitized LEW rats and results in perman ent acceptance of LBNF(1) cardiac allografts in conjunction with the f eatures of infectious tolerance. This study examined the role and func tional significance of the Th1 and Th2 cytokine network and systemic h ost allospecific Ab (allo-Ab) responses in the development of the infe ctious tolerance pathway in this model. Long term survival of cardiac transplants in rats treated with the tolerizing RIB-5/2 mAb regimen wa s accompanied by profound depression of Th1 (IL-2 and IFN-gamma) and T h2 (IL-4, IL-10) cytokines at the graft site, as shown by competitive template reverse transcritpion-PCR and immunohistochemistry. In contra st, the expression of Th2-type cytokines was selectively up-regulated after transfer of infectious tolerance by spleen cells into new genera tions of primary and secondary test recipients. Donor-specific circula ting IgM allo-Ab responses were diminished throughout, and the switch from IgM to IgG allo-Ab was completely prevented in tolerant hosts, as shown by flow cytometry, The demonstration that treatment with cytoly tic anti-CD4, but not anti-CD8, mAb recreated rejection of test cardia c allografts with simultaneous down-regulation of IL-4 mRNA/protein ex pression underlines the importance of this cytokine in the development of infectious tolerance. Hence, this report documents distinct cytoki ne elaboration patterns in animals tolerized by CD4-targeted therapy c ompared with those rendered tolerant by putative regulatory Th2-like c ells. The mechanism of tolerance in anti-CD4 mAb-treated hosts appears distinct from that operating in the absence of mAb, when the tolerant state is being transferred in an infectious manner to new cohorts of test recipients.