Continuous secretion of human soluble CD4 in mice transplanted with genetically modified cells.
Somatic transgenesis can be used to confer endogenous production of proteins with therapeutic properties. One such product, recombinant soluble human CD4 (sCD4), has been shown to be an efficient inhibitor of human immunodeficiency virus 1 (HIV-1) in vitro, but its too short half-life in vivo has impaired long-term clinical trials in AIDS patients. Using a retroviral vector, we introduced the cDNA of sCD4 into primary mouse fibroblasts. The cells were enclosed in a lattice of collagen and synthetic fibers coated with basic fibroblast growth factor, and implanted in the peritoneal cavity of syngeneic mice. Implantation of such sCD4-secreting organoids into cyclosporin A-treated C3H mice elicited a strong antibody response against sCD4. Implantation of sCD4-secreting organoids into immunotolerant mice (transgenic for transmembrane human CD4) resulted in continuous sCD4 production, detected during 60 days in animal sera. The serum levels obtained were significant, but too limited as yet for anti-HIV purposes. Nevertheless, this model may be of interest in various fields, as it provides the first demonstration that one potentially therapeutic protein, despite its half-life of a few hours, could remain present in vivo 2 months after a single somatic transgenesis.
Valere
T
T
Institut Cochin de Génétique Moléculaire (ICGM-CNRS UPR415), Paris, France.
Bohl
D
D
Klatzmann
D
D
Danos
O
O
Sonigo
P
P
Heard
J M
JM
D000818:Animals; D000906:Antibodies / Q000097:blood; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000276:immunology; D016572:Cyclosporine; D005347:Fibroblasts / Q000637:transplantation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008979:Moloney murine leukemia virus / Q000235:genetics; D009940:Organoids / Q000637:transplantation; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000276:immunology
D000906:Antibodies; D015704:CD4 Antigens; D011994:Recombinant Proteins; C076613:recombinant soluble CD4; D016572:Cyclosporine