The contextual role of TNFR family members in CD8(+) T-cell control of viral infections.

Immunity to viruses must be tightly controlled to avoid pathology. Receptors and ligands of the tumor necrosis factor (TNF) family play important roles in controlling lymphocyte activation and survival during an immune response. The role of specific TNF receptor (TNFR) family members in antiviral immunity depends on the stage of the immune response and can vary with the virus type and its virulence. Here, we focus on five members of the TNFR family that are prominently expressed on CD8(+) T cells during viral infections, namely, 4-1BB (CD137), CD27, OX40 (CD134), GITR, and TNFR2. 4-1BB, CD27, OX40, and GITR have primarily prosurvival roles for CD8(+) T cells during viral infection, although under some circumstances 4-1BB, GITR, or CD27 signals can limit immunity. Although TNFR2 can be costimulatory under some circumstances, its main role in CD8(+) T-cell responses during viral infection appears to be in contraction of the response. Several TNF family ligands are being explored as adjuvants for viral vaccines, and agonistic antibodies to TNFR family members are being investigated for immunotherapy of chronic viral infection alone and in combination with checkpoint blockade. Such therapies will require thorough and specific optimization to avoid pathology induced by hyperstimulation of these pathways.

T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapy.

GITR [glucocorticoid inducible tumor necrosis factor receptor (TNFR)-related protein] and 4-1BB are costimulatory TNFR family members that are expressed on regulatory and effector T cells as well as on other cells of the immune system. Here we discuss the role of GITR and 4-1BB on T cells during viral infections and in cancer immunotherapy. Systemic treatment with agonistic anti-4-1BB antibody leads to a number of immune system abnormalities, and clinical trials of anti-4-1BB have been terminated. However, other modes of 4-1BB ligation may be less toxic. To date, similar toxicities have not been reported for anti-GITR treatment of mice, although anti-GITR antibodies can exacerbate mouse autoimmune models. Intrinsic effects of GITR and 4-1BB on effector T cells appear to predominate over their effects on other cell types in some models. Despite their similarities in enhancing T-cell survival, 4-1BB and GITR are clearly not redundant, and both pathways are required for maximal CD8(+) T-cell responses and mouse survival following severe respiratory influenza infection. GITR uses TNFR-associated factor (TRAF) 2 and TRAF5, whereas 4-1BB recruits TRAF1 and TRAF2 to mediate survival signaling in T cells. The differential use of signaling adapters combined with their differential expression may explain the non-redundant roles of GITR and 4-1BB in the immune system.

Opposing roles for TRAF1 in the alternative versus classical NF-κB pathway in T cells.

T cells lacking TRAF1 hyperproliferate in response to T cell receptor signaling but have impaired signaling downstream of specific TNFR family members such as 4-1BB. Here we resolve this paradox by showing that while TRAF1 is required for maximal activation of the classical NF-κB pathway downstream of 4-1BB in primary T cells, TRAF1 also restricts the constitutive activation of NIK in anti-CD3-activated T cells. Activation of the alternative NF-κB pathway is restricted in unstimulated cells by a cIAP1/2:TRAF2:TRAF3:NIK complex. Using knockdown of NIK by siRNA we show that in activated CD8 T cells TRAF1 is also involved in this process and that constitutive activation of the alternative NF-κB pathway is responsible for costimulation independent hyperproliferation and excess cytokine production in TRAF1-deficient CD8 T cells compared with WT CD8 T cells. The T cell costimulatory molecule 4-1BB critically regulates the survival of activated and memory CD8 T cells. We demonstrate that stimulation through 4-1BB induces cIAP1-dependent TRAF3 degradation and activation of the alternative NF-κB pathway. We also show that while both TRAF1 and cIAP1 have non-redundant roles in suppressing the alternative NF-κB pathway in T cells activated in the absence of costimulation, activation of the classical NF-κB pathway downstream of 4-1BB requires TRAF1, whereas cIAP1 plays a redundant role with cIAP2. Collectively these results demonstrate that TRAF1 plays a critical role in regulating T cell activation both through restricting the costimulation independent activation of NIK in activated T cells and by promoting the 4-1BB-induced classical NF-κB pathway.

