title: Surface camouflage of pancreatic islets using 6-arm-PEG-catechol in combined therapy with tacrolimus and anti-CD154 monoclonal antibody for xenotransplantation.
abstract: This study proposes a new combination method of using 6-arm-PEG-catechol to enhance the PEG effect on one hand and another combination of using low doses of Tacrolimus (FK506) and anti-CD154 mAb (MR1) with PEGylation for effective immunoprotection on the other in a xenogenic islet transplantation model. The surface coverage of PEG, viability and functionality of islets were evaluated in vitro, and the effect of surface camouflage on immunoprotection for transplanted islets was evaluated. In addition, the synergistic effects of surface camouflaged islets with low doses of immunosuppressant drugs, such as FK506 and MR1, were evaluated in the xenotransplantation model. The median survival time (MST) of 6-arm-PEG-catechol grafted islets (12.0 ± 1.1 days) was not significantly increased, compared to that of unmodified islets (10.5 ± 1.3 days). However, when 0.2 mg/kg of FK506 was daily administered, the MST of 6-arm-PEG-catechol grafted islet (21.0 ± 1.9 days) was increased twice, compared to that of unmodified islets treated with 0.2 mg/kg of FK506 (10.0 ± 0.9 days). Interestingly, when the recipients of 6-arm-PEG-catechol grafted islets were treated with 0.2 mg/kg of FK506 and 0.1 mg/mouse of MR1, normoglycemia was maintained up to 50 days of transplantation without any fluctuation of glucose level. Therefore, a newly developed protocol using 6-arm-PEG-catechol with FK506 and MR1 would certainly be an effective combination therapy for the treatment of type 1 diabetes.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Jee-Heon
authors.initials: JH
authors.lastname: Jeong
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Hong
authors.forename: Seonki
authors.initials: S
authors.lastname: Hong
authors.forename: Simmyung
authors.initials: S
authors.lastname: Yook
authors.forename: Yoonsuk
authors.initials: Y
authors.lastname: Jung
authors.forename: Jun-Beom
authors.initials: JB
authors.lastname: Park
authors.forename: Cao Duy
authors.initials: CD
authors.lastname: Khue
authors.forename: Bok-Hyeon
authors.initials: BH
authors.lastname: Im
authors.forename: Jinwon
authors.initials: J
authors.lastname: Seo
authors.forename: Haeshin
authors.initials: H
authors.lastname: Lee
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Ahn
authors.forename: Dong Yun
authors.initials: DY
authors.lastname: Lee
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology*; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000473:pathology / Q000628:therapy; D004359:Drug Therapy, Combination; D005215:Fasting / Q000097:blood; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013499:Surface Properties / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D002109:Caffeic Acids; D002396:Catechols; D007328:Insulin; D023201:CD40 Ligand; D011092:Polyethylene Glycols; D016650:Fluorescein-5-isothiocyanate; D005947:Glucose; C034221:catechol; D016559:Tacrolimus