Distinct tolerance pathways in sensitized allograft recipients after selective blockade of activation signal 1 or signal 2

Background. CD4-targeted therapy or blocking of CD28-B7 T-cell costimulatio n may produce indefinite cardiac allograft survival in presensitized rats. This study analyzes the immune events associated with tolerance pathways af ter the blockade of activation signal 1 (CD4 monoclonal antibody [mAb]) or signal 2 (CTLA4Ig). Methods and Results. Lewis rats sensitized with Brown Norway skin grafts re ject LBNF1 cardiac allografts in <36 hr. Animals were treated with RIB-5/2, a nondepleting CD4 mAb, or with CTLA4Ig + LBNF1 spleen cells. RIB-5/2 mono therapy uniformly produced permanent cardiac graft acceptance, whereas CTLA 4Ig produced indefinite graft survival in about 50% of sensitized rats. Spl een cells (100x10(6)) from CD4 mAb-treated rats conferred donor-specific to lerance after transfer into new sets of recipients. This tolerant state cou ld be then transferred with regulatory cells in an infectious manner into n ew cohorts of engrafted rats. In contrast, features of infectious tolerance could be detected in CTLA4Ig-treated hosts after infusion of >300x10(6) of splenocytes. CD4 mAb therapy abolished the transcription of both T helper (Th)1 and Th2 cytokines compared with rejecting controls. In contrast, CTLA 4Ig treatment resulted in a selective sparing of Th2-type cytokines. Surviv ing grafts in both groups were largely protected from signs of chronic reje ction. Conclusions. CD4 mAb-induced blockage of activation signal 1 or CTLA4Ig-med iated blockage of costimulatory signal 2 may induce a true transplantation tolerance in sensitized rats, as documented by permanent graft acceptance a nd attenuation of chronic injury. The infectious pathway operates in a cell dose-dependent manner. Th2-type deviation in the graft itself is not requi red for tolerance maintenance, and it does not necessarily lead to chronic injury.