ICAM-1 Antisense Oligodeoxynucleotide Improves Islet Allograft Survival and Function

Abstract

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.

Prolonged Islet Allograft Survival by Adenovirus-Mediated Transfer of sICAM-1/Ig Immunoadhesin Gene

“…In the present study, a high systemic production of an immunoadhesin, using Ad-mediated in vivo transfer of the gene encoding sICAM-1/Ig, interfered with the LFA-1-ICAM-1 pathway and significantly prolonged islet allograft survival in mice. Monoclonal antibodies directed against ICAM-1 (Zeng et al, 1994;Katz et al, 2000), LFA-1 (Nishihara et al, 1997;Katz et al, 2000;Nicolls et al, 2000), or both (Grochowiecki et al, 2000;Katz et al, 2000) as well as ICAM-1 antisense oligonucleotides (Katz et al, 2000) have already been used in multiple animal models. According to these data, anti-LFA-1 MAb-specific tolerance has been reported using short-term administration of anti-LFA-1 MAb, confirming the critical role of the LFA-1-ICAM-1 pathway in allograft rejection.…”

“…The LFA-1-ICAM-1 interaction plays an essential role in the adhesion of leukocytes to endothelial cells, and is an important costimulatory signal in immunocompetent cells (Springer, 1994). Administration of anti-ICAM-1 and/or anti-LFA-1 monoclonal antibodies (MAbs) has been used in various allo-or xenograft rodent models such as heart (Isobe et al, 1992), islet (Gotoh et al, 1994;Zeng et al, 1994;Nishihara et al, 1997;Katz et al, 2000;Nicolls et al, 2000), small bowel (Sarnacki et al, 2000), pancreas (Kawabe et al, 1996), and liver transplantation (Harihara et al, 1996). Studies of humans confirmed that anti-ICAM-1 or anti-LFA-1 antibodies can significantly prolong kidney or bone marrow graft survival (Fischer et al, 1991;Haug et al, 1993;Hourmant et al, 1996).…”

Biological and Biomaterial Approaches for Improved Islet Transplantation

“…Thus, Katz et al (2000) have explored the benefit of silencing ICAM-1 and its ligand, LFA-1, in mice pancreatic islet allotransplants by post-transplantation treatment of recipients with phosphorothioate ODNs. The authors observed that ICAM-1/LFA-1 blockade improved islet function and reduced inflammation compared with untreated controls (Katz et al, 2000).…”

In Vivo Application of Non-viral Vectors to the Liver

“…The potential of antisense technology is not confined to anti-viral therapy. Recently, antisense oligonucleotides have been used in diverse studies, examining allograft survival by targeting intracellular adhesion molecule-1 expression (Katz et al, 2000); inhibition of hepatoma growth by reducing vascular endothelial growth factor levels (Kang et al, 2000); reduction of FAS levels in the mouse liver to protect against acute liver failure ; and development of a tumor vaccine with molecules targeting TGF-b2 resulting in a reduction in tumor burden (Maggard et al, 2001).…”