Cross-species interaction of porcine and human integrins with their respective ligands: implications for xenogeneic tolerance induction.
BACKGROUND
Organ transplantation is limited by the number of available donors. One possible solution would be the use of pigs as organ donors. However, current immunosuppressive protocols cannot prevent rejection of these organs. If donor-specific tolerance toward porcine antigens could be induced in recipients, subsequent implantation of porcine organs would be possible without further immunosuppression. Induction of tolerance can be achieved with a bone marrow transplant if donor antigen-presenting cells successfully differentiate in the recipient thymus to induce deletion of donor-reactive host cells. Migration of porcine progenitor cells to the host marrow and thymus and differentiation into tolerance-inducing antigen-presenting cells is likely to require successful interaction of porcine adhesion molecules with human ligands. In this study, we investigated whether very late antigen (VLA)4 and VLA-6 integrins, which play important roles in homing and differentiation of hematopoietic progenitor cells, function across the pig-to-human species barrier.


METHODS
Static cell-to-cell and cell-to-extracellular matrix protein adhesion assays were used to examine the cross-species interaction of porcine adhesion molecules with human ligands.


RESULTS
Our studies show that porcine cells adhere to various human endothelial cell monolayers and extracellular matrix proteins and demonstrate that porcine VLA-4 and VLA-6 appear to be fully cross-reactive to the human ligands vascular cell adhesion molecule-1 and laminin, respectively.


CONCLUSIONS
It is likely that porcine hematopoietic progenitor cells will be able to successfully employ pVLA-4- and pVLA-6-human ligand interactions in a pig-to-human bone marrow transplantation model in order to induce donor-specific tolerance.
Simon
A R
AR
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston 02129, USA.
Warrens
A N
AN
Yazzie
N P
NP
Seebach
J D
JD
Sachs
D H
DH
Sykes
M
M
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D039041:Integrin alpha4beta1; D039121:Integrin alpha6beta1; D016023:Integrins / Q000502:physiology*; D007797:Laminin / Q000502:physiology; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D016029:Receptors, Very Late Antigen / Q000502:physiology*; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
D039041:Integrin alpha4beta1; D039121:Integrin alpha6beta1; D016023:Integrins; D007797:Laminin; D016201:Receptors, Lymphocyte Homing; D016029:Receptors, Very Late Antigen; D019010:Vascular Cell Adhesion Molecule-1