A dendritic cell line genetically modified to express CTLA4-IG as a means to prolong islet allograft survival.
BACKGROUND
Dendritic cells are potent antigen-presenting cells that bind allogeneic T cells. They are thus candidates for targeting immunoregulatory molecules to the alloreactive T cell compartment and suppressing the alloimmune response.


METHODS
A dendritic cell line derived from the BALB/c mouse (H2d) was genetically modified to express the immunoregulatory molecule CTLA4-Ig. The ability of these dendritic cell transfectants to downregulate the alloimmune response was tested in an islet transplant model. Allogeneic C57Bl/6 (H2b) mice were rendered diabetic with streptozocin, and they received BALB/c islet (H2d) transplants. Mice were administered 25 million untransfected or CTLA4-Ig-transfected D2SC/1 cells i.v. on the day of islet transplantation and 6 days later[fnc].


RESULTS
Mice treated with CTLA4-Ig-transfected D2SC/1 cells demonstrated prolonged allograft survival (mean = 20 days, median = 17 days, SD = 9.39) compared with mice treated with untransfected D2SC/1 cells (mean = 12 days, median = 11 days, SD=2.74) or untreated control mice (mean = 11 days, median = 11 days SD = 1.41). Third party allograft survival was not prolonged in mice receiving similar treatment.


CONCLUSIONS
These results demonstrate that a genetically modified dendritic cell line can suppress the alloimmune response and prolong islet allograft survival in an allospecific manner. The findings also suggest that genetically modified dendritic cells may be useful in targeting alloreactive T cells and prolonging allograft survival.
O'Rourke
R W
RW
Transplantation Laboratory, and Hormone Research Institute, University of California, San Francisco 94143-0780, USA.
Kang
S M
SM
Lower
J A
JA
Feng
S
S
Ascher
N L
NL
Baekkeskov
S
S
Stock
P G
PG
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000097:blood / Q000235:genetics*; D060908:CTLA-4 Antigen; D002460:Cell Line; D002470:Cell Survival; D003713:Dendritic Cells / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D015870:Gene Expression; D005819:Genetic Markers; D006085:Graft Survival; D018796:Immunoconjugates; D016381:Islets of Langerhans Transplantation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D014162:Transfection; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D005819:Genetic Markers; D018796:Immunoconjugates; D000069594:Abatacept