Natalizumab for Active Crohn's Disease

Ghosh, Subrata; Goldin, Eran; Gordon, F.; Malchow, H; Rask-Madsen, J; Rutgeerts, Paul; Vyhnálek, P; Zádorová, Zdena; Palmer, Tanya; Donoghue, Stephen

doi:10.1056/nejmoa020732

Cited by 775 publications

(450 citation statements)

References 23 publications

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“…This finding may be useful for the treatment of autoimmune hepatitis, a feared complication occurring in 10-20% of APS I patients, using the VLA-4 therapy blocking VCAM-1 interaction [54,55]. Taken together, our results demonstrate that Aire plays a role in peripheral DC in maintaining self tolerance by regulating the antigenic response of T cells.…”

Section: Discussionsupporting

confidence: 52%

“…We were able to eliminate Aire -/-DC induction of increased T cell stimulation by blocking the VCAM-1 molecules. This finding is interesting since recent clinical studies using a monoclonal antibody directed against a4-integrin, a coreceptor of VLA-4, resulted in beneficial treatment of two autoimmune disorders: multiple sclerosis [54] and Crohn's disease [55]. Furthermore, blocking the costimulatory effect of VCAM-1 has been shown to alleviate the effect of graft-versus-host disease [56].…”

Section: Discussionmentioning

confidence: 99%

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Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire -/-dendritic cells (DC) activate naive T cells more efficiently than do Aire +/+ DC. Expression array analyses of Aire -/-DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire -/-DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire -/-DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire -/-DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire -/-mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35240_s.pdf IntroductionInactivation of the autoimmune regulator gene (AIRE) [1][2][3] causes autoimmunity in patients with autoimmune polyendocrine syndrome type I (APS I, APECED, OMIM 240300) and in a gene targeted mouse model [4,5]. APS I is a rare monogenic autosomal recessive disease without HLA association [6,7], which is prevalent in isolated populations [8][9][10]. APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14]. Functional studies of AIRE suggest a role as a transcription factor and in vitro transactivating studies support this notion [15][16][17][18]. Moreover, the PHD1 domain of AIRE has been suggested to have an E3 ubiquitin ligase activity in cell-free assays [19], findings in variance with a recent report [20]. Aire is highly expressed in a subset of the medullary thymic epithelial cells (mTEC) as well as in DC in the spleen and lymph nodes [21][22][23][24], indicating a potential role in immunological tolerance.To characterize the function of Aire, we previously engineered an Aire-deficient mouse targeting the most common APS I mutation [4]. Aire-deficient mice develop multiple organ-specific autoantibodies and lymphocytic infiltrates, thus mimicking some of the features of human APS I [4]. Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mic...

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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“…Experimental studies indicated that blockade of activated lympho cyte homing to the inflamed gut might provide a new approach for therapy of intestinal inflammation 51,52 . Subsequently, the anti α4 integrin antibody natalizumab was tested in clinical trials for Crohn's disease therapy to block T cell homing to the inflamed intestine via α4β7 integrins [53][54][55] (FIG. 1).…”

Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

488

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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“…21 Targeting a4 integrin has already been shown to be efficacious in the form of natalizumab for patients with multiple sclerosis 22 and inflammatory bowel disease; 23 however, there have been several patients who have developed JC (John Cunningham) virusassociated progressive multifocal leukoencephalopathy after such a treatment. 24 Targeting a4b7 integrin will likely not put patients at risk for this serious complication, as immunologic protection of the central nervous system should remain intact given the specificity of a4b7 integrin for intestinal tissue.…”

Section: Discussionmentioning

confidence: 99%

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

McDonough

Chen

et al. 2012

Bone Marrow Transplant

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Acute intestinal GVHD remains a major source of morbidity after allogeneic hematopoietic cell transplantation (HCT). a4b7 integrin is a cell surface molecule that mediates lymphocyte trafficking to intestinal tissue. In this analysis, peripheral blood was collected at the time of presentation of symptoms of acute GVHD and before any treatment. In all, 45 samples were collected and divided into three groups on the basis of subsequent evaluation: intestinal GVHD (n ¼ 15), skin GVHD (n ¼ 20) and no GVHD (n ¼ 10). Two patients developed intestinal GVHD after DLI. The no-GVHD group comprised 10 patients who presented with suspicious symptoms, but evaluation yielded other etiologies. Analysis by flow cytometry showed that intestinal GVHD patients had a significantly higher percentage of a4b7 integrin-expressing memory CD8 þ T cells (median 7.69%; lower and upper quartiles, 1.06% and 11.64%, respectively) compared with patients with skin GVHD (1.26%; 0.57% and 2.49%) and no GVHD (0.96%; 0.44% and 1.85%), P ¼ 0.03. No differences were found in a4b7 expression in any CD4 þ T-cell subsets or naive CD8 þ T cells. This study adds to the evidence that a4b7 integrin is involved in lymphocyte trafficking in acute intestinal GVHD.

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Natalizumab for Active Crohn's Disease

Cited by 775 publications

References 23 publications

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Current and emerging therapeutic targets for IBD

Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD

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