Immune regulation by 4-1BB and 4-1BBL: complexities and challenges.

SUMMARY: The tumor necrosis factor receptor family member 4-1BB plays a key role in the survival of activated and memory CD8(+) T cells. Depending on the disease model, 4-1BB can participate at different stages and influence different aspects of the immune response, likely due to the differential expression of receptor and ligand relative to other costimulatory molecules. Studies comparing mild versus severe influenza infection of mice suggest that the immune system uses inducible receptors such as 4-1BB to prolong the immune response when pathogens take longer to clear. The expression of 4-1BB on diverse cell types, evidence for bidirectional as well as receptor-independent signaling by 4-1BBL, the unexpected hyperproliferation of 4-1BB-deficient T cells, and complex effects of agonistic anti-4-1BB therapy have revealed additional roles for the 4-1BB/4-1BBL receptor/ligand pair in the immune system. In this review, we discuss these diverse roles of 4-1BB and its ligand in the immune response, exploring possible mechanisms for the observed complexities and implications for therapeutic applications of 4-1BB/4-1BBL.

CD8 T cell-intrinsic GITR is required for T cell clonal expansion and mouse survival following severe influenza infection.

The regulation of T cell expansion by TNFR family members plays an important role in determining the magnitude of the immune response to pathogens. As several members of the TNFR family, including glucocorticoid-induced TNFR-related protein (GITR), are found on both regulatory and effector T cells, there is much interest in understanding how their effects on these opposing arms of the immune system affect disease outcome. Whereas much work has focused on the role of GITR on regulatory T cells, little is known about its intrinsic role on effector T cells in an infectious disease context. In this study, we demonstrate that GITR signaling on CD8 T cells leads to TNFR-associated factor (TRAF) 2/5-dependent, TRAF1-independent NF-κB induction, resulting in increased Bcl-x(L). In vivo, GITR on CD8 T cells has a profound effect on CD8 T cell expansion, via effects on T cell survival. Moreover, GITR is required on CD8 T cells for enhancement of influenza-specific CD8 T cell expansion upon administration of agonistic anti-GITR Ab, DTA-1. Remarkably, CD8 T cell-intrinsic GITR is essential for mouse survival during severe, but dispensable during mild respiratory influenza infection. These studies highlight the importance of GITR as a CD8 T cell costimulator during acute viral infection, and argue that despite the similarity among several TNFR family members in inducing T lymphocyte survival, they clearly have nonredundant functions in protection from severe infection.

Interviews and internet forums: a comparison of two sources of qualitative data.

We report a comparative keyword analysis of interviews and Internet postings involving people with breast and prostate cancer and discussion of sexual health. Interviewees produce retrospective accounts, their content guided by interviewers' questions, which might elicit rich biographical and contextual details. Internet exchanges concern participants' current experiences and contain detailed accounts of disease processes, medical procedures, bodily processes, and, in the case of sexual health, sexual practices. They are used by participants to exchange information and support in a relatively anonymous context. Because of the ease with which large amounts of such archived Internet materials can be accessed and analyzed, this source has considerable potential for direct observation of illness experiences, although some disadvantages also exist. This reverses an earlier situation where observational research was more laborious than qualitative interviews. Observational material for research purposes is, through the Internet, now easy to obtain and produces naturalistic data.

What affects the uptake of screening for bowel cancer using a faecal occult blood test (FOBt): a qualitative study.

