June 15, 2015
Editor: Andrew H. Lichtman, MD, PhD, Brigham & Women's Hospital
Editorial Board: Abul K. Abbas, MD, University of California, San Francisco | Carla J. Greenbaum, MD, Benaroya Research Institute | Andrew H. Lichtman, MD, PhD, Brigham & Women's Hospital
|Highlights from Recent Literature|
A review of Julia Cuende et al. Monoclonal antibodies against GARP/TGFβ-1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Science Translational Medicine (2015) 7, 274ra18. PMID: 25904740
Regulatory T cells (Treg) play critical roles in initiating and maintaining self tolerance but they can also interfere with tumor immunity and permit the persistence of chronic infections. One of the mechanisms by which Treg suppress other T cells is by presenting inactive TGFβ1 on the cell surface that becomes activated to immunosuppressive active TGFβ1 by unknown mechanisms. The authors demonstrate that the protein GARP plays a key role in TGFβ1 activation and that a monoclonal antibody that blocks this conversion inhibits Treg function.
By creating and studying antibodies against GARP, a protein that associates with latent TGFβ1 on the surface of Treg, the authors demonstrated that GARP is involved in the activation of TGFβ1 by Treg and that inhibition of this activity abrogates Treg mediated suppression in vitro and in an in vivo human anti-mouse GvHD model. Neutralizing anti-GARP antibodies are therefore a novel new class of Treg inhibitory therapeutics that may be valuable in the treatment of cancers and chronic infections.
Reviewed by Rachael A. Clark, MD, PhD, Brigham and Women's Hospital
A review of Silvia A. Fuertes Marraco, et al. Long-lasting stem cell–like memory CD8+ T cells with a naïve-like profile upon yellow fever vaccination. Science Translational Medicine (2015) 7, 282ra48. PMID:25855494
The yellow fever (YF) vaccine is a live attenuated virus that confers lifelong protection in humans. Protection is thought to be mediated by CD8+ T cells but there are no studies on how immunity is maintained long term. The authors studied long term immune responses in vaccinated patients and found that a stem cell-like population of CD8+ memory T cells persisted and mediated immune protection for decades after vaccination.
The YF vaccine is one of the few vaccines that induces lifelong immunity in humans and the mechanism behind this long term protection was previously unknown. The authors demonstrate that long-term protection against YF in vaccinated patients was mediated by a unique population of T cells that had some features in common with naïve T cells, although they were clearly distinct, and also in common with a recently described population of stem cell-like memory T cells. These studies are the first to identify these cells in humans, implicate them in long-lived immune responses and demonstrate that they can persist for decades. Further studies of this cell type may lead to better vaccination strategies that confer life-long immune protection.
Reviewed by Rachel A. Clark, MD, PhD, Brigham and Women's Hospital
A review of Watanabe et al. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Science Translational Medicine (2015) 279: 279ra39. PMID: 25787765
To better understand the components of the human cutaneous immune response, this study from the Clark lab extends earlier work on murine skin T cells and human cutaneous T cell lymphoma (CTCL) patients to characterize the populations of skin tropic non-recirculating (resident) memory T cells and recirculating T cells.
This group was able to delve deeper than previous studies into the nature and migration patterns of human cutaneous CD4+ T cell responses. They confirmed the presence of four groups of skin tropic human T cells (two recirculating populations and two resident populations). They employed clever tools, including using infant foreskin engrafted onto mice with subsequent PBMC infusion to create inflammation and thus foster the development of the appropriate T cell infiltrate in the graft. In order to fully treat skin diseases including CTCL and psoriasis, we need an increased understanding of the baseline pathways of cutaneous immunity to allow optimization of our therapies. In addition, this knowledge improves our understanding of a fundamental component of our immune system.
Reviewed by Sarah Henrickson, MD, PhD, Children's Hospital of Philadelphia
A review of Cao et al. “Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis.” Science Translational Medicine (2015) 287: 287 PMID: 25972006.
While there are anti-myelin T cells in patients with MS, it has been hard to implicate these cells directly to disease pathogenesis as similar numbers of anti-myelin T cells have been found in healthy controls. What has not been possible to examine previously is whether there is a difference between the function of those cell populations in the two different patient groups. In this study, anti-myelin T cells are isolated from patients with MS and healthy controls and compared functionally (both by cytokine production and proliferation) and transcriptionally.
