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Prolongation of xenoegeneic islet function using an HGF-based immunosuppressive regimen in a CLAWN miniature swine-to-cynomologous monkey model

Masayuki Tasaki¹, Hisashi Sahara¹, Teru Okitsu², Manei Oku¹, Hiroaki Nishimura¹, Mitsuhiro Sekijima¹, Kentaro Setoyama¹, Akira Shimizu¹, Kazuhiko Yamada¹

¹Kagoshima University, XTS/FSRC, Kagoshima; ²Kyoto University, Surgery, Kyoto; Japan

Background: We recently demonstrated that a short-course of human-recombinant Hepatocyte Growth Factor (h-rHGF) inhibited acute rejection of allogeneic renal grafts with evidence of maintenance of Tregs in CLAWN-miniature swine. Because of HGF’s immunoprotective and angiogeneitic effects, we hypothesized that it may be effective for xenogeneic islet transplantation. Here, we included h-rHGF in our regimen for xenogeneic islet transplants in a Gal+/+ CLAWN-miniature swine-to-monkey model and observed prolonged graft survival.

Methods: Five CLAWN-miniature swine (45-66kg) were totally pancreatectomized (Px) and islets were isolated with <1 minute warm ischemic time. Following a 1-day culture, islets were transplanted (Tx) into six monkeys via SMV injection. All animals received stereptozotocin (STZ) before islet Tx to induce IDDM; 1 animal also had a total-Px. Three monkeys were sacrificed on Days 2 or 10 for histologic examination of early engraftment. The remaining monkeys received a single dose of ATG followed by maintenance FK506, MMF and h-rHGF.

Results: An average of 595,000±108,000 islets/pancreas were isolated (n=5). Monkeys received 147,156 IE/kg (M-1), 35,081IE/kg (M-2), 36,162IE/kg (M-3), 70,495IEkg (M-4), 107,245IE/kg (M-5) and 69,196IE/kg (M-6). All 3 monkeys (M-1, 2, 3) used for histologic examination had insulin-positive porcine islets in the liver at day 2 or 10. M-4 (total Px + STZ) maintained normoglycemia until day 59, but died of unrelated causes. BS in M-5 (STZ alone) gradually increased starting on day 30 and serum porcine insulin was not detected after day 58. M-6 (STZ alone) maintained normoglycemia until day 15, but lost function thereafter. M-6 was the only monkey to develop anti-non Gal IgG.

Conclusion: Xenogeneic islets maintained BS in monkeys with IDDM for up to 59 days using a regimen including h-rHGF in a pig-to-monkey model. The administration of h-rHGF may have contributed to this prolongation of xenogeneic islet function with otherwise minimal immunosuppression.