Antagonizing the α4β1 Integrin, but Not α4β7, Inhibits Leukocytic Infiltration of the Central Nervous System in Rhesus Monkey Experimental Autoimmune Encephalomyelitis

Haanstra, Krista G.; Hofman, Sam; Estêvão, Dave M. Lopes; Blezer, Erwin L. A.; Bauer, Jan; Yang, Lili; Wyant, Tim; Csizmadia, Vilmos; Hart, Bert A. ’t; Fedyk, Eric R.

doi:10.4049/jimmunol.1202490

Cited by 78 publications

(60 citation statements)

References 51 publications

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“…In agreement with this, vedolizumab did not affect experimental autoimmune encephalomyelitis in nonhuman primates [57], and, in healthy volunteers, it did not influence trafficking of CD4 + and CD8 + T cells into the CNS.…”

Section: Natalizumabsupporting

confidence: 66%

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Bittner

Wiendl

2016

Neurotherapeutics

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Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific Tcell pathways. While the concept of BT-cell-specific therapyî mplies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cellselective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.

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Section: Natalizumabsupporting

confidence: 66%

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Bittner

Wiendl

2016

Neurotherapeutics

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“…This model is characterized by an early disease onset (between 11 and 40 d) and a very rapid disease progression from first clinical signs until ethical endpoints indicate euthanasia (between a few hours to 1-2 d) (14-16). The disease incidence is 100%, and the model has been validated with the anti-a 4 b 1 mAb natalizumab (Tysabri) (15). We report that FR104 has a profound suppressive effect on the induction of EAE in six treated animals as compared with placebo-treated animals at the level of T and B cell activation, resulting in greatly diminished CNS pathology.…”

mentioning

confidence: 94%

“…To test this, we used stored PBMC, spleen cells, or inguinal lymph node cells from monkeys with EAE, which had an established positive response against rhMOG, as documented previously (15,22). Mononuclear cells (MNC) were cultured in quadruplicate (100,000/well) in culture medium with or without rhMOG (5 mg/ml), in the presence or absence of FR104 (10 mg/ml).…”

Section: Abs and In Vitro Evaluationmentioning

confidence: 99%

Selective Blockade of CD28-Mediated T Cell Costimulation Protects Rhesus Monkeys against Acute Fatal Experimental Autoimmune Encephalomyelitis

Haanstra

Dijkman

Bashir

et al. 2015

The Journal of Immunology

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Costimulatory and coinhibitory receptor–ligand pairs on T cells and APC control the immune response. We have investigated whether selective blockade of CD28–CD80/86 costimulatory interactions, which preserves the coinhibitory CTLA4–CD80/86 interactions and the function of regulatory T (Treg) cells, abrogates the induction of experimental autoimmune encephalomyelitis (EAE) in rhesus monkeys. EAE was induced by intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) in CFA on day 0. FR104 is a monovalent, PEGylated-humanized Fab′ Ab fragment against human CD28, cross-reactive with rhesus monkey CD28. FR104 or placebo was administered on days 0, 7, 14, and 21. FR104 levels remained high until the end of the study (day 42). Placebo-treated animals all developed clinical EAE between days 12 and 27. FR104-treated animals did not develop clinical EAE and were sacrificed at the end of the study resulting in a significantly prolonged survival. FR104 treatment diminished T and B cell responses against rhMOG, significantly reduced CNS inflammation and prevented demyelination. The inflammatory profile in the cerebrospinal fluid and brain material was also strongly reduced. Recrudescence of latent virus was investigated in blood, spleen, and brain. No differences between groups were observed for the β-herpesvirus CMV and the polyomaviruses SV40 and SA12. Cross-sectional measurement of lymphocryptovirus, the rhesus monkey EBV, demonstrated elevated levels in the blood of FR104-treated animals. Blocking rhesus monkey CD28 with FR104 mitigated autoreactive T and B cell activation and prevented CNS pathology in the rhMOG/CFA EAE model in rhesus monkeys.

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“…Vedolizumab, a humanized monoclonal antibody that specifically recognizes the α4β7 heterodimer, selectively blocks gut lymphocyte trafficking without interfering with trafficking to the central nervous system [26][27][28] (Figure 1).…”

Section: Vedolizumabmentioning

confidence: 99%

Promising biological therapies for ulcerative colitis: A review of the literature

Akiho¹,

Yokoyama²,

Abe³

et al. 2015

WJGP

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Ulcerative colitis (UC) is a chronic lifelong condition characterized by alternating flare-ups and remission. There is no single known unifying cause, and the pathogenesis is multifactorial, with genetics, environmental factors, microbiota, and the immune system all playing roles. Current treatment modalities for UC include 5-aminosalicylates, corticosteroids, immunosuppressants (including purine antimetabolites, cyclosporine, and tacrolimus), and surgery. Therapeutic goals for UC are evolving. Medical treatment aims to induce remission and prevent relapse of disease activity. Infliximab, an anti-tumor necrosis factor (TNF)-α monoclonal antibody, is the first biological agent for the treatment of UC. Over the last decade, infliximab and adalimumab (anti-TNF-α agents) have been used for moderate to severe UC, and have been shown to be effective in inducing and maintaining remission. Recent studies have indicated that golimumab (another anti-TNF-α agent), tofacitinib (a Janus kinase inhibitor), and vedolizumab and etrolizumab (integrin antagonists), achieved good clinical remission and response rates in UC. Recently, golimumab and vedolizumab have been approved for UC by the United States Food and Drug Administration. Vedolizumab may be used as a first-line alternative to anti-TNF-α therapy in patients with an inadequate response to corticosteroids and/or immunosuppressants. Here, we provide updated information on various biological agents in the treatment of UC.Key words: Ulcerative colitis; Biological therapy; Antitumor necrosis factor α agents; Janus kinase inhibitor; Anti-integrin agents

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Antagonizing the α4β1 Integrin, but Not α4β7, Inhibits Leukocytic Infiltration of the Central Nervous System in Rhesus Monkey Experimental Autoimmune Encephalomyelitis

Cited by 78 publications

References 51 publications

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Selective Blockade of CD28-Mediated T Cell Costimulation Protects Rhesus Monkeys against Acute Fatal Experimental Autoimmune Encephalomyelitis

Promising biological therapies for ulcerative colitis: A review of the literature

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