Anti-adhesion molecule therapies in inflammatory bowel disease: Touch and go

doi:10.1016/j.autrev.2008.01.002

Autoimmunity Reviews

Volume 7, Issue 5, May 2008, Pages 364-369

https://doi.org/10.1016/j.autrev.2008.01.002 Get rights and content

Abstract

Exploration of the mechanisms underlying the inflammatory bowel diseases [N. Mori, Y. Horie, M.E. Gerritsen, D.C. Anderson, D.N. Granger, Anti-inflammatory drugs and endothelial cell adhesion molecule expression in murine vascular beds. Gut 1999;44:186–95] is a leading field of medical research that drives the application of biological therapies to human diseases. Indeed, many inflammatory mediators can be targeted in the gut by monoclonal antibodies. A recent direction for these therapeutics is targeting of the adhesion molecule family. This molecule family mediates the adhesion and extravasation of leukocytes through the endothelium at sites of inflammation. This is a complex multistep process that has been extensively investigated in recent years; thanks to these studies some adhesion molecules have been identified to specifically mediate leukocyte migration to gut inflammatory sites, like α₄β₇ integrin. This review outlines the scientific basis behind this therapeutic approach, and describes the principal clinical studies that have been carried out on these new molecules in patients with IBD.

Introduction

The inflammatory bowel diseases [1] are the greatest challenge facing contemporary gastroenterologists. Although their precise etiology is still unknown, the two major forms of IBD, i.e., ulcerative colitis [2] and Crohn's disease [1], are commonly defined as auto-inflammatory process [3]. An as yet unidentified primary event or the interaction between a genetically predisposed subject and the environment causes a breakdown of tolerance in the intestinal immune system of the host, resulting in a chronic inflammatory process in the gut involving immune cells reacting against self antigens [4], [5], [6].

In addition to activation of the immune system, non-immune cells are actively involved in the pathophysiology of IBD. In particular, the endothelium is activated in patient's with IBD, and is an active participant in the development of both CD and UC, as they enhance leukocyte and platelet recruitment, acquire a procoagulant phenotype, and undergo angiogenesis [7], [8].

Finally, leukocyte recruitment is a common feature in the complex picture of IBD pathogenesis, and plays a central role in initiation and progression of the disease. This recruitment is driven by many families of cell adhesion molecules that are mainly expressed on the surface of endothelial cells and intercellular spaces. Due to the crucial role played by adhesion molecules in the pathogenesis of IBD, targeting of these molecules has recently been proposed as a new direction for the development of anti-inflammatory biological therapies.

Section snippets

The leukocye adhesion cascade

Leukocyte rolling, adhesion and transmigration through the endothelial cell layer is a tightly regulated process that involves direct interaction between microvasculature cells and the leukocytes. This complex multistep process is composed of a leukocyte capture phase, a rolling phase, arrest, adhesion, spreading, and paracellular or transcellular migration (Fig. 1). All these steps are mediated by many different molecules, including selectins, integrins, and chemokines, as well as other

Adhesion molecule blockade in preclinical models

Many studies have demonstrated the ability of biological therapies that target adhesion molecules to ameliorate experimental IBD. The earliest studies targeted integrins and their ligands. Indeed, over a decade ago, Picarella et al. administered anti-β₇ integrin and anti-MAdCAM-1 antibodies to colitic SCID mice, which significantly reduced the number of leukocytes infiltrating the lamina propria and mesenteric lymph nodes of inflamed colons, as well as the clinical disease scores [25]. In

Natalizumab

The crucial role of adhesion molecules in the pathophysiology of IBD makes them a very interesting target for drug development. Several agents have reached clinical trials in patients with IBD, the majority of which target the α₄ integrins and ICAM-1. Of these the one whose development is most advanced is natalizumab, a humanized (95% human-derived) IgG₄ monoclonal antibody against human α₄ integrin. Natalizumab inhibits both the VCAM-1/α₄β₁ and MAdCAM-1/α₄β₇ pathways of transendothelial

Conclusions

Anti-adhesion molecule therapy is poised to assume a crucial role in the therapeutic approach to the treatment of moderate-to-severe CD. The regulatory approval of drugs targeting integrins will soon expand the family of biological therapies available for patients with CD. This accelerates the need for the development of a clear algorithm that will provide clinicians with the evidence-based data needed to allow them to choose between the available biological therapeutics and select the most

Acknowledgements

The costs of this review is supported by a grant from the Italian Ministery of Health (Ricerca Finalizzata 2006, n.72) and by a Grant from the Broad Medical Research Program to S.D.

