Renal, central nervous system and pancreatic overexpression of recombinant soluble Crry in transgenic mice. A novel means of protection from complement-mediated injury.
Crry is a potent complement regulator that inhibits classical and alternative pathway C3 convertases in rodents. We have produced transgenic animals expressing Crry as a recombinant soluble protein driven by the broadly active metallothionein-I promoter. These animals have high serum and urinary levels of rsCrry leading to inhibition of complement activity. In nephrotoxic serum nephritis (NSN), injected antibodies bind to glomeruli, leading to complement activation and subsequent glomerular injury and albuminuria. We have shown that rsCrry can block such injury and reduce albuminuria by as much as 75%. Corresponding to the reduction in albuminuria was the complete absence of C3 staining in glomeruli by immunofluorescence microscopy in 17/20 transgene positive animals. Support for a local source of protective rsCrry in this model is provided by the demonstration of Crry transgene mRNA in the glomerulus and a very high fractional excretion of rsCrry in the urine. Therefore, rsCrry expression markedly ameliorates an antibody-induced disease model in vivo. In addition, local synthesis of Crry in other organs that are targets of immune injury has been found. For example, Crry transgene mRNA is present throughout the central nervous system and in pancreatic islets. Thus, continuous complement inhibition at the C3 convertase step appears to be feasible and is effective in complement-mediated injury states. A number of disease models affecting these target organs can be tested using these mice.
Department of Medicine, The University of Chicago, IL 60637, USA.
J J
JJ
Alexander
A
A
Lim
C
C
He
R L
RL
MacDonald
V M
VM
Holers
R J
RJ
Quigg
D000818:Animals; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D003169:Complement Inactivator Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D015316:Genetic Therapy; D005921:Glomerulonephritis / Q000134:cerebrospinal fluid / Q000276:immunology / Q000517:prevention & control; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism*; D011951:Receptors, Complement / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D017463:Receptors, Complement 3b; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000134:cerebrospinal fluid* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D019076:Transgenes
D003169:Complement Inactivator Proteins; C081470:Cr1l protein, mouse; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D011994:Recombinant Proteins