This study demonstrates that while autoreactive cells can be found in both affected patients with MS and healthy controls, there are functional differences at the levels of proliferation and cytokine production as well as transcriptional differences, in the autoreactive cells from patients versus healthy controls. The functional differences and transcriptional differences link mechanisms proposed in the major murine model of MS (EAE) as well as previous human studies at least in part to the autoreactive cells identified in the MS patients. In addition, protective signatures are seen in the autoreactive cells in healthy controls, which may help explain the presence of the cells without disease in healthy controls. There are many more studies that will need to be performed to further characterize these rare cells in their native state, but this study furthers our understanding of a longstanding paradox in the field.
Reviewed by Sarah Henrickson, MD, PHD, Children's Hospital of Philadelphia
A review of Carreno, B. M. et al. “A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells”. Science 348, 803–808 (2015). PMID:25837513
Melanoma cells harbor up to hundreds of somatic mutations that provide a putative source of tumor-specific neoantigens for personalized tumor vaccines. Although the induction of T cell immunity against tumor mutation-specific neoantigens has been reported, it remains unknown whether vaccination can augment neoantigen-specific T cell responses. Carreno et al. explore the effect of a personalized vaccine on the repertoire of neoantigen specific T cells. The authors sequenced the exomes of three patients with stage 3C cutaneous melanoma, then created and administered a personalized vaccine composed of seven neoepitope peptides pulsed on to autologous dendritic cells.
Carreno et al. provide a valuable paradigm for the discussion of cancer neoepitopes; they classify pre-existing neoantigens as “dominant”, and vaccine-induced neoantigens as “subdominant”. The abundance of these subdominant neoantigens highlights the importance of vaccination in an immunotherapy regimen, as T cells targeting these epitopes are unlikely to arise from immunomodulatory treatment (anti-CTLA4, anti-PD1, etc.) alone. The authors have shown that personalized cancer vaccines are able to induce a strong anti-tumor immune response. The pipeline for the creation of these vaccines is currently too expensive and time consuming for widespread use; however falling sequencing costs and improved in silico methods for antigen identification are bringing personalized vaccine therapy closer to fruition.
Reviewed by Alexander Hopkins, Johns Hopkins University, Cellular and Molecular Medicine Program and Eric Lutz, PhD, Johns Hopkins University, Sidney Kimmel Cancer Center.
Identification of Human T Cell Receptors with Optimal Affinity to Cancer Antigens Using Antigen-negative Humanized Mice
A review of Obenaus, M. et al. “Identification of human T cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice.” Nature Biotechnology 33, 402–407 (2015). PMID: 25774714
High affinity tumor-reactive T cells that bind to unmutated tumor-associated antigens (TAAs) are subject to deletion via central tolerance in the thymus and thus are rarely found in the periphery. Those that do escape deletion are often of low affinity and are susceptible to peripheral tolerance mechanisms. Obenaus et al. use antigen negative, HLA-A2 and human T cell receptor (TCR) transgenic mice to isolate CD8+ T cells specific for the unmutated tumor antigens MAGE-A1 and NY-ESO. These T cells have improved cytolytic activity and interferon (IFN) γ production when compared to MAGE-A1- and NY-ESO-reactive CD8+ T cells isolated from human donors. Furthermore, these TCRs derived from mice exhibit no alloreactivity or functional antigen cross-reactivity, contributing to their potential utility in future adoptive cell therapies.
Isolation of tumor antigen-specific T cells from patients has yielded low avidity T cells due to mechanisms of central and peripheral tolerance, which limits the available repertoire of tumor-reactive T cells. Obenaus et al. demonstrate that antigen-negative hosts expressing cognate human TCR-αβ gene loci and chimeric HLA molecules provide a system for identifying and expanding tumor-reactive T cells with increased functional avidities capable of inducing an anti-tumor response.