Take home messages

•
Intestinal endothelium actively participate in IBD pathogenesis
•
Leukocyte adhesion and migration are crucial events in intestinal inflammation
•
Blockade of leukocyte–endothelial interactions is a promising therapy for IBD treatment
•
Monoclonal antibodies against surface molecules actually are the most

References (34)

C. Berlin et al.
Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1
Cell
(1993)
K.S. Lang et al.
The role of the innate immune response in autoimmune disease
J Autoimmun
(2007)
J. Milner et al.
Repertoire-dependent immunopathology
J Autoimmun
(2007)
Y. Peng et al.
Innate and adaptive immune response to apoptotic cells
J Autoimmun
(2007)
S. Danese et al.
Platelets trigger a CD40-dependent inflammatory response in the microvasculature of inflammatory bowel disease patients
Gastroenterology
(2003)
K. Ley
The role of selectins in inflammation and disease
Trends Mol Med
(2003)
B. Cambien et al.
A new role in hemostasis for the adhesion receptor P-selectin
Trends Mol Med
(2004)
D. Sako et al.
Expression cloning of a functional glycoprotein ligand for P-selectin
Cell
(1993)
L.A. Lasky et al.
An endothelial ligand for L-selectin is a novel mucin-like molecule
Cell
(1992)
S.D. Marlin et al.
Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1)
Cell
(1987)

S. Ben-Horin et al.

The role of very late antigen-1 in immune-mediated inflammation

Clin Immunol

(2004)

M.J. Elices et al.

VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site

Cell

(1990)

S.J. Kent et al.

A monoclonal antibody to alpha 4 integrin suppresses and reverses active experimental allergic encephalomyelitis

J Neuroimmunol

(1995)

F.H. Gordon et al.

A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn's disease

Gastroenterology

(2001)

S.R. Targan et al.

Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial

Gastroenterology

(2007)

N. Mori et al.

Anti-inflammatory drugs and endothelial cell adhesion molecule expression in murine vascular beds

Gut

(1999)

S. Danese et al.

Etiopathogenesis of inflammatory bowel diseases

World J Gastroenterol

(2006)

Cited by (38)

