Immunomodulation by adenoviral-mediated SCD40-Ig gene therapy for mouse allogeneic islet transplantation.
BACKGROUND
The success of pancreatic islet transplantation is limited because of immune rejection of allogeneic transplanted tissue and potential adverse side effects of nonspecific immunosuppression. Local expression of an immunosuppressive agent at the site of islet transplant could promote long-term engraftment without associated systemic side effects.


METHODS
We have examined the ability of adenoviral vector mediated local production of sCD40-immunoglobulin (Ig), blocking the CD40-CD40 ligand (CD40L) costimulatory pathway, from genetically modified allogeneic islets to facilitate long-term engraftment in fully allogeneic mouse model.


RESULTS
Transplantation of islets infected with an adenoviral vector expressing sCD40-Ig resulted in allograft survival longer than 120 days in five of the nine recipient mice (56%). However, mice that received mock infected (n=5) or control adenoviral vector (Ad.eGFP; n=6) rejected the allograft with a median survival of 15 and 16 days, respectively. Histopathology demonstrated that the grafts of the long-term surviving animals preserved islets with minimal mononuclear cell infiltration.


CONCLUSIONS
These results demonstrate that local inhibition of the CD40-CD40L pathway by adenoviral gene transfer of sCD40-Ig to the islets prior to transplant significantly prolonged islet allograft acceptance. This approach could be used clinically to facilitate islet transplantation.
Rehman
Khaja K
KK
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine Pittsburgh, PA 15261, USA.
Bertera
Suzanne
S
Trucco
Massimo
M
Gambotto
Andrea
A
Robbins
Paul D
PD
D000256:Adenoviridae / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000235:genetics*; D000818:Animals; D019013:CD40 Antigens / Q000037:antagonists & inhibitors; D023201:CD40 Ligand / Q000037:antagonists & inhibitors; D049109:Cell Proliferation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006085:Graft Survival / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D013154:Spleen / Q000166:cytology; D023001:Transplantation Tolerance / Q000276:immunology
D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; C499839:CD40Ig protein, recombinant; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand