FTY720 Markedly Increases Alloengraftment but Does Not Eliminate Host Anti-Donor T Cells that Cause Graft Rejection on Its Withdrawal

Taylor, Patricia A.; Kelly, Ryan; Bade, Nick D.; Smith, Michelle J.; Stefanski, Heather E.; Blazar, Bruce R.

doi:10.1016/j.bbmt.2012.06.007

Cited by 11 publications

(11 citation statements)

References 34 publications

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“…In the context of non‐myeloablative transplants, FTY720 treatment in mice markedly but only transiently inhibited graft rejection due to the emigration of mature graft rejecting T cells from the host thymus upon drug withdrawal. However, when combined with tolerigenic anti‐CD154 mAb, graft rejection did not occur upon drug withdrawal . In the canine model, graft rejection rates did not differ from non‐treated historical controls .…”

Section: Blockade Of T‐cell Trafficking To Secondary Lymph Nodes Andmentioning

confidence: 90%

“…As with anti‐LFA‐1 and anti‐VLA4, there is also evidence to suggest that FTY720 can prevent acute GVHD, and at least temporarily prevent rejection as assessed in preclinical murine models of transplantation . In murine acute GVHD systems, FTY720 has been shown to prevent GVHD lethality without impairing graft‐versus‐lymphoma or ‐leukemia effects.…”

Section: Blockade Of T‐cell Trafficking To Secondary Lymph Nodes Andmentioning

confidence: 99%

“…In murine acute GVHD systems, FTY720 has been shown to prevent GVHD lethality without impairing graft‐versus‐lymphoma or ‐leukemia effects. Mechanisms in these studies have been attributed to impairing lymphocyte migration, inducing donor anti‐host alloreactive T‐cell apoptosis, and reducing splenic CD11c + cells along with T‐cell responder frequencies . In a chronic GVHD scleroderma model, FTY720 suppressed the immune response by promoting the expansion of Tregs and reducing vascular damage and infiltration of immune cells into the skin.…”

Section: Blockade Of T‐cell Trafficking To Secondary Lymph Nodes Andmentioning

confidence: 99%

“…As with anti-LFA-1 and anti-VLA4, there is also evidence to suggest that FTY720 can prevent acute GVHD, and at least temporarily prevent rejection as assessed in preclinical murine models of transplantation. [200][201][202][203][204][205][206][207][208][209][210][211][212][213][214] In murine acute GVHD systems, FTY720 has been shown to prevent GVHD lethality without impairing graft-versuslymphoma or -leukemia effects. Mechanisms in these studies have been attributed to impairing lymphocyte migration, inducing donor anti-host alloreactive T-cell apoptosis, and reducing splenic CD11c + cells along with T-cell responder frequencies.…”

Section: Blockade Of T-cell Trafficking To Secondary Lymph Nodes Anmentioning

confidence: 99%

“…Mechanisms in these studies have been attributed to impairing lymphocyte migration, inducing donor anti-host alloreactive T-cell apoptosis, and reducing splenic CD11c + cells along with T-cell responder frequencies. 205,208,212,214,215 In a chronic GVHD scleroderma model, FTY720 suppressed the immune response by promoting the expansion of Tregs and reducing vascular damage and infiltration of immune cells into the skin. In contrast to these positive results in GVHD in mice, in a large animal DLA nonidentical acute GVHD model, FTY720 was ineffective in reducing acute GVHD, though the number of recipients studied was somewhat limited.…”

Section: Blockade Of T-cell Trafficking To Secondary Lymph Nodes Anmentioning

confidence: 99%

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Advances in targeting co‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy

Kean

Turka

Blazar

2017

Immunological Reviews

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Summary In the past decade, the power of harnessing T cell co-signaling pathways has become increasingly understood to have significant clinical importance. In cancer immunotherapy, the field has concentrated on two related modalities: First, targeting cancer antigens through highly activated chimeric antigen T cells (CAR-Ts) and second, re-animating endogenous quiescent T cells through checkpoint blockade. In each of these strategies, the therapeutic goal is to re-ignite T cell immunity, in order to eradicate tumors. In transplantation, there is also great interest in targeting T cell co-signaling, but with the opposite goal: in this field, we seek the Yin to cancer immunotherapy’s Yang, and focus on manipulating T cell co-signaling to induce tolerance rather than activation. In this review, we discuss the major T cell signaling pathways that are being investigated for tolerance-induction, detailing pre-clinical studies and the path to the clinic for many of these molecules. These include blockade of co-stimulation pathways and agonism of coinhibitory pathways, in order to achieve the delicate state of balance that is transplant tolerance: a state which guarantees lifelong transplant acceptance without ongoing immunosuppression, and with preservation of protective immune responses. In the context of the clinical translation of immune tolerance strategies, we discuss the significant challenge that is embodied by the fact that targeted pathway modulators may have opposing effects on tolerance based on their impact on effector versus regulatory T cell biology. Achieving this delicate balance holds the key to the major challenge of transplantation: lifelong control of alloreactivity while maintaining an otherwise intact immune system.

