Antisense ICAM-1 oligonucleotides block allograft rejection in rats

Stepkowski, Stanislaw M.; Wang, M.E.; Amante, Angel J.; Калинин, Д. В.; Qu, Xiumei; Blasdel, T.; Condon, Thomas P.; Kahan, Barry D.; Bennett, Frank

doi:10.1016/s0041-1345(96)00638-0

Cited by 16 publications

(3 citation statements)

References 7 publications

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“…Blocking ICAM-1 expression with an antisense oligodeoxynucleotide (given intravenously over 1 to 2 weeks) in the setting of cardiac allograft transplantation was shown to have more of an immunomodulatory effect (to reduce rejection) rather than to reduce immediate graft injury and primary graft failure. [59][60][61] In other experiments, anti-interferon-␥ antisense oligodeoxynucleotides indirectly reduced ICAM-1 expression as well as cell surface induction of major histocompatibility complex (MHC) class I and II molecules. 62,63 However, this alternative mechanism of action (interferon-␥ inhibition) is not likely to apply to the current model, in which isogeneic grafts (seen as "self" by the recipient) were used, diminishing a potential intermediary role for MHC class I or II molecule inhibition in reducing acute graft injury.…”

Section: Toda Et Al Antisense Icam-1 In Lung Transplantationmentioning

confidence: 99%

Antisense Intercellular Adhesion Molecule-1 (ICAM-1) Oligodeoxyribonucleotide Delivered During Organ Preservation Inhibits Posttransplant ICAM-1 Expression and Reduces Primary Lung Isograft Failure

Toda

Kayano

Karimova

et al. 2000

Circulation Research

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Abstract-Transiently increased expression of leukocyte adhesion receptors after lung preservation contributes to early graft demise by recruiting leukocytes, activating complement, and causing microcirculatory stasis. We hypothesized that inhibiting intercellular adhesion molecule-1 (ICAM-1) expression even briefly may significantly improve lung graft function and that the preservation period might provide a unique window to deliver a therapeutic pulse of antisense oligonucleotide ICAM-1 to inhibit ICAM-1 expression after transplantation. Interleukin-1␤-treated rat pulmonary endothelial cells given a 20-mer phosphorothioate oligonucleotide comprising an antisense span targeted to the 3Ј-untranslated region of rat ICAM-1 demonstrated an oligonucleotide dose-dependent reduction in ICAM-1 expression. Using a cationic liposomal carrier, this same antisense oligonucleotide (but not the sense control) instilled into the pulmonary vasculature at the time of preservation reduced subsequent graft ICAM-1 expression and graft leukostasis and markedly improved oxygenation, pulmonary blood flow, and graft survival. These experiments demonstrate that the preservation period presents a window during which to target an anti-ICAM-1 expression strategy to inhibit early adhesion receptor expression and improve functional outcome after lung transplantation. (Circ Res. 2000;86:166-174.)Key Words: intercellular adhesion molecule-1 Ⅲ lung transplantation Ⅲ isograft Ⅲ leukocyte adhesion receptor C linical lung transplantation at its best is a harrowing experience, because lung grafts can fail catastrophically shortly after reperfusion for reasons that are often not understood. 1,2 Clinical lung preservation strategies are directed toward maintaining proper electrolyte and osmotic homeostasis, but surprisingly little is done to protect the vast pulmonary vascular network on which the lung depends for both integrity and function. Because the early expression of the leukocyte adhesion receptor P-selectin can result in rapid sequestration of neutrophils (polymorphonuclear leukocytes [PMNs]) after lung transplantation, 3 promoting microcirculatory stasis and local tissue destruction, we hypothesized that a strategy that protects the lungs from early leukocyte recruitment could confer clinical benefit. Because P-selectin places neutrophils into a favorable steric relationship for intercellular adhesion molecule-1 (ICAM-1) binding to ␤ 2 -integrins, we hypothesized that early inhibition of inducible ICAM-1 expression might serve as a useful target for therapeutic intervention in lung transplantation to prevent acute graft injury. Toward this end, we have focused on the unique opportunity provided by the lung harvest procedure, during which it is possible to deliver agents (such as antisense oligodeoxynucleotides) ex vivo directly into the vasculature, which can block adhesion receptor expression during the first few critical hours after reperfusion. The current studies were designed to (1) elucidate the nature and functional relevance of endo...

