Fully and long-term xenogeneic hematopoietic chimeras created in poorly concordant rat-mouse combinations: expression...

We created fully and stable xenogeneic hematopoietic chimeras in "poorly concordant" rat-mouse strain combinations defined by their high histocompatibility-antigen disparity and by the high titer of mouse-serum natural cytotoxic antibodies (NcAb) to rat donor bone marrow cells (BMC). Recipients were adult male (C57BL/6 x DBA/2)F1 (BDF1) mice, and donors of untreated BMC were adult male WAG strain rats. We tried several approaches to improve the quality and the stability of the rat-cell 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 immunocompetence; 2) irradiated recipients were implanted with a newborn BDF1 thymus, which allows maturing rat T lymphoid cells to be made tolerant to mouse antigens in vivo, which lowered the risk of GVHR; and 3) recipients were given a high number of untreated rat BMC (4-5 injections of 1.6 x 10(7) cells) to reduce the risk of rejection of rat BMC by mouse NcAb. We found that rat BMC engraftment was highly effective (75 to 100% rat hemoglobin and 100% rat IgG) and long-lasting (more than 10 months). The grafted rat cells were very tolerant toward host histocompatibility antigens but maintained all their immunological potentialities. Moreover, using the "poorly concordant" Wistar Furth (WF)-BDF1 combination, we showed that a genetically controlled characteristic of the hematopoietic system of the WF rat donor was maintained and functionally expressed in the xenogeneic environment of BDF1 mice.