Enhancement of swine progenitor chimerism in mixed swine/human bone marrow cultures with swine cytokines.
OBJECTIVE
The induction of transplantation tolerance across xenogeneic barriers by bone marrow transplantation holds great promise, but engraftment of xenogeneic stem cells has been difficult to achieve. Part of this difficulty is due to species-specific differences in regulatory cytokines and elements of the stromal microenvironment, which we studied here.


METHODS
We developed a system where fresh bone marrow cells from swine and human are cultured on human bone marrow stroma in order to study these limiting factors in a clinically relevant species combination.


RESULTS
We report here the ability of recombinant swine interleukin (IL)-3 and c-kit ligand (KL) to specifically enhance swine hematopoietic chimerism in this system. In the absence of exogenous swine cytokines, there were about half as many swine progenitors as human progenitors at 1, 2, and 4 weeks of culture. When used alone, swine IL-3 led to a notable but transient increase in the relative ratio of swine progenitors, while addition of swine KL increased the ratio of swine progenitors only modestly and only at later time points. In contrast, when swine IL-3 and KL were added together, there was a two- to fourfold increase in the ratio of swine to human progenitors at all times tested.


CONCLUSIONS
These data demonstrate that both swine IL-3 and KL are needed for prolonged enhancement of swine progenitor chimerism under these conditions, and suggest that the species specificity of either one or both of these cytokines may represent an important barrier to prolonged engraftment of swine bone marrow in humans.
Emery
D W
DW
Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USA.
Holley
K
K
Sachs
D H
DH
D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002678:Chimera / Q000276:immunology*; D018920:Coculture Techniques; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013045:Species Specificity; D019089:Stem Cell Factor / Q000494:pharmacology*; D017154:Stromal Cells / Q000166:cytology; D013552:Swine / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology*
D007377:Interleukin-3; D011994:Recombinant Proteins; D019089:Stem Cell Factor