Transplantation of islets transduced with CTLA4-Ig and TGFbeta using adenovirus and lentivirus vectors.
BACKGROUND
A major problem facing islet transplantation is immune destruction of grafts by transplant rejection and autoimmunity. Some success in prolonging graft rejection has been obtained by transducing islets prior to transplantation with adenoviral (Ad) vectors containing CTLA4-Ig and TGFbeta. The purpose of this study was to see if lentiviral (LV) vectors would provide superior results compared with adenoviral vectors.


METHODS
Islets were isolated from Sprague-Dawley rats and transduced with Ad or LV vectors containing LacZ, CTLA4-Ig, CTLA4, and TGFbeta1 using various MOIs. Islets transduced with LV were healthy as judged by DNA and insulin content, and insulin secretion. Using the kidney capsule transplant site, 500 transduced rat islets were transplanted into streptozotocin diabetic B6AF1 mice.


RESULTS
Maintenance of normoglycemia was prolonged in recipient mice carrying islets transduced with Ad vectors containing CTLA4-Ig, CTLA4, and TGFbeta1. Return of hyperglycemia in controls was 17-18 days while loss of function for the experimental groups occurred at 20-27 days. For the lentivirus transduced islets, rejection of controls was 20+/-1.6 days, for CTLA4-Ig was 42+/-21 days and for TGFbeta was 28+/-3.2 days.


CONCLUSIONS
Although islets transduced with either adenovirus or lentivirus containing CTLA4-Ig, CTLA4, and TGFbeta1 could prolong graft survival in a rat to mouse transplantation model, with the conditions of this study lentivirus provided no advantage over adenovirus vectors.
Fernandes
Justin R
JR
Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Room 535, Boston, MA 02215, USA.
Duvivier-Kali
Valérie F
VF
Keegan
Mitchell
M
Hollister-Lock
Jennifer
J
Omer
Abdulkadir
A
Su
Stacey
S
Bonner-Weir
Susan
S
Feng
Sandy
S
Lee
Jeng-Shin
JS
Mulligan
Richard C
RC
Weir
Gordon C
GC
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000494:pharmacology*; D060908:CTLA-4 Antigen; D004247:DNA / Q000032:analysis; D015870:Gene Expression; D005822:Genetic Vectors; D006085:Graft Survival / Q000187:drug effects; D018796:Immunoconjugates / Q000235:genetics / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D012313:RNA / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D012313:RNA; D000069594:Abatacept; D004247:DNA