Human CD59 expressed in transgenic mouse hearts inhibits the activation of complement.
Porcine-to-human xenotransplantation offers a potential solution to the critical shortage of human organs. The major immunological barrier to xenotransplantation between these species is a rapid rejection process mediated by preformed natural antibodies and complement. Xenogeneic organ grafts are especially susceptible to complement mediated injury because complement regulatory proteins, which ordinarily protect cells from inadvertent injury during the activation of complement, function poorly in regulating activation of heterologous complement. Removal of xenoreactive antibodies or systemic inhibition of complement activity has been shown to prolong graft survival. As an alternative to the systemic inhibition of complement activity, we have established a model system using transgenic animals to test whether the expression of human membrane bound complement regulatory proteins on mouse endothelial cells can inhibit the activation of human complement. CD59, which acts at the terminal stage of complement activation by inhibiting the formation of the membrane attack complex, was used as a paradigm for this model. A CD59 construct containing the putative CD59 gene promoter linked to the CD59 coding region was used to demonstrate expression of the human CD59 protein in various tissues of transgenic mice, including endothelial cells in the heart. In addition, we show that the transgenic CD59 protein is biologically active as determined by the ability to inhibit the formation of membrane attack complex in transgenic mouse hearts perfused ex vivo with human plasma. These results demonstrate that expression of membrane bound complement regulatory proteins can achieve complement inhibition in a xenogeneic organ and suggest that this approach may be useful for successful xenotransplantation between discordant species.
Diamond
L E
LE
DNX Biotherapeutics Inc., Princeton, New Jersey 08540, USA.
McCurry
K R
KR
Oldham
E R
ER
Tone
M
M
Waldmann
H
H
Platt
J L
JL
Logan
J S
JS
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D018957:CD59 Antigens / Q000096:biosynthesis* / Q000235:genetics*; D003167:Complement Activation; D015938:Complement Membrane Attack Complex; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009206:Myocardium / Q000276:immunology*; D009928:Organ Specificity; D019076:Transgenes
D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex