DONOR-SPECIFIC GROWTH-FACTORS PROMOTE SWINE HEMATOPOIESIS IN SEVERE COMBINED IMMUNE-DEFICIENT MICE

Induction of a state of mixed hematopoietic chimerism following bone m arrow transplantation is associated with donor-specific tolerance in t he concordant xenogeneic rat-to-mouse species combination. We are now attempting to induce such tolerance in a discordant species combinatio n, pig to mouse. Our initial studies showed that non-immune physiologi c factors limited the level of swine hematopoietic reconstitution in s evere combined immune deficient (SCID) mice. We have now examined the ability of swine-specific growth factors, interleukin-3 (IL-3), granul ocyte macrophage-colony stimulating factor (GM-CSF), and stem cell fac tor (SCF) to enhance repopulation by swine bone marrow cells in SCID r ecipients. The results indicate that swine IL-3 promotes pig hematopoi esis in SCID mouse recipients. The percentage of swine class I+ cells in bone marrow, spleen, and peripheral blood was markedly increased by a 3-week treatment course with porcine IL-3. In longer-term studies, the effect of IL-3 was further enhanced by combining it with porcine G M-CSF. Almost all repopulating porcine cells expressed a swine myeloid marker. Colony-forming assays showed a correlation of the number of p ig-specific colonies with the number of swine cells detected by flow c ytometry in transplanted-SCID bone marrow recipients. Porcine CD2(+) c ells which did not express CD4 or CD8 coreceptors were also detected i n SCID mouse recipients of pig bone marrow, and their numbers were als o increased by swine cytokine treatment. Swine IgG, but not B cells we re detected in SCID recipients at 3 and 6 weeks following bone marrow transplantation, and declined over time, suggesting that mature B cell s engrafted, but that de novo B lymphopoiesis did not occur in these m ice. Thus, our study demonstrates that donor-specific growth factors c an help to overcome the physiologic barrier to xenogeneic hematopoiesi s in the discordant pig to mouse species combination.