FULLY AND LONG-TERM XENOGENEIC HEMATOPOIETIC CHIMERAS CREATED IN POORLY CONCORDANT RAT-MOUSE COMBINATIONS - EXPRESSION OF HEREDITARY DONOR CHARACTERISTICS

We created fully and stable xenogeneic hematopoietic chimeras in ''poo rly concordant'' rat-mouse strain combinations defined by their high h istocompatibility-antigen disparity and by the high titer of mouse-ser um natural cytotoxic antibodies (NcAb) to rat donor bone marrow cells (BMC). Recipients were adult male (C57BL/6 x DBA/2)F-1 (BDF1) mice, an d donors of untreated BMC were adult male WAG strain rats. We tried se veral approaches to improve the quality and the stability of the rat-c ell engraftment and to avoid the risk of graft-vs.-host reaction (GVHR ). Best results were obtained when: 1) BDF1 recipients were previously thymectomized and then heavily irradiated to lower their immunocompet ence; 2) irradiated recipients were implanted with a newborn BDF1 thym us, which allows maturing rat T lymphoid cells to be made tolerant to mouse antigens in vivo, which lowered the risk of GVHR; and 3) recipie nts were given a high number of untreated rat BMC (4-5 injections of 1 .6x10(7) cells) to reduce the risk of rejection of rat BMC by mouse Nc Ab. We found that rat BMC engraftment was highly effective (75 to 100% rat hemoglobin and 100% rat IgG) and long-lasting (more than 10 month s). The grafted rat cells were very tolerant toward host histocompatib ility antigens but maintained all their immunological potentialities. Moreover, using the ''poorly concordant'' Wistar Furth (WF)-BDF1 combi nation, we showed that a genetically controlled characteristic of the hematopoietic system of the WF rat donor was maintained and functional ly expressed in the xenogeneic environment of BDF1 mice.