Donor-specific growth factors promote swine hematopoiesis in severe combined immune deficient mice

Induction of a state of mixed hematopoietic chimerism following bone marrow transplantation is associated with donor-specific tolerance in the concordant xenogeneic rat-to-mouse species combination. We are now attempting to induce such tolerance in a discordant species combination, pig to mouse. Our initial studies showed that non-immune physiologic factors limited the level of swine hematopoietic reconstitution in severe combined immune deficient (SCID) mice. We have now examined the ability of swine-specific growth factors, interleukin-3 (IL-3), granulocyte macrophage-colony stimulating factor (GM-CSF), and stem cell factor (SCF) to enhance repopulation by swine bone marrow cells in SCID recipients. The results indicate that swine IL-3 promotes pig hematopoiesis 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 GM-CSF. Almost all repopulating porcine cells expressed a swine myeloid marker. Colony-forming assays showed a correlation of the number of pig-specific colonies with the number of swine cells detected by flow cytometry in transplanted-SCID bone marrow recipients. Porcine CD2(+) cells which did not express CD4 or CD8 coreceptors were also detected in SCID mouse recipients of pig bone marrow, and their numbers were also increased by swine cytokine treatment. Swine IgG, but not B cells were detected in SCID recipients at 3 and 6 weeks following bone marrow transplantation, and declined over time, suggesting that mature B cells engrafted, but that de novo B lymphopoiesis did not occur in these mice. Thus, our study demonstrates that donor-specific growth factors can help to overcome the physiologic barrier to xenogeneic hematopoiesis in the discordant pig to mouse species combination.