Patterns of allosensitization in allograft recipients: long-term cardiac allograft acceptance is associated with active alloantibody production in conjunction with active inhibition of alloreactive delayed-type hypersensitivity

BACKGROUND: The immunologic characteristics of experimental allograft acceptance remain ill-defined. This study evaluates humoral and cell-mediated immunity in transiently immunosuppressed mice that have accepted cardiac allografts. METHODS: DBA/2-->C57BL/6 heterotopic cardiac allograft recipients were immunosuppressed with either GK1.5 monoclonal antibody or gallium nitrate and monitored for donor-reactive delayed-type hypersensitivity (DTH) assessed by ear challenge and for alloantibody production detected by flow cytometry. RESULTS: Cardiac allograft function continued for >90 days in approximately 50% of GK1.5-treated and 97% of gallium nitrate-treated transplant recipients. All nonsuppressed recipients lost graft function within 7 to 10 days. Among mice that accepted allografts, donor-reactive IgG was produced by about 50% of GK1.5 monoclonal antibody-treated mice and 80% of gallium nitrate-treated mice. None of the these mice exhibited donor-reactive DTH responses, and all could down-regulate third-party DTH responses in a donor alloantigen-dependent manner. This down-regulation is not found in nonsuppressed allograft recipients or in naive mice. Importantly, transfer into SCID mice of splenocytes from mice that accepted allografts, but not naive splenocytes, provided them with a similar ability to accept cardiac allografts, even if the grafts co-expressed third-party alloantigens. CONCLUSIONS: IgG alloantibody production by murine cardiac allograft recipients is not a precise indicator of allosensitization leading to either cardiac allograft rejection or acceptance. However, expression of alloreactive DTH is a reliable indicator of allosensitization leading to acute rejection, and the absence of DTH in association with active DTH down-regulatory mechanisms is a reliable indicator of allograft acceptance in this experimental model. Thus, DTH analysis may hold more promise than alloantibody detection for clinical assessment of posttransplant immune status.