HOW DO MONOCLONAL-ANTIBODIES INDUCE TOLERANCE - A ROLE FOR INFECTIOUSTOLERANCE

One of the major goals in therapeutic immunosuppression has been to ac hieve long-term benefit from short-term therapy. The discovery in the mid-1980s that CD4 antibodies can induce immunological tolerance witho ut depleting CD4(+) T cells has reawakened interest in the use of nond epleting monoclonal antibodies for reprogramming the immune system in autoimmunity and in transplantation. Since that time, antibodies to CD 11a, CD4OL, CD25, CD3, and CTLA4-Ig have all been shown capable of fac ilitating tolerance. In order to apply the principle of reprogramming in the clinic, we have sought to understand the mechanisms that are in volved in its induction and its maintenance. In a number of allogeneic transplant models (heart, skin, bone marrow) anti-CD4 (+/-CD8) antibo dies can be shown to block the rejection process while selectively pro moting the development of CD4(+) regulatory T cells responsible for a dominant tolerance that is reflected in findings of linked suppression and infectious tolerance. In these models, T cells that have never be en exposed to CD4 antibodies become tolerant to grafted antigens by ex periencing antigen in the microenvironment of regulatory T cells. Domi nant tolerance is not the only mechanism that can be facilitated by CD 4 Mab therapy. If allogeneic marrow is given at high cell doses under the umbrella of CD4 and CD8 antibodies, then tolerance can be achieved through clonal deletion. The mechanism by which regulatory CD4(+) T c ells suppress is not yet defined but could be active or passive. We ha ve proposed the ''civil service model'' to explain how tolerant T cell s might interfere with the responses of competent T cells in such a wa y as to render them tolerant. The application of dominant infectious t olerance and linked suppression to clinical immunosuppression should n ot be underestimated because it suggests that tolerance acquired (thro ugh therapy) to a limited set of antigens can spread to embrace all ot hers in the tissues under attack.