Unravelling the influence of host genetic factors on malaria susceptibility in Asian populations
2024, Acta Tropica
Malaria is a deadly blood-borne disease caused by a Plasmodium parasite. Infection results in various forms of malaria, including an asymptomatic state, uncomplicated disease, or severe disease. Severe malaria (SM) is particularly prevalent among young children and is a significant cause of mortality. SM is associated with the sequestration of parasitized erythrocytes in the microvasculature of vital host organs, disrupting the normal functioning of the immune system. Although the exact mechanisms of malaria pathogenesis are yet to be fully understood, researchers have been investigating the role of host genetics in determining the severity of the disease and the outcome of infection. The objective of this study is to identify specific host genes that have been examined for their association with malaria in Asian populations and pinpoint those most likely to influence susceptibility. Through an extensive screening process, a total of 982 articles were initially identified, and after careful review, 40 articles discussing 68 genes were included in this review. By constructing a network of protein-protein interactions (PPIs), we identified six key proteins (TNF, IL6, TLR4, IL1β, IL10, and IL8) that exhibited substantial interactions (more than 30 edges), suggesting their potential as significant targets for influencing malaria susceptibility. Notably, these six proteins have been previously identified as crucial components of the immune response, associated with malaria susceptibility, and capable of affecting different clinical forms of the disease. Identifying genes that contribute to malaria susceptibility or resistance holds the promise of enhancing the diagnosis and treatment of this debilitating illness. Such knowledge has the potential to pave the way for more targeted and effective strategies in combating malaria, particularly in Asian populations where controlling Plasmodium vivax is challenging, and India contributes the highest number of cases. By understanding the genetic factors underlying malaria vulnerability, we can develop interventions that are tailored to the specific needs of Asian populations, ultimately leading to better outcomes in the fight against this disease.
Close homolog of L1-deficient ameliorates inflammatory bowel disease by regulating the balance of Th17/Treg
2020, Gene
The aim of this study is to investigate the role of close homolog of L1 (CHL1) on inflammatory bowel disease (IBD), and the correlation with the balance of Th17/Treg.
Dextran sodium sulfate (DSS)-induced IBD mice model was established. CHL1 knockout (KO) mice and CHL1 wild-type (WT) mice were subjected to DSS. CHL1 expression was detected using qRT-PCR. Weight was recorded daily, and disease activity index (DAI) score was assessed. The colon length and histological changes were measured. The number of neutrophils, macrophages and T cells was observed by immunohistochemistry. The expression of inflammatory cytokines and the proportion of Th17/Treg cells were detected by qRT-PCR and flow cytometry. The expression of RORγt, STAT3 and Foxp3 was detected by using immunohistochemistry and Western blot.
CHL1 expression was upregulated in DSS-induced IBD mice. DSS-CHLl-KO mice exhibited less weight loss than the DSS-CHLl-WT mice. The DAI score and histological score were decreased in DSS-CHLl-KO mice compared with DSS-CHLl-WT mice, while colon length was increased. Number of neutrophils, macrophages and T cells, and expression of TNF-α, IL-6, IL-17A, IL-21 and IL-23 were decreased in DSS-CHLl-KO mice, while IL-10 expression was increased. Moreover, CHL1-deficient inhibited Th17 cells differentiation and promoted Treg cells differentiation in IBD mice. CHL1-deficient also inhibited the expression of RORγt and STAT3, and promoted the expression of Foxp3 in IBD mice.
CHL1-deficient reduces the inflammatory response by regulating the balance of Th17/Treg in mice with IBD. CHL1 is expected to be a new target for the treatment of IBD.
The effect of the novel tellurium compound AS101 on autoimmune diseases
2014, Autoimmunity Reviews
Citation Excerpt :
Therapeutic interventions based on the use of monoclonal antibodies against cell adhesion molecules have been extensively studied. In preclinical studies using various animal models, promising results have been obtained demonstrating that blocking of adhesion receptors of the integrin and selectin families mitigated the inflammation process in models of ulcerative colitis [33,36,37], autoimmune encephalomyelitis [38], rheumatoid arthritis [39,40] and other pathologies. Th17 cells are potent inflammatory mediators that contribute to a list of disorders such as lupus, IBD, RA, psoriasis, asthma, allergy and MS. Therapeutic strategies aimed at attenuating but not abrogating the IL-17/IL-17R response or other associated factors such as IL-6/IL-6R signaling may be promising means to ameliorate inflammatory and autoimmune diseases [41].
Tellurium is a rare element, which has been regarded as a non-essential trace element despite its relative abundance in the human body. The chemistry of tellurium supports a plethora of activities, but its biochemistry is not clearly established to date. The small tellurium^IV compound, ammonium trichloro (dioxoethylene-o,o′)tellurate (AS101) developed and initially investigated by us, is currently being evaluated in Phase II clinical trials in psoriasis patients. AS101 is the first tellurium compound to be tested for clinical efficacy. This compound is a potent immunomodulator both in vitro and in vivo with a variety of potential therapeutic applications. The present review will focus on the immunomodulatory properties of AS101, and specifically, its effects in mitigating autoimmune diseases. AS101 has several activities that act on the immune system, including: 1) its ability to reduce IL-17 levels and to inhibit the function of Th17 cells; 2) its specific unique redox-modulating activities enabling the inhibition of specific leukocyte integrins such as α4β1 and α4β7, that are pivotal for diapedesis of macrophages and CD4⁺ T inflammatory/auto-reactive cells into the autoimmune tissues; and 3) its ability to enhance the activity of regulatory T cells (Treg). These activities coupled with its excellent safety profile suggest that AS101 may be a promising candidate for the management of autoimmune diseases.
Metabolome and inflammasome in inflammatory bowel disease
2012, Translational Research
Citation Excerpt :
Leukocyte infiltration is a tightly regulated process, comprising of capture, rolling, arrest, adhesion, spreading, and paracellular or transcellular migration of the leukocyte. Numerous molecules, among them selectins, integrins, chemokines, and other members of the immunoglobulin superfamily, mediate these steps.64 Selectins are expressed on the surface of endothelial cells, leukocytes, or platelets.
Inflammatory bowel disease (IBD) encompasses several chronic inflammatory disorders leading to the damage of the gastrointestinal tract. The 2 principal forms of these disorders are ulcerative colitis (UC) and Crohn’s disease (CD). Bacteria are involved in the etiology of IBD. Many microorganisms have been put forward as causative factors in IBD, but the primary etiologic agents are still not known. The underlying genetic, environmental, and lifestyle issues can affect the individual’s predisposition to these diseases. Immune factors identified in IBD are: dysregulation of the innate and adaptive immune system directed against luminal bacteria or their products found in the intestinal lumen and inappropriate immune responses to organisms in the intestine that normally do not elicit a response, possibly because of intrinsic alterations in mucosal barrier function. However, recent advances in basic science research revealed new insights into the role of specific immune cells and their mediators in intestinal inflammation. The inflammatory mediators known as “inflammasome” are a consequence of the metabolic products (metabolom) of cells and commensal or pathogenic bacteria. Elucidation of inflammasome and metabolom has led to the development of biomarkers specific for each disease that are involved into management strategies targeted at altering specific pathogenic mechanisms that have the potential to modify or change the natural course of these disease entities. The review discusses the potential role of biomarkers in monitoring the inflammasome and therefore the severity of intestinal damage. The microbial ecosystem in the human gut in different microhabitats and metabolic niches contribute to the bowel metabolome.In addition, this review will focus on our expanding understanding of microbial factors associated with both the initiation and maintenance of IBD. New insights acquired from murine genetic models of inflammatory bowel disease will also be discussed.
Identification, characterization, and epitope mapping of human monoclonal antibody J19 that specifically recognizes activated integrin α<inf>4</inf>β<inf>7</inf>
2012, Journal of Biological Chemistry
Integrin α₄β₇ is a lymphocyte homing receptor that mediates both rolling and firm adhesion of lymphocytes on vascular endothelium, two of the critical steps in lymphocyte migration and tissue-specific homing. The rolling and firm adhesions of lymphocytes rely on the dynamic shift between the inactive and active states of integrin α₄β₇, which is associated with the conformational rearrangement of integrin molecules. Activation-specific antibodies, which specifically recognize the activated integrins, have been used as powerful tools in integrin studies, whereas there is no well characterized activation-specific antibody to integrin α₄β₇. Here, we report the identification, characterization, and epitope mapping of an activation-specific human mAb J19 against integrin α₄β₇. J19 was discovered by screening a human single-chain variable fragment phage library using an activated α₄β₇ mutant as target. J19 IgG specifically bound to the high affinity α₄β₇ induced by Mn²⁺, DTT, ADP, or CXCL12, but not to the low affinity integrin. Moreover, J19 IgG did not interfere with α₄β₇-MAdCAM-1 interaction. The epitope of J19 IgG was mapped to Ser-331, Ala-332, and Ala-333 of β₇ I domain and a seven-residue segment from 184 to 190 of α₄ β-propeller domain, which are buried in low affinity integrin with bent conformation and only exposed in the high affinity extended conformation. Taken together, J19 is a potentially powerful tool for both studies on α₄β₇ activation mechanism and development of novel therapeutics targeting the activated lymphocyte expressing high affinity α₄β₇.
Effect of garlic sulfur compounds on neutrophil infiltration and damage to the intestinal mucosa by endotoxin in rats
2012, Food and Chemical Toxicology
We investigated the protective effects of garlic sulfur compounds (GSCs), specifically, diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), on endotoxin-induced intestinal damage. Wistar rats received by gavage 0.125 or 0.025 mmol/kg body wt of each GSC or the vehicle (corn oil; 2 mL/kg body wt) every other day for 2 weeks before being injected with endotoxin (ip, 5 mg/kg body wt). Control rats were administered corn oil and were injected with sterile saline. Rats were killed at 18 h after injection. Both doses of DAS suppressed endotoxin-induced neutrophilia, serum levels of sICAM-1 and CINC-1, cellular CD11b on neutrophils, and intestinal contents of ICAM-1, CINC-1, TNF-alpha, and IL-1beta (p < 0.05). DADS suppressed endotoxin-induced intestinal contents of ICAM-1, TNF-alpha, and IL-1beta at both doses, but only suppressed the serum sICAM-1 level and cellular CD11b on neutrophils at the low dose (p < 0.05). DATS did not ameliorate the endotoxin-induced serum level of sICAM-1 or CINC-1 but suppressed intestinal IL-1beta at both doses. The low but not the high dose of DATS also ameliorated the intestinal contents of ICAM-1 and TNF-alpha (p < 0.05). All GSCs reversed endotoxin-induced neutrophil infiltration and damage in the intestine, and the order of the effects of these GSCs to normalize intestinal morphology was DAS > DADS > DATS.

View all citing articles on Scopus

^☆: Competing interests. The authors have declared that no competing interests exist.

View full text

ReviewAnti-adhesion molecule therapies in inflammatory bowel disease: Touch and go☆

Abstract

Introduction

Section snippets

The leukocye adhesion cascade

Adhesion molecule blockade in preclinical models

Natalizumab

Conclusions

Acknowledgements

Cell

J Autoimmun

J Autoimmun

J Autoimmun

Gastroenterology

Trends Mol Med

Trends Mol Med

Cell

Cell

Cell

Clin Immunol

Cell

J Neuroimmunol

Gastroenterology

Gastroenterology

Anti-inflammatory drugs and endothelial cell adhesion molecule expression in murine vascular beds

Gut

Etiopathogenesis of inflammatory bowel diseases

World J Gastroenterol

Review
Anti-adhesion molecule therapies in inflammatory bowel disease: Touch and go☆