Smith C V, Sablinski T, Arn J S, Myers D E, Rosengard B R, Uckun F M, Sachs D H
Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston 02129.
J Immunother Emphasis Tumor Immunol. 1994 Aug;16(2):105-14. doi: 10.1097/00002371-199408000-00004.
Two monoclonal antibodies (mAb) with specificities for mature T-cell subsets in miniature swine have been characterized previously. Antibody 74-12-4 recognizes the porcine CD4 accessory molecule and 76-2-11 is specific for the CD8 molecule. We have now examined the effects of in vivo administration of 74-12-4 and 76-2-11 on several parameters of transplantation immunity. No prolongation of class I disparate skin or kidney graft survival was observed in animals treated with either mAb alone or with a combination of both. In addition, in vivo treatment with these mAbs, in combination with subtherapeutic total body irradiation, failed to permit engraftment of allogenic bone marrow. These therapeutic failures were thought likely to be a consequence of the fact that 74-12-4 coats, but does not deplete, CD4 cells in vivo. Because there are numerous anti-human mAbs that likewise fail to deplete in vivo, we have used 74-12-4 as a prototype to further manipulations aimed at achieving depletion. We attempted to eliminate 74-12-4-coated cells in two animals by subsequent administration of a hyperimmune pig anti-mouse Ig serum. In both such treated animals, administration of this serum produced surprisingly rapid clearance of 74-12-4 from the circulation and caused uncoating of CD4 cells, but no significant cell elimination was detected by flow cytometry. We have also prepared an anti-porcine-CD4 immunotoxin by conjugating 74-12-4 to the ribosome inhibitory plant toxin, pokeweed antiviral protein. This immunotoxin led to significant but not complete CD4 cell depletion from the peripheral blood in four of four treated animals. Further manipulations and possibly development of new anti-porcine CD4 mAbs may therefore be required to achieve complete depletion and successful mAb-mediated modification of transplantation responses.
