Beyond the red cell: pegylation of other blood cells and tissues.
Immunological recognition of allogeneic tissue is of critical concern in transfusion and transplantation medicine. While the major emphasis of our work on the immunocamouflage of cells has been focused on the erythrocyte, we have extended this research beyond the red blood cell (RBC) to other tissues. Our studies from blood transfusion (i.e., a specialized form of cellular transplantation) suggest that covalent modification of cells and tissues with methoxypoly(ethylene glycol) mPEG can significantly diminish immunologic recognition of other allogeneic tissues and, furthermore, may enhance the induction of tolerance. The mechanisms underlying the mPEG-mediated immunocamouflage of alloantigens is the global camouflaging of antigenic sites, membrane surface charge and the attenuation of receptor-ligand and cell-cell interactions. As a consequence of the immunocamouflage imparted by the grafted mPEG, weak costimulation of alloreactive T cells is observed which subsequently induces apoptosis of these reactive cells. As a result of this clonal deletion, a pro-tolerance state is induced. The potency of immunocamouflage is readily observed in in vivo murine models of transfusion-associated graft versus host disease. Furthermore, initial studies on the in vivo transplantation of pegylated rat and murine pancreatic islets have demonstrated that mPEG-derivatization does not impair the finely tuned signaling necessary for glucose homeostasis. Finally, in contrast to the pharmacological inhibition of the immune response by agents such as cyclosporine, mPEG-mediated immunocamouflage directly attenuates the inherent antigenicity and immunogenicity of the donor tissue itself while leaving the recipient a fully competent immune system.
Canadian Blood Services, Department of Pathology, University of British Columbia, Koerner Pavilion, Room GF-401, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5. mscott@pathology.ubc.ca
Mark D
MD
Scott
Audrey M
AM
Chen
D000818:Animals; D004910:Erythrocyte Membrane / Q000737:chemistry / Q000276:immunology; D006086:Graft vs Host Disease / Q000517:prevention & control; D006789:Host vs Graft Reaction; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007515:Islets of Langerhans / Q000276:immunology / Q000502:physiology; D007519:Isoantigens / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats; D017634:Self Tolerance / Q000276:immunology; D012756:Sheep
D007519:Isoantigens; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol