Utilization of I-domain of LFA-1 to Target Drug and Marker Molecules to Leukocytes

Manikwar, Prakash; Tejo, Bimo Ario; Shinogle, Heather E.; Moore, David S.; Zimmerman, Tahl; Blanco, Francisco J.; Siahaan, Teruna J.

doi:10.7150/thno/v01p0277

Cited by 14 publications

(26 citation statements)

References 49 publications

(48 reference statements)

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“…122 Animal studies have tested the possibility of blocking leukocyte adhesion molecules by antibodies to reduce venous ischemic injury. 123–126 More specifically, these studies have used different antibodies specific to different molecules, capable of inhibiting adhesion molecules of interest in order to prevent reperfusion injury in animal models of myocardial infarction.…”

Section: Potential Novel Therapies and Future Research Directionsmentioning

confidence: 99%

Circulating adhesion molecules in obstructive sleep apnea and cardiovascular disease

Pak

Grandner

Pack

2014

Sleep Medicine Reviews

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SUMMARY Over 20 years of evidence indicates a strong association between obstructive sleep apnea (OSA) and cardiovascular disease. Although inflammatory processes have been heavily implicated as an important link between the two, the mechanism for this has not been conclusively established. Atherosclerosis may be one of the mechanisms linking OSA to cardiovascular morbidity. This review addresses the role of circulating adhesion molecules in patients with OSA, and how these may be part of the link between cardiovascular disease and OSA. There is evidence for the role of adhesion molecules in cardiovascular disease risk. Some studies, albeit with small sample sizes, also show higher levels of adhesion molecules in patients with OSA compared to controls. There are also studies that show that levels of adhesion molecules diminish with continuous positive airway pressure therapy. Limitations of these studies include small sample sizes, cross-sectional sampling, and inconsistent control for confounding variables known to influence adhesion molecule levels. There are potential novel therapies to reduce circulating adhesion molecules in patients with OSA to diminish cardiovascular disease. Understanding the role of cell adhesion molecules generated in OSA will help elucidate one mechanistic link to cardiovascular disease in patients with OSA.

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Section: Potential Novel Therapies and Future Research Directionsmentioning

confidence: 99%

Circulating adhesion molecules in obstructive sleep apnea and cardiovascular disease

Pak

Grandner

Pack

2014

Sleep Medicine Reviews

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“…We have shown that the fluorescence-labeled I-domain binds LFA-1 and is internalized by lymphocytes. 25 Similar to BPI molecules, IDAC conjugates are hypothesized to inhibit the immunological synapse formation during the process of T-cell activation by simultaneous binding of the PLP peptide and I-domain to MHC-II and ICAM-1, respectively, on APC. This simultaneous binding forms a bridge between the two receptors and eventually prevents the translocation and reorganization of Signal-1 and Signal-2.…”

Section: Discussionmentioning

confidence: 99%

I-Domain-Antigen Conjugate (IDAC) for Delivering Antigenic Peptides to APC: Synthesis, Characterization, and in Vivo EAE Suppression

et al. 2012

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The objectives of this work are to characterize the identity of I-domain-antigen conjugate (IDAC) and to evaluate the in vivo efficacy of IDAC in suppressing experimental autoimmune encephalomyelitis (EAE) in mouse model. The hypothesis is that the I-domain delivers PLP139-151 peptides to antigen-presenting cells (APC) and alters the immune system by simultaneously binding to ICAM-1 and MHC-II, blocking immunological synapse formation. IDAC was synthesized by derivatizing the lysine residues with maleimide groups followed by conjugation with PLP-Cys-OH peptide. Conjugation with PLP peptide does not alter the secondary structure of the protein as determined by CD. IDAC suppresses the progression of EAE while I-domain and GMB-I-domain could only delay the onset of EAE. As a positive control, Ac-PLP-BPI-NH2-2 can effectively suppress the progress of EAE. The number of conjugation sites and the sites of conjugations in IDAC were determined using tryptic digest followed by LC-MS analysis. In conclusion, conjugation of I-domain with an antigenic peptide (PLP) resulted in an active molecule to suppress EAE in vivo.

