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3. Blockade of individual Notch ligands and receptors controls graft-versus-host disease

Author

Tran, Ivy T., Sandy, Ashley R., Carulli, Alexis J., Ebens, Christen, Chung, Jooho, Shan, Gloria T., Radojcic, Vedran, Friedman, Ann, Gridley, Thomas, Shelton, Amy, Reddy, Pavan, Samuelson, Linda C., Yan, Minhong, Siebel, Christian W., and Maillard, Ivan

Subjects
T cells -- Research -- Physiological aspects, Bone marrow -- Transplantation, Graft versus host reaction -- Risk factors -- Prevention, Proteins -- Research -- Physiological aspects, Health care industry
Abstract

Graft-versus-host disease (GVHD) is the main complication of allogeneic bone marrow transplantation. Current strategies to control GVHD rely on global immunosuppression. These strategies are incompletely effective and decrease the anticancer [...]

Published
2013
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10. In Vivo Blockade of Individual Notch Ligands and Receptors Provides a New Targeted Therapeutic Approach In Graft-Versus-Host Disease

Author

Tran, Ivy T, primary, Sandy, Ashley R, additional, Carulli, Alexis, additional, Shan, Gloria T, additional, Radojcic, Vedran, additional, Friedman, Ann, additional, Shelton, Amy, additional, Samuelson, Linda C, additional, Yan, Minhong, additional, Siebel, Christian W, additional, and Maillard, Ivan, additional

Published
2011
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16. T Cell-Specific Notch Inhibition Blocks Graft-versus-Host Disease by Inducing a Hyporesponsive Program in Alloreactive CD4+ and CD8+ T Cells.

Author

Sandy, Ashley R., Jooho Chung, Tomomi Toubai, Shan, Gloria T., Tran, Ivy T., Friedman, Ann, Blackwell, Timothy S., Reddy, Pavan, King, Philip D., and Maillard, Ivan

Subjects
*GRAFT versus host disease, *T cells, *NOTCH proteins, *CD4 antigen, *CD8 antigen, *BONE marrow transplantation, *MITOGEN-activated protein kinases, *NF-kappa B, *THERAPEUTICS, *PHYSIOLOGY
Abstract

Graft-versus-host disease (GVHD) induced by donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). We previously reported that the pan-Notch inhibitor dominant-negative form of Mastermind-like 1 (DNMAML) markedly decreased the severity and mortality of acute GVHD mediated by CD4+ T cells in mice. To elucidate the mechanisms of Notch action in GVHD and its role in CD8+ T cells, we studied the effects of Notch inhibition in alloreactive CD4+ and CD8+ T cells using mouse models of allo-BMT. DNMAML blocked GVHD induced by either CD4+ or CD8+ T cells. Both CD4+ and CD8+ Notch-deprived T cells had preserved expansion in lymphoid organs of recipients, but profoundly decreased IFN-γ production despite normal T-bet and enhanced Eomesodermin expression. Alloreactive DNMAML T cells exhibited decreased Ras/MAPK and NF-κB activity upon ex vivo restimulation through the TCR. In addition, alloreactive T cells primed in the absence of Notch signaling had increased expression of several negative regulators of T cell activation, including Dgka, Cblb, and Pdcd1. DNMAML expression had modest effects on in vivo proliferation but preserved overall alloreactive T cell expansion while enhancing accumulation of pre-existing natural regulatory T cells. Overall, DNMAML T cells acquired a hyporesponsive phenotype that blocked cytokine production but maintained their expansion in irradiated allo-BMT recipients, as well as their in vivo and ex vivo cytotoxic potential. Our results reveal parallel roles for Notch signaling in alloreactive CD4+ and CD8+ T cells that differ from past reports of Notch action and highlight the therapeutic potential of Notch inhibition in GVHD. [ABSTRACT FROM AUTHOR]

Published
2013
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17. Notch signaling is a critical regulator of allogeneic CD4+T-cell responses mediating graft-versus-host disease

Author

Zhang, Yi, Sandy, Ashley R., Wang, Jina, Radojcic, Vedran, Shan, Gloria T., Tran, Ivy T., Friedman, Ann, Kato, Koji, He, Shan, Cui, Shuaiying, Hexner, Elizabeth, Frank, Dale M., Emerson, Stephen G., Pear, Warren S., and Maillard, Ivan

Abstract

Graft-versus-host disease (GVHD) remains the major barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is caused by donor T cells that mediate host tissue injury through multiple inflammatory mechanisms. Blockade of individual effector molecules has limited efficacy in controlling GVHD. Here, we report that Notch signaling is a potent regulator of T-cell activation, differentiation, and function during acute GVHD. Inhibition of canonical Notch signaling in donor T cells markedly reduced GVHD severity and mortality in mouse models of allogeneic HSCT. Although Notch-deprived T cells proliferated and expanded in response to alloantigens in vivo, their ability to produce interleukin-2 and inflammatory cytokines was defective, and both CD4+and CD8+T cells failed to up-regulate selected effector molecules. Notch inhibition decreased the accumulation of alloreactive T cells in the intestine, a key GVHD target organ. However, Notch-deprived alloreactive CD4+T cells retained significant cytotoxic potential and antileukemic activity, leading to improved overall survival of the recipients. These results identify Notch as a novel essential regulator of pathogenic CD4+T-cell responses during acute GVHD and suggest that Notch signaling in T cells should be investigated as a therapeutic target after allogeneic HSCT.

Published
2011
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18. The Role of Notch Signaling in T Cell-mediated Immune Disorders.

Author

Sandy, Ashley R.

Subjects
Notch in T Cell-mediated Immune Disorders
Abstract

Notch is a highly conserved cell-to-cell communication pathway that plays an essential role in many biological processes. Notch exerts multiple effects in the hematopoietic system, especially during T cell development. Recent data suggest that Notch also regulates mature T cell differentiation and function. Here, we studied Notch signaling specifically in mature T cells using genetic loss-of-function approaches in two medically relevant T cell-mediated immune disorders: graft-versus-host disease (GVHD) and experimental autoimmune encephalomyelitis (EAE). We found that inhibition of Notch signaling provided long-term protection from lethal GVHD and EAE in mice. In GVHD, Notch-deprived alloreactive T cells had markedly decreased production of multiple pro-inflammatory cytokines, including IL-17A, and IFNγ, despite preserved expression of the master transcription factors T-bet and Eomesodermin. Notch-inhibited T cells acquired a hyporesponsive phenotype, but maintained in vivo expansion and cytotoxic potential. Notch1/2 and Dll1/4 mediated all the effects of Notch signaling in T cells during GVHD. Therapeutic targeting of the Notch ligands Dll1 and Dll4 prevented GVHD even with a short-course of treatment. In EAE, Notch-deprived T cells had preserved effector differentiation in secondary lymphoid organs but failed to accumulate in the central nervous system (CNS). Parking wild-type T cells with Notch-inhibited T cells allowed Notch-deprived T cells to accumulate in the CNS, although they failed to suppress disease induced by wild-type T cells. Once in the CNS, Notch-deprived T cells produced markedly decreased IL-17A and IFNγ, despite preserved T-bet expression. Collectively, these data suggest that Notch signaling augments T cell responses in a context-dependent fashion. Inhibition of cytokine production with preserved expression of master transcription factors is reminiscent of costimulation blockade in T cells in mouse models of GVHD and EAE. Notch may regulate T cell responses in a context-dependent manner by acting similarly to a costimulatory receptor. Thus, blockade of Notch signaling could be an attractive therapeutic target in T cell-mediated immune disorders.

Published
2013

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