Reviewed by Heather Kinkead, Johns Hopkins University, Cellular and Molecular Medicine Program and Eric Lutz, PhD, Johns Hopkins University, Sidney Kimmel Cancer Center
|Highlights From Clinical Immunology, the Official Journal of FOCIS|
A review of Batoulis H. et al. “Central nervous system infiltrates are characterized by features of ongoing B cell-related immune activity in MP4-induced experimental autoimmune encephalomyelitis.” Clinical Immunology. (2015) 158, 47–58 PMID: 25796192
B cell aggregates and perhaps tertiary lymphoid organs (TLOs) form in the meninges of multiple sclerosis (MS) patients, and these have been correlated with more aggressive disease. Nonetheless, the contribution of B cells, antibodies, and TLOs to MS is poorly understood. Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of mice that is widely used as model of human MS. EAE is induced by immunization with myelin proteins and strong adjuvant, but the disease is usually helper T cell dependent. The authors have previously described a B cell-dependent variation of the EAE model, induced by immunization of C57BL/6 mice with MP4, a fusion protein of myelin basic protein (MBP) and parts of proteolipid protein (PLP). In this report, the authors goal was to determine the function and disease impact of B ell infiltrates in the CNS in MP4-EAE. There main findings were:
The authors state that these data are consistent with the development of tertiary lymphoid organs with active germinal centers that contribute to chronic B cell-dependent EAE. Further direct analysis of B cells within aggregates in their model, using laser capture, will be required to better characterize the TLO-like structures. The relationship between their MP4-EAE model, and T cell dependent EAE or human MS, where TLOs are in meninges and not in the cerebellum, remains to be clarified.
Reviewed by Andrew H. Lichtman, MD, PhD, Brigham and Women’s Hospital
A review of Golden-Mason L. et al. “Hepatitis C viral infection is associated with activated cytolytic natural killer cells expressing high levels of T cell immunoglobulin- and mucin-domain-containing molecule-3.”Clinical Immunology (2015) 156, 1–8. PMID 25797693
Chronic viral infections, including hepatitis C virus (HCV) infection, are associated with exhausted T cells which express high levels of various inhibitory molecules, and are unresponsive to viral antigens. Among these inhibitory molecules is T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3). Previous studies have shown highTim-3 expression on human natural killer (NK) cells, but the expression and function of NK Tim-3 in chronic viral infections is not well characterized. In this study, the authors examined Tim-3 expression on NK cells in chronic hepatitis-C virus (HCV)-infected patients. They examined blood NK cells from 37 chronically HCV-infected subjects and 20 uninfected controls, using FACS, qRT-PCR, and functional assays. The findings include the following:
These results show that high Tim-3 expression on NKs in the setting of chronic HCV infection is not a marker of functional exhaustion, but rather of activation and enhanced cytotoxic activity. This is consistent with other published data, but in contrast to studies showing that NK Tim-3 marks exhausted NK cells in HBV infection. The authors advise that more studies on Tim-3 expression and function on different cell types and in different infections are needed to better understand how stimulating and blocking Tim-3 reagents might be considered therapeutically.
Reviewed by: Andrew Lichtman, MD, PhD, Brigham and Women’s Hospital
|Human Immunophenotyping Update|
Catherine A. Blish, MD, PhD, Stanford University School of Medicine
Natural killer (NK) cells are innate lymphocytes that can rapidly respond to tumor or infected cells by killing (cytolysis) or by secreting cytokines. Unlike adaptive T and B lymphocytes that somatically rearrange antigen-specific receptors, NK cells express a variety of germline-encoded activating and inhibitory receptors on their cell surface. These receptors include the killer immunoglobulin-like receptors (KIR), C-type-lectin-like receptors (for example, NKG2A, NKG2C, and NKG2D), leukocyte immunoglobulin-like receptor subfamily b member 1 (LILRB1, also known as ILT-2 and CD85j), natural cytotoxicity receptors (NCRs, including NKp30, NKp44, NKp46, and NKp80), and signaling lymphocyte activation molecule (SLAM) family receptors (for example, 2B4, NTB-A). NK cells also express a variety of adhesion molecules such as CD2 and DNAM-1 that influence their function. These receptors allow NK cells to recognize ‘altered self’ on virus-infected, malignant or stressed cells.
