TNFRSF25 Agonistic Antibody and Galectin-9 Combination Therapy Controls Herpes Simplex Virus-Induced Immunoinflammatory Lesions

Reddy, Pradeep B. J.; Schreiber, Taylor H.; Rajasagi, Naveen K.; Suryawanshi, Amol; Mulik, Sachin; Veiga-Parga, Tamara; Niki, Toshiro; Hirashima, Mitsuomi; Podack, Eckhard R.; Rouse, Barry T.

doi:10.1128/jvi.01391-12

Cited by 23 publications

(28 citation statements)

References 32 publications

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“…Indeed, TNFRSF25-mediated expansion of endogenous Treg population prior to transplantation results in prolongation of cardiac allograft survival in a mouse model of fully MHCmismatched ectopic heart transplants (47). Similarly, TNFRSF25 stimulation prior to infection in a model of corneal infection with HSV reduced the severity of subsequent stromal keratitis lesions (48), which was attributed to the expansion of the Treg population that additionally expressed activation markers such as CD103 needed to access inflammatory sites.…”

Section: Discussionmentioning

confidence: 99%

Cloning, Expression, and Functional Characterization of TL1A-Ig

Khan

Tsai

Schreiber

et al. 2013

The Journal of Immunology

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TNF superfamily member 15 (TL1A) is the ligand for TNFR superfamily (TNFRSF)25. We previously reported that TNFRSF25 stimulation with an agonist Ab, 4C12, expands pre-existing CD4+Foxp3+ regulatory T cells (Tregs) in vivo. To determine how the physiological ligand differs from the Ab, we generated a soluble mouse TL1A-Ig fusion protein that forms a dimer of TL1A trimers in solution with an apparent molecular mass of 516 kDa. In vitro, TL1A-Ig mediated rapid proliferation of Foxp3+ Tregs and a population of CD4+Foxp3− conventional T cells. TL1A-Ig also blocked de novo biogenesis of inducible Tregs and it attenuated the suppressive function of Tregs. TNFRSF25 stimulation by TL1A-Ig in vivo induced expansion of Tregs such that they increased to 30–35% of all CD4+ T cells in the peripheral blood within 5 d of treatment. Treg proliferation in vivo was dependent on TCR engagement with MHC class II. Elevated Treg levels can be maintained for at least 20 d with daily injections of TL1A-Ig. TL1A-Ig–expanded Tregs expressed high levels of activation/memory markers KLRG1 and CD103 and were highly suppressive ex vivo. TL1A-Ig–mediated Treg expansion in vivo was protective against allergic lung inflammation, a mouse model for asthma, by reversing the ratio of conventional T cells to Tregs in the lung and blocking eosinophil exudation into the bronchoalveolar fluid. Thus, TL1A-Ig fusion proteins are highly active and tightly controllable agents to stimulate Treg proliferation in vivo, and they are uniquely able to maintain high levels of expanded Tregs by repeated administration.

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Section: Discussionmentioning

confidence: 99%

Cloning, Expression, and Functional Characterization of TL1A-Ig

Khan

Tsai

Schreiber

et al. 2013

The Journal of Immunology

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“…Approaches that enhance the function of Treg cells and dampen effector T cells can be effective to limit SK lesion severity (7)(8)(9)(10). In this report, we have explored the novel approach of inhibiting DNA methyltransferase activity using 5-azacytidine (cytosine analog) to limit HSV-induced ocular lesions.…”

Section: Discussionmentioning

confidence: 99%

“…The Treg suppression assay was done as previously described (9). Briefly, Foxp3-GFP mice infected with HSV-1 were divided into multiple groups.…”

Section: Methodsmentioning

confidence: 99%

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Azacytidine Treatment Inhibits the Progression of Herpes Stromal Keratitis by Enhancing Regulatory T Cell Function

