Abstract:
:To develop somatic gene therapy for diabetes, we studied an animal model with proinsulin-producing fibroblasts with an immunological safety system. Cultured mouse fibroblasts of the Ltk- cell line were transfected first with the efficient human proinsulin expression vector pBMG-Neo-Ins. Initially, 2 x 10(6) cells with a proinsulin-production rate of 91 ng.24 h-1.10(6) cells-1 were transplanted i.p. into streptozocin-induced diabetic C3H mice. The blood glucose concentrations improved between the first and the 28th day, but the animals died of hypoglycemia between the 29th and 46th days. The proinsulin-producing Ltk- cells were further transfected with a second plasmid, pHEBo-CD8.2, encoding BALB/c mouse T-cell differentiation antigen. The CD8.2 allotype is different from CD8.1 allotype by only one amino acid substitution and should be only slightly antigenic to the recipient C3H mice. Somatic gene therapy with these doubly transfected cells followed by the consecutive administration of a monoclonal antibody to CD8.2 resulted in an initial decrease of blood glucose concentrations followed by the permanent recurrence of hyperglycemia, thus proving the complete removal of the transplanted cells. Cultured fibroblasts were thus proven capable of supplying sufficient proinsulin to lower the blood glucose concentrations in diabetic animals. The immunological safety system with a combination of artificial expression of cell surface antigen and the administration of the specific monoclonal antibody was an effective safety system for somatic gene therapy.
journal_name
Diabetesjournal_title
Diabetesauthors
Kawakami Y,Yamaoka T,Hirochika R,Yamashita K,Itakura M,Nakauchi Hdoi
10.2337/diab.41.8.956subject
Has Abstractpub_date
1992-08-01 00:00:00pages
956-61issue
8eissn
0012-1797issn
1939-327Xjournal_volume
41pub_type
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