NK cells rely on combinatorial signaling from this diverse array of receptors (1). The inhibitory receptors, which include inhibitory KIR (e.g., KIR3DL1, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5), LILRB1, and NKG2A, are specific for self-HLA class I molecules, and provide an “all clear” or “back off” signal to the NK cell. Engagement of these receptors by HLA dampens the NK cell response. However, engagement of activating receptors, which recognize a variety of stress-related molecules and pathogen- or tumor-derived ligands, activates the NK cells to kill or secrete cytokines by indicating that the cell is a threat. Since the ultimate outcome of the interaction between an NK cell and a target cell is determined by the combinatorial effects of these inhibitory and activating signals, NK cell phenotype and function are closely and uniquely linked.
This vast array of receptors has presented a challenge for the immunophenotyping of NK cells. There has been increasing recognition that the NK cell receptor repertoire, as determined by the expression patterns of this array of receptors, is incredibly complex (2,3). Further complicating this matter is the challenge of determining which cells are actually NK cells, because unlike a B or a T cell, there is no single receptor that defines the subset. In the classic definition, NK cells are broken down into two subsets based on expression of CD56 and CD16 (the FcγRIII). In the peripheral blood, the vast majority (~90%) of NK cells express CD56 at low levels and also express CD16. These CD56dimCD16+ NK cells are considered mature NK cells that are highly effective in cytolysis. The more rare CD16brightCD16- NK cells are thought to be relatively immature NK cells that are specialized for cytokine secretion (4). However, this classification ignores many subsets, including intermediate populations such as rare CD56brightCD16+ NK cells, or the CD56-CD16+ NK cells that are particularly prominent during chronic viral infections (5). Thus, NK cells are best defined as much as what they are not (not B cells, T cells, monocytes, or dendritic cells) as by what they are (lymphocytes with cytolytic activity or cytokine secretion that express CD56 and/or CD16). Finally, within these populations there are a vast array of different subsets based on expression of other NK cell receptors, whose functional significance we are only beginning to unravel. In fact, based on combinatorial expression of 28 NK cell receptors, Horowitz et al. estimated that each individual has between 6,000-30,000 unique NK cell phenotypes, and more than 100,000 subsets in a small population of 22 individuals (3).
With this framework in mind, the first step in immunophenotyping is to carefully identify the NK cell subset. While the most common approach to do this is to identify CD3-CD56+ NK cells, as discussed above, this approach fails to identify CD56- NK cells which are present at varying levels in human subjects. In fact, CD56 expression alone is not particularly specific to NK cells (6), as it is expressed on activated T cells and NKT cells. Of all the NK cell markers, NKp46 is the most specific to NK cells, but like CD56, it is not expressed on all NK cells (6). Thus, the best approach to identify NK cells is to perform serial negative gating.
In standard fluroresence cytometry, a simple approach is to gate first on lymphocytes by forward and side scatter. Depending on the number of channels available, either a single “dump” channel or sequential negative gating should be performed on CD3, CD19 and/or CD20, and CD14 and/or CD33. Then NK cells can be identified as the remaining cells that express CD56 and/or CD16. As monocytes, in particular, can express CD14 and/or CD33 at low levels, this approach can result in some monocytes within the NK cell gate. This can be avoided by adding a stain for CD7, as NK cells and T cells, but not monocytes, express CD7 (7). Thus, NK cells are CD3-CD19-CD20-CD33-CD14-CD7+ cells that express either CD56 or CD16. In mass cytometry, or CyTOF, more channels are available; however, there is no forward or side scatter to help identify lymphocytes vs. monocytes. Thus, in addition to the scheme recommended above, additional gating to avoid CD56-HLA-DRbright cells and LILRB1bright cells will help to further decrease the number of monocytes inadvertently included in the NK cell gate (6).
Once NK cells have been identified, antibodies to a variety of NK receptors or functions can be used. Beziat and colleagues have recently reported a detailed flow cytometry method to identify KIR gene expression patterns in peripheral blood mononuclear cells (8). CyTOF, with it ability to identify up to 42 parameters simultaneously, is currentlyt the most comprehensive platform to identify expression patterns of multiple classes of NK cell receptors, including KIRs, C-type lectin-like receptors, LILRB1, natural cytotoxicity receptors, and adhesion molecules (3,6). The specific receptors queried should be tailored to the question.