Varanasi

Reddy

Bhela

et al. 2017

J Virol

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Ocular infection with herpes simplex virus 1 (HSV-1) sets off an inflammatory reaction in the cornea which leads to both virus clearance and chronic lesions that are orchestrated by CD4 T cells. Approaches that enhance the function of regulatory T cells (Treg) and dampen effector T cells can be effective to limit stromal keratitis (SK) lesion severity. In this report, we explore the novel approach of inhibiting DNA methyltransferase activity using 5-azacytidine (Aza; a cytosine analog) to limit HSV-1-induced ocular lesions. We show that therapy begun after infection when virus was no longer actively replicating resulted in a pronounced reduction in lesion severity, with markedly diminished numbers of T cells and nonlymphoid inflammatory cells, along with reduced cytokine mediators. The remaining inflammatory reactions had a change in the ratio of CD4 Foxp3 ϩ Treg to effector Th1 CD4 T cells in ocular lesions and lymphoid tissues, with Treg becoming predominant over the effectors. In addition, compared to those from control mice, Treg from Aza-treated mice showed more suppressor activity in vitro and expressed higher levels of activation molecules. Additionally, cells induced in vitro in the presence of Aza showed epigenetic differences in the Treg-specific demethylated region (TSDR) of Foxp3 and were more stable when exposed to inflammatory cytokines. Our results show that therapy with Aza is an effective means of controlling a virusinduced inflammatory reaction and may act mainly by the effects on Treg.IMPORTANCE HSV-1 infection has been shown to initiate an inflammatory reaction in the cornea that leads to tissue damage and loss of vision. The inflammatory reaction is orchestrated by gamma interferon (IFN-␥)-secreting Th1 cells, and regulatory T cells play a protective role. Hence, novel therapeutics that can rebalance the ratio of regulatory T cells to effectors are a relevant issue. This study opens up a new avenue in treating HSV-induced SK lesions by increasing the stability and function of regulatory T cells using the DNA methyltransferase inhibitor 5-azacytidine (Aza). Aza increased the function of regulatory T cells, leading to enhanced suppressive activity and diminished lesions. Hence, therapy with Aza, which acts mainly by its effects on Treg, can be an effective means to control virus-induced inflammatory lesions.

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“…Gal-9 and Etanercept as a control were injected as described in Figure. cell population that additionally expressed activation markers such as CD103 needed to access inflammatory sites. Additionally, there was a marked reduction of IFN-γ-producing CD4 + T cells responsible for the tissue damage (44).…”

Section: F Gal-9 In Infectious Diseasesmentioning

confidence: 99%

Galectin-9 Changes Its Function to Maintain Homeostasis

Hirashima

Niki

Masaki

2018

TIGG

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Galectin-9 (Gal-9)/Ecalectin was first identified as a T cell-derived eosinophil chemoattractant. We found that Gal-9 plays a role in not only the accumulation but also the activation of eosinophils in experimental allergic models and human allergic patients; Gal-9 was shown to induce eosinophil chemotaxis in vitro and in vivo and activated eosinophils in various aspects. Recent studies, however, showed that Gal-9 has other functions in the differentiation, maturation, aggregation, adhesion, and death of various cells. Presently, we and other groups are in the process of investigating the function of Gal-9 in a variety of physiological and pathological conditions. In this article, we will show the in vivo therapeutic effects of Gal-9 in various disease models (both hyper-immune and immune-compromised conditions), suggesting that Gal-9's immune function changes according to the context. Indeed, the accumulated evidence suggests that Gal-9 orchestrates a variety of biological phenomena to maintain homeostasis. A. IntroductionIn 1998, we purified and identified the human homologue of the guinea-pig eosinophil chemoattractant that mediated tissue eosinophilia in 24-h-old allergic skin lesions. The human homologue, Ecalectin, was first identified as a variant of Galectin-9 (Gal-9), and as the first and only galectin purified as a biologically active molecule, opened the door to speculation that other galectins might play crucial roles in vivo, as well (1). Since only Ecalectin has been found in human cells, we proposed changing its name from Ecalectin to Gal-9. Thereafter, many investigators including us undertook investigations of the role of Gal-9 in human health and diseases using human cells and model animals. Since Gal-9 is a β-galactosidebinding lectin, it functions by binding the carbohydrate moiety of cell surface proteins. It is well known that changed environments alter carbohydrate moieties on the cell surface. Therefore, to clarify the exact in vivo role of Gal-9, experiments involving in vivo Gal-9 administration to disease model animals, in addition to in vitro experiments, are required. In this chapter, we propose that Gal-9 is a substance that works to maintain homeostasis and may be a therapeutic candidate for various diseases. B. Biochemical Characteristics of Gal-9Gal-9 is a tandem-repeat type galectin that has N-and Cterminal carbohydrate-recognition domains (CRDs) connected by a linker peptide. Gal-9 is widely expressed in a variety of organs including immune-related tissues and cells. Since Gal-9 does not have a secretion signal, like most galectins, it is supposed to be secreted by so called "a non-classical secretion pathway," and hence Gal-9 does not have a carbohydrate modification.By alternative splicing, three types of human Gal-9 are generated differing in the length of the linker peptides: L-(355 aa), M-(323 aa) and S-type (311 aa) Gal-9. The linker peptide is highly susceptible to proteolysis, resulting in the truncated Gal-9 at the linker and in the loss of the activity; nevert...

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TNFRSF25 Agonistic Antibody and Galectin-9 Combination Therapy Controls Herpes Simplex Virus-Induced Immunoinflammatory Lesions

Cited by 23 publications

References 32 publications

Cloning, Expression, and Functional Characterization of TL1A-Ig

Cloning, Expression, and Functional Characterization of TL1A-Ig

Azacytidine Treatment Inhibits the Progression of Herpes Stromal Keratitis by Enhancing Regulatory T Cell Function

Galectin-9 Changes Its Function to Maintain Homeostasis

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