Porcine pancreatic icosapeptide as a marker of graft survival and rejection in xenotransplantation

Abstract

The previous study showed that it is possible to monitor the viability of xenografted fetal pig pancrease in the first 3 weeks after transplantation in a normoglycemic immunoincompetent mouse [1]. This is achieved by measuring serum levels of porcine pancreatic icosapeptide (PI) in the host using a specific immunoassay. PI is secreted from the pancreatic polypeptide (PP) cell, the first mature endocrine cell of the fetal pig pancreas. Insufficient insulin is produced by the graft at this time to use it as a marker of graft viability. We have now examined the usefulness of PI to monitor graft survival in diabetic immunoincompetent mice and in immunosuppressed mice. Fetal porcine pancreatic tissue was transplanted beneath the renal capsule of streptozotocin-diabetic non-obese diabetic severe combined immunodeficient mice (NOD-SCID) and BALB/c mice given cyclosporin (CsA) for 21 or 10 days, respectively. Blood and grafts were analyzed periodically over 15 and 3 weeks, respectively, for porcine PI and C-peptide/insulin. In the diabetic mice, porcine PI was detected in sera up to 2 weeks following transplantation and was absent thereafter. Serum porcine C-peptide was detectable at 3 weeks and reached maximum levels at 12 to 15 weeks. PI content of the grafts was highest at day 4 and 3 weeks and lowest from 9 weeks onwards while insulin levels in the graft were highest from 9 weeks onwards. In BALB/c mice immunosuppressed with CsA, serum PI was detectable for 21 days. In the mice given CsA only for 10 days, serum PI was detectable for that time, but not on day 14 although PI was detectable in the graft. In mice given no CsA, PI was undetectable in serum at any time although PI was present in the graft at day 4. The presence of porcine PI in sera is a marker of graft survival of fetal porcine pancreatic tissue in diabetic immunocompetent mice in the first 2 weeks after transplantation. Its absence in immunosuppressed mice in this period is an early indicator of graft rejection.

Embryonic pig liver, pancreas, and lung as a source for transplantation: Optimal organogenesis without teratoma depends on distinct time windows

“…Among them are such widespread diseases as diabetes, end-stage renal disease, Parkinson's disease, acute and chronic liver failure, and inherited metabolic disorders. The efficacy of committed embryonic pig or human kidney (13,28), pancreas (29)(30)(31)(32)(33)(34), lung (35), heart, or intestine (35,36) as well as hepatocytes (37)(38)(39)(40) or neuronal precursors (41)(42)(43), which grew and differentiated upon implantation into SCID or nude mice or rats, has been extensively Embryonic pig pancreas tissues obtained at various gestational ages were implanted under the kidney capsule. Tissue growth and serum levels of pig insulin were evaluated 6 weeks after implantation as described in Methods.…”

Xenotransplantation Literature Update October–December, 2003

“…Human CD46 transgenic fetal pig pancreatic tissue was transplanted in mice and was shown to be resistant to antibody, but not to cell‐mediated destruction [10]. To monitor survival of porcine fetal pig pancreas tissue, icosapeptide was shown to be a useful marker during the first 2 weeks after Tx, at a time when fetal grafts do not secrete insulin [11]. Tacrolimus was used as monotherapy to prevent rejection of fetal porcine islet‐like cell clusters transplanted into rats [12]; in comparison to other immunosuppressive agents, tacrolimus monotherapy efficiently delayed xenograft rejection up to 24 days.…”

Intra-articular Xenotransplantation of Adipose-Derived Stromal Cells to Treat Osteoarthritis in a Goat Model

“…Immunosuppressive drugs (ISDs) suppress or reduce the strength of the body's immune system. In xenotransplantation, ISDs are used to prevent the rejection of implanted foreign tissue or cells [19,23,24]. ISD use considerably raises the cost and complexity of an animal model, and lowers the resistance of the animals to infection.…”