With the new attention to the potential of harnessing NK cells in immunotherapeutic approaches(9,10), it is becoming increasingly apparent that we need to identify which subsets of NK cells should be targeted. For this to be effective, stringent efforts to identify NK cells by flow cytometry, with particular attention to avoiding monocyte inclusion in NK cell gates, will be critical. Given the vast array of surface receptors expressed by NK cells, highly parametric flow cytometry techniques, including new use of highly intense fluorescent dyes (11), or the use of the highly parametric mass cytometry platform (12), will be central to these efforts.
|Selected Recent Clinical Trial Results|
Clinical Trial: George Du Toit, Graham Roberts, Peter Sayre, et.al. “Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy.” New England Journal of Medicine 2015;372(9):803-813
Disease: Peanut allergy
Intervention: Consumption of peanuts or avoidance of peanuts until age 5 in infants with eczema and/or egg allergy.
Why the Trial is of Interest to the Broader FOCIS community:
The prevalence of peanut allergies in Western countries has doubled in the past 10 years and represents a significant lifestyle and financial burden to individuals and families (1). The mainstay of treatment has been avoidance of peanuts when possible, along with preparation for and treatment of accidental exposures. However, there has been limited evidence to guide prevention of peanut allergy. In 2000, the American Academy of Pediatrics (AAP) published guidelines advising parents to delay the introduction of peanuts to children at high risk of allergies until age 3. In 2008, the AAP revised its guidelines, stating that there was no evidence that delayed introduction of particular foods beyond 4-6 months (the current age at which parents are advised to introduce solid foods) would prevent allergies. The 2008 AAP revision was supported by increasing observational data suggesting that early and sustained oral exposure to peanut protein could reduce the risk of clinical peanut allergy. In particular, a 2008 study conducted by the same investigators as the reviewed study compared Jewish children raised in Israel, where peanut protein is introduced at a median age of 7 months, to Jewish children raised in the UK, where peanut consumption in infancy is discouraged. It was found that school age children in the UK have 10-fold higher rate of peanut allergy than school age children in Israel (2). The reviewed study, the Learning Early About Peanut Allergy (LEAP) Study was launched from the 2008 study and is the first randomized trial to demonstrate that earlier and sustained exposure to peanut protein may prevent peanut allergies in at-risk individuals.
Submitted by Sandra Lord, MD, Benaroya Research Institute
Effects Of High-dose Oral Insulin on Immune Responses in Children at High Risk for Type 1 Diabetes: The Pre-point Randomized Clinical Trial
Clinical Trial: Ezio Bonifacio, Anette-G Ziegler, Georgeanna Klingensmith, et. al, Effects of High-Dose Oral Insulin on Immune Responses in Children at High Risk for Type 1 Diabetes: the Pre-POINT Randomized Clinical Trial. JAMA, 2015;313(15):1541-1549
Disease: Islet autoimmunity/Type 1 diabetes (TID)
Drug: Oral insulin
Why the Trial is of Interest to the Broader FOCIS Community:
The Pre-POINT study was a dose-finding and feasibility study in anticipation of the phase 2 POINT study to determine if oral insulin can delay or prevent TID in those at high risk based on HLA haplotype and family history. The study aimed to correlate specific oral insulin dosing in this islet antibody negative group with desirable and expected immune responses. The results support the plan to use the higher dose in the fully powered POINT trial. Nonetheless, this pilot study highlights the difficulties in making such judgements; few responses were seen overall and whether these are salutatory will depend on the definitive study.
Submitted by Sandra Lord, MD, Benaroya Research Institute
Clinical Trial: Monteleone G., Neurath M., Ardizzone, et al. Monbersen, an Oral SMAD7 Antisense Oligonucleotide, and Crohn’s Disease. New England Journal of Medicine 2015:372:1104-13
Disease: Active Crohn’s Disease (CD)
Drug: Mongersen, an oral SMAD7 Antisense oligonucleotide. SMAD7 acts as an inhibitor of the immunosuppressive cytokine TGF-β1. Mongerson targets ileal and colonic SMAD7, via an anti-sense mechanism that facilitates SMAD7 messenger RNA degradation.
