Monocytes and γδ T cells control the acute-phase response to intravenous zoledronate: Insights from a phase IV safety trial

Welton, Joanne L.; Kift-Morgan, Ann; Martí, S.; Stone, Michael D.; Moser, Bernhard; Sewell, Andrew K.; Turton, Jane F.; Eberl, Matthias

doi:10.1002/jbmr.1797

Cited by 63 publications

(64 citation statements)

References 42 publications

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“…In reminiscence of the earlier observation of CD80 upregulation on circulating DCs in zoledronate-treated HIV patients [54], our own clinical trial in otherwise healthy individuals with osteoporosis demonstrated a significant although transient increase in the surface expression of CD14, CD40, CD80, and HLA-DR of circulating CD14 + monocytes after first time treatment with zoledronate [65]. This study also identified pre-treatment levels of monocytes and central/memory Vc9/Vd2 T cells as predictive risk factors for the occurrence of subclinical and clinical symptoms, in support of the interaction of these two cell types in vivo.…”

Section: Differentiation Of Monocytes: Local Generation Of Inflammatomentioning

confidence: 51%

“…Monocytes are critical for the activation and proliferation of Vc9/Vd2 T cells in response to neutrophil-released microbial compounds [9,10], and are thus likely to drive early inflammatory responses in acute microbial infections [60], which can be mimicked in vitro by providing soluble HMB-PP [61,62]. In addition, monocytes are also essential for Vc9/Vd2 T cell responses to aminobisphosphonates such as zoledronate by facilitating uptake of these compounds through endocytosis and intracellular accumulation of IPP [63][64][65]. However, only a few studies have examined the feedback of activated Vc9/Vd2 T cells on monocytes.…”

Section: Differentiation Of Monocytes: Local Generation Of Inflammatomentioning

confidence: 99%

“…In addition, monocytes are also essential for Vc9/Vd2 T cell responses to aminobisphosphonates such as zoledronate by facilitating uptake of these compounds through endocytosis and intracellular accumulation of IPP [63][64][65]. However, only a few studies have examined the feedback of activated Vc9/Vd2 T cells on monocytes.…”

Section: Differentiation Of Monocytes: Local Generation Of Inflammatomentioning

confidence: 99%

“…Naturally, local access to inflamed tissues and draining lymph nodes in humans is very limited, thereby severely compromising investigations into the APC function of Vc9/Vd2 T cells -or, as a matter of fact, into the APC function of any human immune cell. Indirect support for a possible role as APC stems from observations that HLA-DR is expressed by activated Vc9/Vd2 T cells in patients with severe inflammation or during acute infection [123,[138][139][140], and in patients receiving intravenous zoledronate with and without IL-2 [65,141,142]. However, functional evidence into the potential of activated Vc9/Vd2 T cells to act as APC ex vivo is only beginning to emerge [123,143].…”

Section: Priming Of Cd4 + and Cd8 + T Cells By Vc9/vd2 T Cells: A Newmentioning

confidence: 99%

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Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

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a b s t r a c tUnconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vc9/Vd2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vc9/Vd2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines.Ó 2015 Published by Elsevier Inc. Introduction cd T cells represent a third lineage of lymphocytes expressingre-arranged antigen receptors that co-evolved with 'classical' B cells and ab T cells over 400 million years, arguing for a crucial and non-redundant contribution of each lymphocyte to effective immune responses, and hence the evolutionary survival of all jawed vertebrate species [1]. 30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition. However, the manifold contributions of cd T cells to homeostasis, inflammation, infection and tumor surveillance have historically been neglected and are only beginning to be integrated into comprehensive models of the immune system [1][2][3][4][5][6][7].1. Innate-like pattern recognition by human Vc9/Vd2 T cells Like other 'unconventional' T cells carrying an ab TCR such as mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells, cd T cells are characterized by a markedly restrictedTCR usage that allows them to recognize self and non-self molecules in the absence of classical antigen presentation via MHC I or MHC II. Vc9/Vd2 + cd T cells represent the major cd T cell subset in human peripheral blood where they typically comprise 1-5% in healthy adults [8]. In many microbial infections, Vc9/Vd2 T cells increase locally and/or systemically [9,10] and can reach in excess of 50% of all peripheral T cells within a matter of days [11], revealing a fundamental role of this unconventional T cell population in acute disease and suggesting their exploitation for diagnostic and therapeutic purposes [12][13][14]. Vc9/Vd2 T cells uniformly respond to a class of low molecular weight molecules often referred to as 'phosphoantigens' that represent metabolites of the isoprenoid biosynthesis...

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Section: Differentiation Of Monocytes: Local Generation Of Inflammatomentioning

confidence: 51%

Section: Differentiation Of Monocytes: Local Generation Of Inflammatomentioning

confidence: 99%

Section: Differentiation Of Monocytes: Local Generation Of Inflammatomentioning

confidence: 99%

Section: Priming Of Cd4 + and Cd8 + T Cells By Vc9/vd2 T Cells: A Newmentioning

confidence: 99%

See 2 more Smart Citations

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

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“…The clinical benefit may in fact stem, at least in part, from the activity of zoledronate on the patient's immune system by specifically stimulating V␥9/V␦2 T cells, which compose 0.5%-5% of circulating T cells in healthy adults [5]. Targeted immunotherapy studies directly exploiting the potent non-major histocompatibility complexrestricted cytotoxicity of V␥9/V␦2 T cells have shown excellent safety profiles and promising clinical observations in a variety of hematological and solid cancers [6], including metastatic breast cancer [7].Studies by us and others have demonstrated that zoledronate treatment induces a rapid and long-lasting conversion of the peripheral V␥9/V␦2 T-cell phenotype from CD27 ϩ CD45RA Ϫ central memory T (T CM ) cells to CD27 Ϫ CD45RA Ϫ effector memory T (T EM ) cells in many, but not all, individuals [7][8][9]. In Figure 1, zoledronate-treated breast cancer patients with stable disease showed elevated proportions of V␥9/V␦2 T EM cells at the time of blood sampling compared with patients with progressing disease and untreated controls (Fig.…”

