Hepatocyte growth factor gene therapy for pancreatic islets in diabetes: reducing the minimal islet transplant mass required in a glucocorticoid-free rat model of allogeneic portal vein islet transplantation.
Islet transplantation for diabetes is limited by the availability of human islet donors. Hepatocyte growth factor (HGF) is a potent beta-cell mitogen and survival factor and improves islet transplant outcomes in a murine model. However, the murine model employs renal subcapsular transplant and immunodeficient mice, features not representative of human islet transplantation protocols. Therefore, we have developed a more rigorous, marginal-mass rat islet transplant model that more closely resembles human islet transplantation protocols: islet donors are allogeneic Lewis islets; recipients are normal Sprague Dawley rats; islets are delivered intraportally; and immunosuppression is accomplished using the same immunosuppressants employed by the Edmonton group. We demonstrate that 1) surprisingly, the Edmonton immunosuppression regimen induces marked insulin resistance and beta-cell toxicity in rats, 2) adenovirus does not adversely affect islet transplant outcomes, 3) the Edmonton immunosuppressants may delay or block rejection of adenovirally transduced islets, and more importantly, 4) pretransplant islet adenoviral gene therapy with HGF markedly improves islet transplant outcomes, 5) this enhanced function persists for months, and 6) HGF enhances islet function and survival even in the setting of immunosuppressant-induced insulin resistance and beta-cell toxicity. This approach may enhance islet transplantation outcomes in humans.
Lopez-Talavera
Juan Carlos
JC
Division of Endocrinology, BST E-1140, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15213, USA.
Garcia-Ocaña
Adolfo
A
Sipula
Ian
I
Takane
Karen K
KK
Cozar-Castellano
Irene
I
Stewart
Andrew F
AF
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects; D006085:Graft Survival; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D011169:Portal Vein; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014184:Transplantation, Homologous
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D007328:Insulin; D017228:Hepatocyte Growth Factor