Screening can reduce bowel cancer mortality. The UK National Health Service Bowel Cancer Screening Programme (NHS BCSP), using the Faecal Occult Blood test (FOBt), is being introduced over three years in the UK, but in some areas uptake is disappointing. We sought to understand why some people decided to participate in screening for bowel cancer while others did not. Interviews were conducted with 44 men and women invited for screening. Most had decided to take part, some were reluctant, and a few had declined to participate. We aimed for a maximum variation sample. Reasons for accepting screening included: knowing someone with cancer, previous positive experience of women's screening programmes, being a "good citizen", previous bowel problems, and encouragement from others. Reasons for reluctance to take part included: feeling healthy, fear of outcome, lack of time, disgust at the idea of handling stools, concern about posting samples in the mail, misunderstanding instructions, and past (negative) experience or fear of colonoscopy. Theoretical models of health behaviours do not mention the sense of civic responsibility that encourages people to avert (later) costs to the NHS. This may be a particular feature of a socialized health system. Our results also suggest that people might feel more inclined to accept screening if they had current information about patients' experiences of colonoscopy and treatment for early bowel cancer.

Health communication and adolescents: what do their emails tell us?

BACKGROUND: It is widely known that barriers exist in communication between adolescents and health professionals. However, little is known about the actual language used by young people articulating such difficulties and whether email might allow them to overcome these problems. OBJECTIVES: The aims of this study were to investigate concerns and difficulties relating to communication among adolescents seeking online health advice. METHODS: The study design was a corpus linguistic analysis of a million-word adolescent health email database based on 62 794 emails from young people requesting health advice from a prominent UK-hosted and doctor-led website. RESULTS: Young people reported various concerns about their health. They described numerous difficulties in disclosing such concerns to other people, in particular to parents and doctors. However, they readily expressed their concerns by email, displaying elevated levels of directness, particularly in relation to potentially sensitive or embarrassing topics. CONCLUSION: Email has the potential to facilitate and supplement face-to-face consultations with health professionals. Increased adoption of email by health providers may be an efficient means of engaging with a generation often reluctant to access more traditional health care services and thus encourage them to enter the primary care setting more readily.

Why men in the United Kingdom still want the prostate specific antigen test.

The prostate specific antigen (PSA) test is widely used to screen men for prostate cancer, but its value in diagnosing prostate cancer in asymptomatic men is controversial. In 2001, the U.K. Department of Health introduced the Prostate Cancer Risk Management Programme (PCRMP), through which men are given relatively detailed information before they make a final decision about a test. Little is known about men's experiences of the test since this program was introduced. We report an analysis of interviews with 30 men who were tested, or considered having a test, since the PCRMP was introduced. Our analysis suggests that men's views of the PSA test are dominated by their construction of testing as responsible health behavior and their perception of PSA as "just a blood test." Men's accounts also suggest that poor communication about the uncertainty of the test--and about treatment for prostate cancer--also persists.

'Am I normal?' Teenagers, sexual health and the internet.

The development of new communication technologies has created a wide variety of new fields in which human beings can construct identities. The past decade has seen a proliferation of opportunities to use the internet for health related advice and information and many new sites have been created where participants can construct identities, formulate problems and seek solutions concerning health related issues. This paper will report on a study of emails written in to a UK-based website concerned with health issues for young people. Our analysis was driven by corpus linguistics, a computational methodology for interrogating extensive datasets, and we have combined both quantitative and qualitative approaches to the study of language. We interrogated a 400,000 word dataset of messages and were able to identify terms whose usage was elevated compared to the English language as a whole. As well as personal pronouns, these included many terms related to sexual health and bodily development, as well as terms such as 'normal' and 'worried' which were identified for further exploration. Whereas previous research on sexual health has discovered the use of vague terms and euphemisms, here, young people described themselves, their anatomy and their identities in meticulous detail. This study enables us to define the role of health topics raised, the presentation of health concerns, and contributes towards the discovery of a distinctive 'genre' of health messages concerning sexual health which differs from that found by other researchers concentrating on face to face encounters. In conclusion we suggest that for researchers and practitioners working in health with young people in the medium of English there could be valuable lessons in communication to be learned from examination of corpora of the health care language concerned.

