Endocrine Abstracts

Transplantation of pancreas or isolated Langerhans islets can cure type 1 diabetes. Xenografts from transgenic pigs represent a promising source to overcome the shortage of organ donors. We investigated the immunosuppressive effect of local LEA29Y expression (a high-affinity variant of CTLA4-Ig) by transplantation of neonatal porcine islet-like clusters (NPICCs) from INSLEA29Y transgenic pigs into humanized mice. NPICCs from 1–5 day-old pigs expressing LEA29Y under the control of the porcine insulin promoter (LEA-tg) or from wild-type pigs (wt) were transplanted under the kidney capsule (Tx) of streptozotocin-diabetic NOD-scid IL2Rgamma^null (NSG) mice (Tx-LEA-tg; Tx-wt). Xenorejection was investigated after transfer of human PBMCs (PBMC-NSG mice). Long-lasting effects of local LEA29Y expression were assessed by Tx in mice carrying a stable human immune system (transfer of hCD34⁺ cells) (HSC-NSG mice). In PBMC-NSG mice, 80% of mice transplanted with wt-NPICCs (n=5) developed overt diabetes within 30 days after transfer of a human immune system indicating xenograft rejection. LEA-tg NPICCs were completely protected from rejection (n=5). In HSC-NSG mice, normalization of blood glucose levels (66.6%) and post-transplant glucose tolerance was comparable in Tx-LEA-tg (n=12) and immunodeficient control mice (n=13). All Tx-wt HSC-NSG mice remained hyperglycemic (n=11). In both animal models, graft-bearing kidneys revealed destruction of wt-NPICCs with massive leukocyte (hCD45⁺) and lymphocyte infiltration (CD4⁺, CD8⁺), which was absent in PBMC- and HSC-NSG mice transplanted with LEA-tg NPICCs. This is the first study providing evidence that beta-cell specific LEA29Y expression has a long-lasting protective effect on inhibition of human anti-pig xenoimmunity. This finding may have important implications for the development of a low-toxic protocol for porcine islet transplantation in patients with type 1 diabetes.