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“…As controls, I-domain and the GMB-I-domain produced slight delays of disease onset but no significant suppression of disease; this activity was probably due to the general inhibition of LFA-1/ICAM-1-mediated leukocyte adhesion. 17 In the future, the effect of injections of IDAC-3 and I-domain on the differentiation of immune cells will be evaluated. Because the therapeutic index of IDAC-3 has not been fully determined, the effect of increasing the dose while maintaining the schedule of 2 injections as well as multiple injections (greater than 3 injections) at low doses (less than 10 nmol) by spreading the injection over a longer timespan will also be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…17 The identity, purity, and secondary structure of the protein were confirmed by mass spectrometry, SDS-PAGE, and CD, respectively.…”

Section: Methodsmentioning

confidence: 98%

“…The advantage of IDAC over BPI molecules is that IDAC can simultaneously deliver several different antigenic peptides to MHC-II molecules to prevent antigenic spreading. 6,17 To improve peptide enzymatic stability and IDAC efficacy, IDAC-3 molecules were synthesized by conjugating Ac-PLP-Cys-NH 2 peptides to the I-domain. The purified IDAC molecules were characterized using mass spectrometry and circular dichroism (CD) spectroscopy.…”

Section: Introductionmentioning

confidence: 99%

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Vaccinelike and Prophylactic Treatments of EAE with Novel I-Domain Antigen Conjugates (IDAC): Targeting Multiple Antigenic Peptides to APC

et al. 2012

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The objective of this work is to utilize novel I-domain antigenic-peptide conjugates (IDAC) for targeting antigenic peptides to antigen-presenting cells (APC) to simulate tolerance in experimental autoimmune encephalomyelitis (EAE). IDAC-1 and IDAC-3 molecules are conjugates between the I-domain protein and PLP-Cys and Ac-PLP-Cys-NH2 peptides, respectively, tethered to N-terminus and Lys residues on the I-domain. The hypothesis is that the I-domain protein binds to ICAM-1 and PLP peptide binds to MHC-II on the surface of APC; this binding event inhibits the formation of the immunological synapse at the APC-T-cell interface to alter T-cell differentiation from inflammatory to regulatory phenotypes. Conjugation of peptides to the I-domain did not change the secondary structure of IDAC molecules as determined by circular dichroism spectroscopy. The efficacies of IDAC-1 and -3 were evaluated in EAE mice by administering i.v or s.c. injections of IDAC in a prophylactic or a vaccine-like dosing schedule. IDAC-3 was better than IDAC-1 in suppressing and delaying the onset of EAE when delivered in prophylactic and vaccine-like manners. IDAC-3 also suppressed subsequent relapse of the disease. The production of IL-17 was lowered in the IDAC-33 treated mice compared to those treated with PBS. In contrast, the production of IL-10 was increased, suggesting that there is a shift from inflammatory to regulatory T-cell populations in IDAC-33treated mice. In conclusion, the I-domain can effectively deliver antigenic peptides in a vaccine-like or prophylactic manner for inducing immunotolerance in the EAE mouse model.

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Utilization of I-domain of LFA-1 to Target Drug and Marker Molecules to Leukocytes

Cited by 14 publications

References 49 publications

Circulating adhesion molecules in obstructive sleep apnea and cardiovascular disease

Circulating adhesion molecules in obstructive sleep apnea and cardiovascular disease

I-Domain-Antigen Conjugate (IDAC) for Delivering Antigenic Peptides to APC: Synthesis, Characterization, and in Vivo EAE Suppression

Vaccinelike and Prophylactic Treatments of EAE with Novel I-Domain Antigen Conjugates (IDAC): Targeting Multiple Antigenic Peptides to APC

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