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confidence: 99%

γδ T Cells Predict Outcome in Zoledronate-Treated Breast Cancer Patients

et al. 2013

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We read with great interest the article by Valachis et al. [1], published in The Oncologist. In a comprehensive meta-analysis of 15 randomized clinical trials on adjuvant therapy for breast cancer patients with zoledronate, the authors identified a significant overall survival benefit with zoledronate treatment, in agreement with one smaller meta-analysis [2] but not another [3] conducted earlier. These new findings support the call for zoledronate to be considered as a new standard of care in adjuvant breast cancer therapy [4].The dilemma remains that the biological mechanism underlying the antitumor role of zoledronate is unclear, as Valachis et al. correctly highlight [1]. The clinical benefit may in fact stem, at least in part, from the activity of zoledronate on the patient's immune system by specifically stimulating V␥9/V␦2 T cells, which compose 0.5%-5% of circulating T cells in healthy adults [5]. Targeted immunotherapy studies directly exploiting the potent non-major histocompatibility complexrestricted cytotoxicity of V␥9/V␦2 T cells have shown excellent safety profiles and promising clinical observations in a variety of hematological and solid cancers [6], including metastatic breast cancer [7].Studies by us and others have demonstrated that zoledronate treatment induces a rapid and long-lasting conversion of the peripheral V␥9/V␦2 T-cell phenotype from CD27 ϩ CD45RA Ϫ central memory T (T CM ) cells to CD27 Ϫ CD45RA Ϫ effector memory T (T EM ) cells in many, but not all, individuals [7][8][9]. In Figure 1, zoledronate-treated breast cancer patients with stable disease showed elevated proportions of V␥9/V␦2 T EM cells at the time of blood sampling compared with patients with progressing disease and untreated controls (Fig. 1A). No such differences were observed with regard to patient age, time on treatment, or pretreatment clinical status. We then stratified the same patient cohort according to their follow-up disease status at 3-9 months after blood sampling. This showed successful conversion from T CM to T EM cells (as evident by a lower frequency of T CM cells) in patients who were stable 3-9 months after blood sampling compared with patients who went on to show progressing disease (Fig. 1B).Our analysis illustrates the diagnostic and prognostic potential of a ␥␦ T-cell-based blood test and implies a link between immune responsiveness and positive outcome with zoledronate therapy, thereby contributing to our understanding of the as yet unexplained clinical benefit of adjuvant therapy. These findings are particularly intriguing because new treatments specifically targeting bone resorption, such as denosumab, lack this potential to act on CD45RAϪ centralmemoryTcellsinrelationtosubsequent clinical outcome at 3-9 months after sampling. Patients received at least two cycles of zoledronic acid (Zometa; Novartis International, Basel, Switzerland, http://www.novartis.com) for Ͼ1 monthandϽ8monthsandhadnootheractivemalignancieswithinthe previousyear;noactiveoruncontrolledinfections;noautoimmunedisorders or ...

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Gamma delta T cells in non‐immune patients during primary schistosomal infection

Schwartz

Rosenthal

Bank

2014

Immunity Inflam & Disease

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The mevalonate pathway is critical for the survival of Schistosoma. γδ T cells, a small subset of peripheral blood (PB) T cells, recognize low molecular weight phosphorylated antigens in the mevalonate pathway, which drive their expansion to exert protective and immunoregulatory effects. To evaluate their role in schistosomiasis, we measured γδ T cells in the PB of non-immune travelers who contracted Schistosoma hematobium or Schistosoma mansoni in Africa. The maximal level of γδ T-cells following infection was 5.78 ± 2.19% of the total T cells, versus 3.72 ± 3.15% in 16 healthy controls [P = 0.09] with no difference between S. hematobium and S. mansoni in this regard. However, among the nine patients in the cohort who presented with acute schistosomiasis syndrome (AS), the level (3.5 ± 1.9%) was significantly lower than in those who did not (8.6 ± 6.4%, P < 0.05), both before and after therapy. Furthermore, γδ T cells increased significantly in response to praziquantel therapy. In a patient with marked expansion of γδ T cells, most expressed the Vδ2 gene segment, a hallmark of cells responding to cognate antigens in the mevalonate pathways of the parasite or the human host. These results suggest an immunoregulatory role of antigen responsive γδ T cells in the clinical manifestations of early schistosomal infection.

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Monocytes and γδ T cells control the acute-phase response to intravenous zoledronate: Insights from a phase IV safety trial

Cited by 63 publications

References 42 publications

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

γδ T Cells Predict Outcome in Zoledronate-Treated Breast Cancer Patients

Gamma delta T cells in non‐immune patients during primary schistosomal infection

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