Local expression of B7-H4 by recombinant adenovirus transduction in mouse islets prolongs allograft survival.
BACKGROUND
Allogeneic pancreatic islet transplantation has the potential to cure type 1 diabetes. One of the barriers to islet transplantation is the alloreactive T-cell response between donors and recipients. Costimulatory molecules, which play a major role in the regulation of the immune response to antigens during graft rejection, may be used to inhibit allograft destruction. B7-H4 is one such member in the costimulatory family, which has established negative regulatory function of T-cell responses.


METHODS
To determine whether local expression of B7-H4 protein can protect beta cells from damage in islet allotransplantation, we have constructed a recombinant adenovirus expressing a B7-H4 complementary deoxyribonucleic acid (Ad-B7-H4). To study the in vivo effects of B7-H4 expression on islet graft survival, adenovirus-transduced islets from donor Balb/c mice were transplanted into streptozotocin-diabetic C57BL/6 mice (n=12).


RESULTS
Expression of B7-H4 in islets by Ad-B7-H4 transduction at an optimized condition did not inhibit glucose-stimulated insulin secretion of the treated islets. The recipient mice transplanted with Ad-B7-H4-transduced islets established euglycemia for a longer time (mean 56.5 days), compared with control mice transplanted with Ad-LacZ-transduced islets (mean 14.5 days, [n=12, P<0.001]). Splenocytes isolated from the recipients of Ad-B7-H4-transduced islets showed hyporesponsiveness to alloantigenic stimulation, compared with control recipients. CD45 and insulin staining of the graft transplanted with Ad-B7-H4-transduced islets indicated the preservation of beta cells and decrease of infiltrating immune cells.


CONCLUSIONS
Local expression of B7-H4 prolongs islet allograft survival in vivo, suggesting translational potential for beta-cell replacement with reduced immune injury.
Wang
Xiaojie
X
Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
Hao
Jianqiang
J
Metzger
Daniel L
DL
Mui
Alice
A
Ao
Ziliang
Z
Verchere
C Bruce
CB
Chen
Lieping
L
Ou
Dawei
D
Warnock
Garth L
GL
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism; D003001:Cloning, Molecular; D005260:Female; D006085:Graft Survival / Q000502:physiology*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology / Q000637:transplantation; D007515:Islets of Langerhans / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000379:methods* / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012313:RNA / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous / Q000502:physiology*; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1
D018122:B7-1 Antigen; D001786:Blood Glucose; D007328:Insulin; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse; D012313:RNA