DONOR-RECIPIENT MICROCHIMERISM IS NOT REQUIRED FOR TOLERANCE INDUCTION FOLLOWING RECIPIENT PRETREATMENT WITH DONOR-SPECIFIC TRANSFUSION ANDANTI-CD4 ANTIBODY - EVIDENCE OF A CLEAR ROLE FOR SHORT-TERM ANTIGEN PERSISTENCE

There is considerable current interest in the possibility that long-te rm graft acceptance in clinical solid-organ transplantation might be d ependent upon the development of a microchimeric state between the don or and recipient, This possibility has been prompted by the observatio n that in some transplant patients cells of donor origin can be detect ed in peripheral sites such as the skin, and it has been proposed that these cells play an essential role in maintaining graft survival. The hypothesis that peripheral microchimerism is an absolute requirement for the long-term survival of solid-organ allografts was tested in a w ell-characterized model of transplantation tolerance in which adult re cipient mice are pretreated 28 days before transplant with a single do nor-specific transfusion under the cover of a depleting anti-CD4 antib ody. Mice pretreated with this protocol accept donor-specific cardiac allografts (MST>100 days) but reject those of a third party (MST 16.5 days). The protocol leads to operational tolerance in the long term in that donor-specific skin grafts show prolonged survival while those f rom a third party strain are rejected acutely. Since peripheral blood contains haematopoietic stem cells we speculated that the success of t he anti-CD4/DST protocol might be dependent on the development of micr ochimerism. To address this possibility the DST was irradiated before administration under anti-CD4 antibody cover in order to prevent donor stem cells in the transfusion from establishing a microchimeric state in the recipient animals. Mice in this group rejected their grafts ac utely (MST 12 days), suggesting indeed that stem cells might be very i mportant in the success of this model. However, when the protocol was modified by giving three additional doses of irradiated whole blood to increase the possibility that recipient T cells would be engaged duri ng antibody-induced immunocompromise, graft prolongation was restored (MST>100 days). These results demonstrate that persistence of donor an tigen at the time of anti-CD4 antibody treatment is critical for the i nduction of unresponsiveness in this model and show that microchimeris m is not an absolute requirement for long-term graft survival.