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Section: Blockade Of T‐cell Trafficking To Secondary Lymph Nodes Andmentioning

confidence: 90%

Section: Blockade Of T‐cell Trafficking To Secondary Lymph Nodes Andmentioning

confidence: 99%

Section: Blockade Of T‐cell Trafficking To Secondary Lymph Nodes Andmentioning

confidence: 99%

Section: Blockade Of T-cell Trafficking To Secondary Lymph Nodes Anmentioning

confidence: 99%

Section: Blockade Of T-cell Trafficking To Secondary Lymph Nodes Anmentioning

confidence: 99%

See 3 more Smart Citations

Advances in targeting co‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy

Kean

Turka

Blazar

2017

Immunological Reviews

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In vivo engineering of mobilized stem cell grafts with the immunomodulatory drug FTY720 for allogeneic transplantation

et al. 2016

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The immunological attributes of stem cell grafts play an important role in the outcome of allogeneic stem cell transplants. Currently, ex vivo manipulation techniques such as bulk T-cell depletion or positive selection of CD34 + cells are utilized to improve the immunological attributes of grafts and minimize the potential for graft-versus-host disease (GvHD). Here, we demonstrate a novel graft engineering technique, which utilizes the immunomodulatory drug FTY720 for in vivo depletion of naïve T (T N ) cells from donor G-CSF-mobilized grafts without ex vivo manipulation. We show that treatment of donor mice with FTY720 during mobilization depletes grafts of T N cells and prevents lethal GvHD following transplantation in a major mismatch setting. Importantly, both stem cells and NK cells are retained in the FTY720-treated grafts. FTY720 treatment does not negatively affect the engraftment potential of stem cells as demonstrated in our congenic transplants or the functionality of NK cells. In addition, potentially useful memory T cells may be retained in the graft. These findings suggest that FTY720 may be used to optimize the immunological attributes of G-CSF-mobilized grafts by removing potentially deleterious T N cells which can contribute to GvHD, and by retaining useful cells which can promote immunity in the recipient.Keywords: Allogeneic stem cell transplantation r Graft engineering r Graft-versus-host disease r Stem cell mobilization r T cellsAdditional supporting information may be found in the online version of this article at the publisher's web-siteCorrespondence: Dr. Julius G. Juarez e-mail: juliusgjuarez@gmail.com * These authors contributed equally to this work. * * These authors contributed equally to this work as senior co-authors.C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1758-1769 Transplantation and tolerance 1759 IntroductionGraft engineering has played a crucial role in improving allogeneic stem cell transplantation (ASCT) and also broadening its potential application [1]. This has been underpinned by our greater understanding of the different cells that constitute the graft and their contribution to alloresponses [2]. Naïve T (T N ) cells from grafts are the major cells responsible for graft-versus-host disease (GvHD), whereas other cells, such as effector memory T (T EM ), central memory T (T CM ), and NK cells, have potential for promoting immunity and antitumor activity, respectively [1,[3][4][5][6]. In order to mitigate alloresponses by donor T N cells, current graftengineering techniques utilize ex vivo bulk T-cell depletion or positive selection of CD34 + cells. These techniques, however, can leave the graft devoid of useful immune cells, potentially making the recipient more susceptible to infection and relapse [1,2].Techniques specifically targeting depletion of T N cells from grafts could potentially help maximize the capacity of grafts for immune reconstitution, antitumor activity as well as prevention of GvHD in recipients [1,[...

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Targeted delivery as key for the success of small osteoinductive molecules

Balmayor

2015

Advanced Drug Delivery Reviews

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FTY720 Markedly Increases Alloengraftment but Does Not Eliminate Host Anti-Donor T Cells that Cause Graft Rejection on Its Withdrawal

Cited by 11 publications

References 34 publications

Advances in targeting co‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy

Advances in targeting co‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy

In vivo engineering of mobilized stem cell grafts with the immunomodulatory drug FTY720 for allogeneic transplantation

Targeted delivery as key for the success of small osteoinductive molecules

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