Local expression of B7-H4 by recombinant adenovirus transduction in mouse islets prolongs allograft survival

Transplantation. 2009 Feb 27;87(4):482-90. doi: 10.1097/TP.0b013e318195e5fa.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • B7-1 Antigen / genetics*
  • Blood Glucose / metabolism
  • Cloning, Molecular
  • Female
  • Graft Survival / physiology*
  • Immunohistochemistry
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / physiology
  • Insulin-Secreting Cells / transplantation
  • Islets of Langerhans / physiology
  • Islets of Langerhans Transplantation / methods*
  • Islets of Langerhans Transplantation / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • RNA / isolation & purification
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transplantation, Homologous / physiology*
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1


  • B7-1 Antigen
  • Blood Glucose
  • Insulin
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • Vtcn1 protein, mouse
  • RNA