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Section: Toda Et Al Antisense Icam-1 In Lung Transplantationmentioning

confidence: 99%

Antisense Intercellular Adhesion Molecule-1 (ICAM-1) Oligodeoxyribonucleotide Delivered During Organ Preservation Inhibits Posttransplant ICAM-1 Expression and Reduces Primary Lung Isograft Failure

Toda

Kayano

Karimova

et al. 2000

Circulation Research

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“…ISIS 2302 has a potent and sequence-dependent capability for inhibiting ICAM-1 protein expression in human cell culture models (4). An oligonucleotide targeted to murine ICAM-1 (ISIS 3082) has exhibited pharmacologic activity in mouse models of inflammatory disease in dose ranges of 0.03-5 mg/kg (7,27,(31)(32)(33). Inhibition of the expression of ICAM-1 during inflammatory reactions can help prevent extravasation of neutrophils from circulation into tissue and also inhibit T-cell activation (3,6).…”

Section: Introductionmentioning

confidence: 99%

Correlation of Toxicity and Pharmacokinetic Properties of a Phosphorothioate Oligonucleotide Designed to Inhibit ICAM-1

et al. 1999

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ISIS 2302 is a phosphorothioate oligodeoxynucleotide with a sequence complementary to the mRNA of human intercellular adhesion molecule 1 (ICAM-1). Hybridization of ISIS 2302 to the mRNA inhibits expression of the ICAM-1 protein in response to inflammatory stimuli. A murine active antisense oligonucleotide, ISIS 3082, has been used for in vivo pharmacology studies and has anti-inflammatory activity in models of organ transplant rejection, ulcerative colitis, and collagen-induced arthritis at doses ranging from 0.03 to 5 mg/kg. The safety assessment for ISIS 2302 includes general toxicity studies up to 6 mo in duration in mice and monkeys, genetic toxicity studies, and reproductive/fertility studies. ISIS 3082 was examined in parallel with ISIS 2302 in mouse toxicity and reproductive studies. The toxicities observed following systemic administration of ISIS 2302 and ISIS 3082 were similar and consistent with those observed for other compounds in this chemical class and, therefore, are independent of the suppression of ICAM-1 expression. Toxicokinetic evaluation demonstrated that toxicities occurred in organs containing the highest concentrations of ISIS 2302. Evidence of immune stimulation. including dose-dependent splenomegaly, lymphoid hyperplasia, and multiorgan mixed mononuclear cell infiltrates, was the most common finding in rodent studies. Monkeys were much less sensitive than mice to immune stimulation. Kidney contained the highest concentrations of ISIS 2302. Morphologic changes observed in kidney included atrophic and regenerative changes in proximal tubular epithelium; however, there was no evidence of functional abnormalities. Additional histologic changes noted in proximal tubular epithelium included basophilic granules, which were reflective of oligonucleotide distribution and uptake in these cells. Liver also contained high concentrations of oligonucleotide, which were associated with Kupffer cell hypertrophy in mice. Changes in serum transaminases, cholesterol, and triglycerides were reflective of hepatic alterations. In monkeys, high concentrations of oligonucleotide caused a transient increase in clotting times and activation of the alternative complement pathway. All toxicities associated with ISIS 2302 were reversible and occurred at doses well above those required for pharmacologic activity or currently used in clinical trials. In addition, there has been no evidence of genetic toxicity associated with ISIS 2302, and no changes in reproductive performance, fertility, or fetal development have been noted in animals treated with ISIS 2302 or ISIS 3082.

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“…A very promising approach is the use of antisense oligonucleotides targeted to specific molecules. Some effects have been studied both in vitro [20] and in vivo [6,8,[21][22][23][24][25][26] shows also a promise for treatment of chronic inflammatory disorders such as Crohn's disease [27] and rheumatoid arthritis [28], that are difficult to treat otherwise. While clinical trials are being carried out to further establish the safety and efficacy of these oligos, in vitro studies are helpful in providing some clues about the mechanisms of action.…”

Section: Discussionmentioning

confidence: 99%

Use of ICAM-1 antibodies and antisense oligonucleotides to inhibit transmigration of neutrophils

Sadowska

Overveld

Luyten

et al. 2004

Inflammation Research

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Antisense ICAM-1 oligonucleotides block allograft rejection in rats

Cited by 16 publications

References 7 publications

Antisense Intercellular Adhesion Molecule-1 (ICAM-1) Oligodeoxyribonucleotide Delivered During Organ Preservation Inhibits Posttransplant ICAM-1 Expression and Reduces Primary Lung Isograft Failure

Antisense Intercellular Adhesion Molecule-1 (ICAM-1) Oligodeoxyribonucleotide Delivered During Organ Preservation Inhibits Posttransplant ICAM-1 Expression and Reduces Primary Lung Isograft Failure

Correlation of Toxicity and Pharmacokinetic Properties of a Phosphorothioate Oligonucleotide Designed to Inhibit ICAM-1

Use of ICAM-1 antibodies and antisense oligonucleotides to inhibit transmigration of neutrophils

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