Why the Trial is of Interest to the Broader FOCIS Community:
Mongersen belongs to a promising new category of therapy for Crohn’s Disease (CD) and other diseases; namely, antisense oligonucleotide therapy. Antisense oligonucleotides bind to messenger RNA, preventing gene translation and effectively turning the gene off. Antisense therapies have been studied as potential drugs for infections, cancers, inflammatory disorders, and genetic disorders. To date, mongersen is the third antisense drug to be approved by the FDA. Fomivirsen is approved for treatment of cytomegalovirus retinitis, and mipomersen for treatment of homozygous familial hypercholesterolemia.
There is an unmet need for additional therapies for CD, as one-third of patients with CD do not respond to currently available therapies, including anti-TNFα antibodies (infliximab, adalimumab, certolizumab pegol), anti-integrin antibodies (vedolizumab, natalizumab) and immunomodulating drugs (azathioprine, 6-mercaptopurine, methotrexate). In addition, the efficacy of TNFα therapies decreases over time, there is no evidence that the TNFα therapies reduce overall disease progression, and there is a risk of infection and malignancy with long term usage. In CD, TGF-β1 intracellular signaling is blocked by the SMAD7 protein (1;2). TGF-β1 has several anti-inflammatory/pro-regulatory effects, including: inhibition of effector T cell proliferation and differentiation, induction of regulatory T cells, reduced macrophage activation and reduced dendritic-cell maturation (3). Mongersen is a SMAD7 antisense oligonucelotide which facilitates mRNA degradation and decreases SMAD7 to increase TGF-b signaling. It provides specific targeting to the terminal ileum and right colon (the most commonly affected areas in CD) via a pH-dependent coating of the tablet. In this phase 2 trial, participants treated with mongersen experienced 2 week remission rates of 65% and 55% with the 2 highest doses, compared to 10% in the placebo group. By comparison, reported remission rates seen in the large trials of TNFα inhibitors in moderate-severe CD range are 32.5-36% (4;5), and remission rates seen with vedolizumab (an LPAM1 antibody, which selectively blocks gut integrin activity) are 14.5-39% (6). Furthermore, despite only 2 weeks of treatment, the majority of participants (62% and 67% in the 40 mg and 160 mg groups respectively) who were in remission after 2 weeks remained in remission after 12 weeks of follow-up. This contrasts with the rapid relapse typically seen after withdrawal of other anti-inflammatory agents.
There are some important caveats to consider. There was limited evaluation of objective markers of disease activity. Namely, there were no required endoscopic evaluations, either at entry or endpoint; therefore, it’s not known whether improvements in CDAI scores correspond to mucosal healing. The CDAI is somewhat subjective: of the 8 criteria, 3 are patient-reported. Moreover, fecal calprotectin, a stool test for colonic inflammation, was not measured. CRP was measured, but interestingly, there was no correlation between clinical response and normalization of CRP. As the investigators suggest, there may be lag between clinical response and normalization of CRP. In addition, treatment duration and follow up (2 weeks and 12 weeks, respectively) were relatively brief, which should impact any conclusions that are made about safety and efficacy. Although there were no significant safety issues identified, longer-term data is needed. There was one instance of intestinal obstruction, which is a known complication of CD, but given that TGFβ1 can promote fibrosis (7;8), this might be of special interest.
Mongersen’s specific targeting to the terminal ileum and right colon is both a strength and a limitation; although it does not appear to have systemic side effects, it also may not be effective for extra-intestinal manifestations of CD or for perianal disease, the latter of which affects about half of patients with CD.
Despite these caveats, mongersen may represent an entirely new, safe, and effective category of Crohn’s Disease therapy. Antisense therapies have been studied for potential treatment of infections and genetic disorders. To date, mongersen is the third antisense drug to be approved by the FDA. Fomivirsen is approved for treatment of cytomegalovirus retinitis, and mipomersen for treatment of homozygous familial hypercholesterolemia. Follow up studies are needed, to include both longer duration of follow up and additional objective measures of disease activity.
Submitted by Sandra Lord, MD, Benaroya Research Institute
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