Inhibition of Leukocyte Adherence and Susceptibility to Infection

Mileski, William J.; Sikes, Pat; Atiles, Luis; Lightfoot, Ellis; Lipsky, Peter E.; Baxter, Charles R.

doi:10.1006/jsre.1993.1056

Cited by 32 publications

(15 citation statements)

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“…The majority of these studies have focused on /32 integrin and ICAM-1 blockade, in most cases showing some amelioration of injury, with the magnitude of effect dependent on both type of injury and organ system involved. Second, studies assessing the effect of/32 integrin blockade on bacterial host defense demonstrate a spectrum of impaired immune defense against bacterial infection, ranging from minimal [75] to intermediate [110] to severe [123], in agreement with the phenotype of congential /32 integrin deficiency found in humans [5,16]. Two points regarding the potential clinical efficacy and safety of/32 integrin blockade deserve emphasis, however.…”

Section: Act I Vat I Ng ~ Ant I Sense Agent S ~ ~L Eeul Es O~gonucl mentioning

confidence: 72%

The adhesion cascade and anti-adhesion therapy: an overview

Sharar

Winn

Harlan

1995

Springer Semin Immunopathol

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Section: Act I Vat I Ng ~ Ant I Sense Agent S ~ ~L Eeul Es O~gonucl mentioning

confidence: 72%

The adhesion cascade and anti-adhesion therapy: an overview

Sharar

Winn

Harlan

1995

Springer Semin Immunopathol

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“…Increased susceptibility to bacterial infections was not observed in the LFA-1 deficient mice nor was it observed in rabbits treated with blocking LFA-1 antibodies. Thus, loss of LFA-1 function alone was insufficient for supporting the life-threatening infections observed in LAD patients where the expression of all β 2 integrin family members was affected [51][52][53][54][55][56][57]131]. These findings coupled with the demonstration that ICAM-1 expression was markedly upregulated in numerous inflammatory diseases provided clear rationale for pursuit of antagonists of the LFA-1/ICAM-1 interaction.…”

Section: The Role Of Lfa-1 In Human Diseasementioning

confidence: 88%

LFA-1 as a Key Regulator of Immune Function: Approaches toward the Development of LFA-1-Based Therapeutics

Rm²

2006

CPD

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Over the past decade, Lymphocyte Function-Associated Antigen-1 (LFA-1, alphaLbeta2, CD11a/CD18) has emerged as an attractive therapeutic target for the treatment of multiple inflammatory diseases. Its established role in the trafficking and activation of leukocytes coupled with the recent elucidation of the global conformational changes that govern its function continue to drive pharmaceutical interest in this target. This sustained interest has led to the implementation of numerous drug discovery strategies leading to the development of antibodies, peptidomimetics, and small molecules that block LFA-1 function. The most successful demonstration of clinical efficacy to date has been with Raptiva, a humanized anti-LFA-1 antibody. In clinical trials of patients with moderate to severe psoriasis, improvements in several disease specific parameters including the Psoriasis Area and Severity Index (PASI) were observed. This review article will provide an overview of LFA-1 biology and structural regulation, as well as strategies that have been adopted in pursuit of effective therapies. Recent findings with different classes of small molecule antagonists will be highlighted with an emphasis on how their different mechanisms of action on the inserted domain (I domain) of CD11a have impacted our understanding of LFA-1 function and illuminated other potential avenues for therapeutic intervention.

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“…As discussed in the Introduction, HBO 2 can ameliorate a variety of insults in animal and clinical trials. Inhibiting ␤ 2 integrins with monoclonal antibodies will also ameliorate ischemia-reperfusion injuries, but in contrast to HBO 2 , antibody therapy causes profound immunocompromise (81,82). Probably the most compelling evidence that HBO 2 does not cause immunocompromise comes from studies in sepsis models, where HBO 2 has a beneficial effect (83,84).…”

Section: Discussionmentioning

confidence: 99%

Actin S-Nitrosylation Inhibits Neutrophil β2 Integrin Function

Thom

Bhopale

Mancini

et al. 2008

Journal of Biological Chemistry

117

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The focus of this work was to elucidate the mechanism for inhibition of neutrophil ␤ 2 integrin adhesion molecules by hyperoxia. Results demonstrate that exposure to high oxygen partial pressures increases synthesis of reactive species derived from type 2 nitric-oxide synthase and myeloperoxidase, leading to excessive S-nitrosylation of ␤-actin and possibly profilin. Hyperoxia causes S-nitrosylation of the four cysteine moieties closest to the carboxyl-terminal end of actin, which results in formation of short actin filaments. This alters actin polymerization, network formation, and intracellular distribution, as well as inhibits ␤ 2 integrin clustering. If neutrophils are exposed to ultraviolet light to reverse S-nitrosylation, or are incubated with N-formyl-methionyl-leucine-phenylalanine to trigger "insideout" activation, the effects of hyperoxia are reversed. We conclude that cytoskeletal changes triggered by hyperoxia inhibit ␤ 2 integrin-dependent neutrophil adhesion.

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Inhibition of Leukocyte Adherence and Susceptibility to Infection

Cited by 32 publications

References 0 publications

The adhesion cascade and anti-adhesion therapy: an overview

The adhesion cascade and anti-adhesion therapy: an overview

LFA-1 as a Key Regulator of Immune Function: Approaches toward the Development of LFA-1-Based Therapeutics

Actin S-Nitrosylation Inhibits Neutrophil β2 Integrin Function

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