FTY720 treatment of kidney transplant patients: A differential effect on B cells, naïve T cells, memory T cells and NK cells

Vaessen, L. M. B.; Besouw, Nicole M. van; Mol, Wendy M.; IJzermans, Jan N.M.; Weimar, Willem

doi:10.1016/j.trim.2006.02.002

Cited by 39 publications

(37 citation statements)

References 30 publications

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“…Therefore, it is conceivable that tissue‐activated CD2 − CD25 + NK cells arriving in the LNs also egress from the LNs through the efferent lymphatic vessel and circulate in a primed state in steady‐state conditions. T and B cells use sphingosine‐phosphate‐receptor 1 (S1P1) to egress from peripheral lymphoid organs;36, 37 however, down‐regulation of S1P1 through administration of FTY720, did not deplete NK cells from the circulation of mice or humans 38, 39. Consequently, it was demonstrated that NK cells express sphingosine‐phosphate‐receptor 5 (S1P5), which permits NK cell exit from the bone marrow and LNs in mice 40, 41.…”

Section: Discussionmentioning

confidence: 99%

Frequency and phenotype of natural killer cells and natural killer cell subsets in bovine lymphoid compartments and blood

et al. 2017

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SummaryNatural killer (NK) cells are widely distributed in lymphoid and non‐lymphoid tissues, but little is known about the recirculation of NK cells between blood and tissues. This is relevant to understanding recirculation in the steady‐state and also for determining the roles for NK cells in vaccine‐induced immunity and responses to infection. Therefore, the percentage of NK cells and their phenotype across peripheral blood, afferent lymph and lymph nodes in steady‐state conditions was investigated in cattle using the pseudo‐afferent lymphatic cannulation model. CD2+ CD25lo NK cells were the predominant subset of NK cells within the blood. In contrast, CD2− CD25hi NK cells were the main subset present within the skin‐draining afferent lymphatic vessels and lymph nodes, indicating that CD2− NK cells are the principal NK cell subset trafficking to lymph nodes via the afferent lymphatic vessel. Furthermore, a low percentage of NK cells were present in efferent lymph, which were predominantly of the CD2− subset, indicating that NK cells can egress from lymph nodes and return to circulation in steady‐state conditions. These compartmentalization data indicate that NK cells represent a population of recirculating lymphocytes in steady‐state conditions and therefore may be important during immune responses to vaccination or infection.

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Section: Discussionmentioning

confidence: 99%

Frequency and phenotype of natural killer cells and natural killer cell subsets in bovine lymphoid compartments and blood

et al. 2017

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“…Although the relative proportion of NK cells within the overall circulating lymphoid population is increased in FTY720-treated MS patients, previous studies have reported that absolute numbers of NK lymphocytes in FTY720-treated mice and humans are unaltered (9,28). In the present study we investigated the relationship of NK cell subset redistribution in FTY720-treated patients based on expression of CCR7.…”

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confidence: 90%

Reduction of the Peripheral Blood CD56bright NK Lymphocyte Subset in FTY720-Treated Multiple Sclerosis Patients

Johnson

Evans

Durafourt

et al. 2011

The Journal of Immunology

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FTY720 (fingolimod) treatment of multiple sclerosis (MS) results in lymphopenia due to increased recruitment into and decreased egress from secondary lymphoid organs of CCR7+ lymphocytes. Although absolute numbers of NK lymphocytes were reported as being unaltered in FTY720-treated MS patients (MS-FTY), such analyses did not detect a change in a minor subset. Because expression of CCR7 has been described on CD56bright NK cells, a minority population of NK cells, we investigated the effect of FTY720 treatment on the phenotype and function of human NK cells in the peripheral circulation of MS patients. MS-FTY patients displayed a decreased proportion of peripheral CD56brightCD62L+CCR7+ NK cells compared with untreated MS and healthy donors. In vitro treatment with FTY720-P increased migration of untreated donor NK cells to CXCL12 while reducing the response to CX3CL1 with similar migration responses seen in NK cells from MS-FTY patients. FTY720-P inhibited sphingosine 1-phosphate–directed migration of CD56bright and CD56dim NK cells subsets from untreated healthy donors. IL-12– and IL-15–stimulated NK cells from MS-FTY patients displayed similar capacity to produce IFN-γ, TNF, IL-10, and MIP-1α cytokines/chemokines compared with NK cells from untreated healthy donors and displayed comparable levels of degranulation in response to K562 tumor cells compared with untreated donors. Subset alterations and function of NK cell populations will need to be considered as part of assessing overall immunosurveillance capacity of patients with MS who will receive sustained FTY720 therapy.

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“…Disruption of the S1P/S1P1 axis leads to inhibition of this egress and accumulation of T N cells in secondary lymphoid organs. Lymphocytes such as T EM cells are less affected due to their different trafficking routes and NK cells are similarly less affected as they utilize a different S1P receptor to exit lymph nodes [8,[11][12][13]. This specific property of T N cells has been exploited in relapsing-remitting multiple sclerosis with the use of the immunomodulatory agent FTY720 [14].…”

Section: Introductionmentioning

confidence: 99%

“…This specific property of T N cells has been exploited in relapsing-remitting multiple sclerosis with the use of the immunomodulatory agent FTY720 [14]. FTY720 disrupts the S1P/S1P1 axis by inducing internalization and degradation of the S1P1 receptor [14], which leads to rapid sequestration of T N cells, as well as B cells into secondary lymphoid organs and their depletion from peripheral blood (PB) [11]. While the immunomodulatory properties of FTY720 have been studied in various inflammatory conditions as a way of impacting disease, its use in manipulating mobilized stem cell grafts has not previously been examined [11,12,15,16].…”

Section: Introductionmentioning

confidence: 99%

“…FTY720 disrupts the S1P/S1P1 axis by inducing internalization and degradation of the S1P1 receptor [14], which leads to rapid sequestration of T N cells, as well as B cells into secondary lymphoid organs and their depletion from peripheral blood (PB) [11]. While the immunomodulatory properties of FTY720 have been studied in various inflammatory conditions as a way of impacting disease, its use in manipulating mobilized stem cell grafts has not previously been examined [11,12,15,16]. Currently, the majority of hematopoietic stem cell transplants are performed using G-CSF-mobilized PB stem cell grafts [17].…”

Section: Introductionmentioning

confidence: 99%

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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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FTY720 treatment of kidney transplant patients: A differential effect on B cells, naïve T cells, memory T cells and NK cells

Cited by 39 publications

References 30 publications

Frequency and phenotype of natural killer cells and natural killer cell subsets in bovine lymphoid compartments and blood

Frequency and phenotype of natural killer cells and natural killer cell subsets in bovine lymphoid compartments and blood

Reduction of the Peripheral Blood CD56bright NK Lymphocyte Subset in FTY720-Treated Multiple Sclerosis Patients

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

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