A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity

Shono, Yusuke; Tuckett, Andrea Z.; Ouk, Samedy; Liou, Hsiou‐Chi; Altan‐Bonnet, Grégoire; Tsai, Jennifer J.; Oyler, Jennifer E.; Smith, Odette M.; West, Mallory L.; Singer, Natalie V.; Doubrovina, Ekaterina; Pankov, Dmitry; Undhad, Chandresh V.; Murphy, Gëorge F.; Lezcano, Cecilia; Liu, Chen; O’Reilly, Richard J.; Brink, Marcel R.M. van den; Zakrzewski, Johannes L.

doi:10.1158/2159-8290.cd-13-0585

Cited by 51 publications

(55 citation statements)

References 48 publications

(63 reference statements)

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“…Mice transferred with siRNA-T-bet transfected splenocytes failed to develop EAE, and administration of siRNA-T-bet has been suggested could effectively alleviate established EAE in mice (47). Although currently unavailable, a small molecular inhibitor to T-bet can be developed; given the inhibitors to other transcription factors such as RORγt and c-Rel have been generated as therapeutic intervention in autoimmunity and transplantation (66, 67). We are therefore optimistic that our findings will be translated into the clinic in the near future to benefit patients for controlling GVHD and leukemia relapse after allo-HSCT.…”

Section: Discussionmentioning

confidence: 99%

T-bet Promotes Acute Graft-versus-Host Disease by Regulating Recipient Hematopoietic Cells in Mice

Nguyen

et al. 2016

The Journal of Immunology

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Beyond its critical role in T cells, T-bet regulates the functions of APCs including dendritic cells (DCs) and B cells, as well as NK cells. Given that recipient APCs are essential for priming allogeneic T cells and recipient NK or T cells are able to reject allogeneic donor cells, we evaluated the role of T-bet on the host in acute graft-versus-host disease (GVHD) using murine models of allogeneic bone marrow transplantation (allo-BMT). T-bet−/− recipients developed significantly milder GVHD than their WT counterparts in MHC-mismatched or CD4-depedent minor histocompatibility antigen (miHA)-mismatched models. Allogeneic donor T cells, in particular CD4 subset, significantly reduced IFN-γ production, proliferation and migration, and caused less injure in liver and gut of T-bet−/− recipients. We further observed that T-bet on recipient hematopoietic cells was primarily responsible for the donor T-cell response and pathogenicity in GVHD. T-bet−/− DCs expressed higher levels of Trail, while produced lower levels of IFN-γ and IL-12/23 p40, as well as chemokine CXCL9, resulting in significantly higher levels of apoptosis, less priming and infiltration of donor T cells. Meanwhile, NK cells in T-bet−/− hosts partially contribute to the decreased donor T-cell proliferation. Furthermore, while T-bet on hematopoietic cells was required for GVHD development, it was largely dispensable for the graft-versus-leukemia (GVL) effect. Taken together with our previous findings, we propose that T-bet is a potential therapeutic target for the control of GVHD through regulating donor T cells as well as recipient hematopoietic cells.

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Section: Discussionmentioning

confidence: 99%

T-bet Promotes Acute Graft-versus-Host Disease by Regulating Recipient Hematopoietic Cells in Mice

Nguyen

et al. 2016

The Journal of Immunology

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“…Targeting T-bet itself is still far from translational application due to a lack of a specific inhibitor. Recently, the small molecule inhibitors for other transcription factors, such as c-Rel and RORγt, have been developed and showed promising results in alleviating GVHD (63) or cutaneous inflammatory disorders (64), respectively. The c-Rel inhibitor also permits the maintenance of the GVL effect.…”

Section: Discussionmentioning

confidence: 99%

T-bet Is Critical for the Development of Acute Graft-versus-Host Disease through Controlling T Cell Differentiation and Function

Wang

et al. 2015

The Journal of Immunology

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T-bet is a master regulator for IFN-γ production and Th1 differentiation. We evaluated the roles of T-bet and IFN-γ in T-cell responses in acute graft-versus-host disease (GVHD) and found that T-bet−/− T cells induced significantly less GVHD compared to WT or IFN-γ−/− counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility antigen (miHA)-mismatched models driven by CD4 T cells. T-bet−/−, but not IFN-γ−/−, CD4 T cells had a markedly reduced ability to cause tissue damage in liver and gut. This distinct outcome is reflected by the differential gene expression on donor CD4 T cells deficient for T-bet or IFN-γ. At mRNA and protein levels, we defined several T-bet-dependent molecules that may account for the impaired ability of T-bet−/− T cells to migrate into target organs and to produce Th1-related cytokines. Moreover, these molecules were independent of either endogenous IFN-γ such as CXCR3 and PD-1, or systematic IFN-γ such as NKG2D, I-Ab, and granzyme B. Although both T-bet−/− and IFN-γ−/− CD4 T cells are prone to differentiate into Th17 cells, polarized Th17 cells deficient for T-bet but not for IFN-γ had a significantly reduced ability to cause GVHD. Finally, T-bet−/− T cells had compromised graft-versus-leukemia (GVL) effect, which could be essentially reversed by neutralization of IL-17 in the recipients. We conclude that T-bet is required for Th1 differentiation and migration, as well as for optimal function of Th17 cells. Thus, targeting T-bet or regulating its downstream effectors independent of IFN-γ may be a promising strategy to control GVHD in the clinic.

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“…For example, although the mammalian target of rapamycin (mTOR) inhibitor sirolimus 13 has a problematic side effect profile (including hypertension, headache, nausea, diarrhea and renal toxicity), this immunosuppressant displays two important beneficial properties: promotion of anti-tumor activity and expansion of regulatory T cells 14 . Other promising drugs are those that inhibit NF-κB 15–17 and histone deacetylase 18 activity. Preclinical evidence suggests that targeting these pathways can tip the immunological balance in favor of allograft tolerance while preserving protective immunity.…”

Section: Lessons From Transplantationmentioning

confidence: 99%

Overcoming immunological barriers in regenerative medicine

2014

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Regenerative therapies that use allogeneic cells are likely to encounter immunological barriers similar to those that occur with transplantation of solid organs and allogeneic hematopoietic stem cells (HSCs). Decades of experience in clinical transplantation hold valuable lessons for regenerative medicine, offering approaches for developing tolerance-induction treatments relevant to cell therapies. Outside the field of solid-organ and allogeneic HSC transplantation, new strategies are emerging for controlling the immune response, such as methods based on biomaterials or mimicry of antigen-specific peripheral tolerance. Novel biomaterials can alter the behavior of cells in tissue-engineered constructs and can blunt host immune responses to cells and biomaterial scaffolds. Approaches to suppress autoreactive immune cells may also be useful in regenerative medicine. The most innovative solutions will be developed through closer collaboration among stem cell biologists, transplantation immunologists and materials scientists.

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A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity

Cited by 51 publications

References 48 publications

T-bet Promotes Acute Graft-versus-Host Disease by Regulating Recipient Hematopoietic Cells in Mice

T-bet Promotes Acute Graft-versus-Host Disease by Regulating Recipient Hematopoietic Cells in Mice

T-bet Is Critical for the Development of Acute Graft-versus-Host Disease through Controlling T Cell Differentiation and Function

Overcoming immunological barriers in regenerative medicine

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