Divergence of integrin function in hematopoiesis in the pig to human xenogeneic combination: implications for bone marrow induced donor-specific tolerance Article

cited authors

  • Theodore, PR; Simon, AR; Warrens, AN; Sackstein, R; Sykes, M

fiu authors

abstract

  • Induction of donor-specific tolerance via bone marrow transplantation has been proposed as a means of overcoming immunologie barriers to xenotransplaniaiion Bone marrow transplantation is dependent on a complex set of adhesive interactions permitting engraftmem, maturation and migration of donor hemalopoielic cells. Thtintegrtn class of adhesion molecules has been demonstrated to be of significance in human and mouse bone marrow transplantation. The purpose of this study was to asses the function of the : integrin VLA-5 via long term bone marrow culture (LTBMC) and static adhesion studies in the pig to human xenogenic combination Human and pig bone marrow stromal layers were cultured and seeded with fresh hematopoietic precursor cells from pig or human bone marrow specimens. Culture cell counts and colony forming assays (CPU) were performed on a weekly basis. A mouse anti-human VLA-5 monoclonal antibody SAM-1, demonstrated by imrnunoprecipitation to be cross-reactive on the porcine molecule, was added to cultures and compared to a control antibody for effects on cellular proliferation and CPU potential. Similar proportions of porcine and human bone marrow cells showed expression of VLA-5 and the binding titer was similar in both species. Hematopoietic proliferation of human cells and CPU development were significantly impaired by the addition of anti-VLA-5 mAb to LTBMC. In contrast, neither hematopoietic cell proliferation nor CPU development of porcine LTBMC were impaired by anti VLA5 mAb. In static adhesion assays, human and porcine leukocytes labeled with calcein were assessed for adhesion to human fibronectin (a principal ligand for VLA-5 ). Monoclonal antibodies directed against VLA-5 were added to assays and compared to control antibody for the ability to block VLA-5- mediated adhesion to fibronectin. Although both porcine and human cells adhered to human fibronectin, the adhesion of human cells to fibronectin-coated plates was impaired by anri-VLA-5 mAB, but that of pig cells was not. The differential blocking effects of anti-VLA-5 mAb on hematopoiesis and adhesion to human fibronectin of pig versus human cells suggests that VLA-5 function differs in a species-specific manner, or that the SAM-1 mAb recognizes a non- functional porcine VLA-5 epitope. Studies are in progress to investigate these possibilities.

publication date

  • December 1, 1998

start page

  • 777

volume

  • 26

issue

  • 8