ICAM-1 antisense oligodeoxynucleotide improves islet allograft survival and function.
Expression of intercellular adhesion molecule-1 (ICAM-1) and its ligand, leukocyte function antigen-1 (LFA-1), after pancreatic islet transplantation may affect both nonspecific and alloantigen-specific phases of graft destruction. We examined the effects of ICAM-1/LFA-1 blockade on the survival of islet allografts. Fresh C57BL/10 (H2h) pancreatic islets were transplanted under the renal subcapsular space (KC) or embolized into the liver after portal vein (PV) injection to C3H (H2k) mice. Recipients remained untreated or were treated for 7 days by i.p. administration of: ICAM-1 antisense phosphorothioate oligodeoxynucleotide (oligo) alone; anti-1CAM-1 (alphaICAM-1) monoclonal antibody (mAb) alone: alphaLFA-1 mAb alone; ICAM-1 oligo/alphaLFA mAb combination; alphaICAM-1 mAb/alphaLFA-1 mAb combination; or control oligo IP-8997 or IP-1082. In some experiments, donors were pretreated with ICAM-1 oligo. Inhibition of single ligand with 5.0 mg/kg ICAM-1 oligo (25.1 +/- 10.3), 100 microg/daily alphaICAM-1 mAb (24.2 +/- 8.0 days), or 50 microg/daily alphaLFA-1 mAb (42.8 +/- 25.9 days) prolonged the survivals of KC islet allografts in comparison with untreated controls (11.9 +/- 1.0 days; all p < 0.01). However, dual ICAM-1/LFA-1 blockade with either ICAM-1 oligo/alphaLFA-1 mAb (78.3 +/- 16.5 days) or (alphaICAM-1 mAb/aLFA-1 mAb (65.2 +/- 31.3 days) was the most effective therapy. Although pretreatment of donors with ICAM-1 oligo alone was ineffective (12.2 +/- 0.8 days; NS), a combination of donor pretreatment and recipient treatment started 1 day prior to grafting with ICAM-1 oligo (39.2 +/- 14.0 days) was more effective than the recipient treatment alone (24.6 +/- 8.8 days). Furthermore, ICAM-1/LFA-1 blockade improved islet function as evaluated by glucose tolerance test, and decreased inflammation in comparison with untreated controls. Similar in vivo results were obtained following PV administration of islet allografts. Thus, ICAM-1/LFA-1 blockade prolongs the survival of pancreatic islet allografts and improves their early function.
Katz
S M
SM
Department of Surgery, The University of Texas Medical School at Houston, 77030, USA. stephen.katz@uth.tme.edu
Bennett
F
F
Stecker
K
K
Clark
J H
JH
Pham
T
T
Wang
M E
ME
Kahan
B D
BD
Stepkowski
S M
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy; D005260:Female; D005951:Glucose Tolerance Test; D006085:Graft Survival; D007275:Injections, Intravenous; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods*; D007668:Kidney / Q000601:surgery; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011169:Portal Vein; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1; D016376:Oligonucleotides, Antisense; D018799:Intercellular Adhesion Molecule-1