Inhibition of cytotoxic alloreactivity by human allogeneic mononuclear cells: evidence for veto function of CD2+ cells.

In animal models of organ transplantation, infusion of donor-derived leucocytes or bone marrow cells can support tolerance induction. To date, little is known about the suppressive effects of human allogeneic mononuclear cells on alloreactivity in the human system. To study this, mixed leucocyte cultures (MLC) were incubated in the presence and absence of viable allogeneic mononuclear cells (MNC) (modulator cells) of stimulator/donor origin, and the cytotoxic and proliferative potential of the resulting effector cells was determined. The experiments showed that: viable allogeneic MNC from bone marrow and from lymph nodes and peripheral blood (PBMC) were able to suppress allospecific cytotoxicity by an average of 60%; that allospecific as well as non-specific inhibitory effects could be observed with unseparated PBMC; that CD2+ PMNC showed predominantly allospecific inhibition of cytotoxicity with little effect on proliferation whereas CD2- PBMC showed non-specific inhibitory effects (both for cytotoxicity and proliferation), which could be eliminated by indomethacin; that addition of interleukin-2 (IL-2) up to 50 U/ml to the MLC could not reverse the inhibitory effect; and that selective removal of CD8+ cells from the CD2+ modulator population diminished the specific inhibitory effect only partially. These findings demonstrate that viable human MNC from different compartments can have a marked suppressive effect on alloreactivity in vitro. For peripheral blood mononuclear cells (PBMC) the data suggest that various mechanisms can contribute to allosuppression, including specific suppressive veto effects by CD2+ cells. Such inhibitory effects might be applicable in vivo for down-regulating allospecific cytotoxicity and to facilitate the acceptance of allografts.