Women's information needs about ductal carcinoma in situ before mammographic screening and after diagnosis: a qualitative study.

OBJECTIVES: To explore the attitudes of women with screen-detected ductal carcinoma in situ (DCIS) towards information provision for mammographic screening. SETTING: Respondents recruited throughout the UK during 2003-2004. METHODS: Qualitative study using semi-structured interviews. PARTICIPANTS: Ten women diagnosed with DCIS as a result of mammographic screening. RESULTS: None of the women with DCIS had heard of it before their diagnosis. Most would have liked more information about DCIS when invited for routine screening. Comprehensive information about the benefits and risks of mammographic screening, including the possibility of a DCIS diagnosis, would have enabled them to make a fully informed choice about attending for screening. CONCLUSION: DCIS is an inescapable outcome of mammographic screening and, until it is better understood, the screening industry needs to inform women about its existence and the lack of understanding of its natural history and management. Being alerted before screening to the possibility of a DCIS diagnosis and the uncertainty associated with it would better enable women to make fully informed decisions about whether to attend and could help to alleviate some of the distress women currently feel when diagnosed with DCIS.

The choice is yours? How women with ovarian cancer make sense of treatment choices.

OBJECTIVE: Much has been made of the need for cancer patients to be involved in choices about their treatments. We explore the different approaches to involvement described by women with ovarian cancer and consider why being invited to make a choice can sometimes seem inappropriate and untimely. METHOD: Qualitative interviews were conducted in the UK with women with ovarian cancer. Interviews were audio tape recorded and transcribed for qualitative analysis. The interviews were collected as part of a broader study of experiences of ovarian cancer as part of the DIPEx (personal experiences of health and illness) project which runs a website featuring further analyses and video and audio clips from the interviews. RESULTS: Women did not always recall being involved in decisions -some felt there had been no 'real' decisions to make or said they preferred their medical team to decide on their behalf. Other women described asking questions and seeking second opinions but still 'going along with' their doctor's recommendation. A few women (including some of those who had felt unable to participate in decisions soon after their diagnosis) said that they had learnt enough to take control or make at least some of their own treatment decisions. The manner in which options were offered to women sometimes led to confusion and concern, especially if women felt the doctor was unwilling to express his or her own preference. Some worried that not accepting the doctor's advice would prejudice their future care. CONCLUSION: Patients and doctors are often uncertain how best to share in decisions about treatments. Being asked about their preferences can surprise or shock women. Clinicians need to explain about clinical uncertainty and how individual values and preferences may relate to treatment decisions. Presenting the rationale for choice can be difficult and even when well presented, women can be left feeling ill prepared, panicky and trying to second guess what they think the doctor 'really' wanted them to do. PRACTICE IMPLICATIONS: When patients are invited to make choices their clinicians need to explain about clinical uncertainty and how individual values and preferences may relate to treatment decisions. The options should be communicated in a clear manner, differences in opinion should be acknowledged and the doctor's own preference stated. Patients need to be encouraged and supported to make their decision-whether or not it reflects their doctor's preference. Patients should also be reassured that whichever decision they make their subsequent care and relationship with their medical team will not be adversely affected.

The specialist palliative care nurse: a qualitative study of the patients' perspective.

BACKGROUND: Relatively little is known about patients' perceptions of the work and role of the specialist palliative care nurse. Understanding the patients' perspective can help to evaluate services, improve quality of care, and identify misunderstandings. OBJECTIVES: To explore the experiences of those who said that they had a 'terminal illness', focusing on patients' perceptions of the work and role of these nurses. DESIGN: Qualitative study with narrative interviews. SETTING: England and Wales. PARTICIPANTS: Forty-one people recruited through those working in hospices, community nurses, general practitioners, support groups, a national newspaper, and a conference on palliative care. Twenty-five people talked about the work of specialist palliative care nurses. METHOD: Interviews were fully transcribed; followed by a thematic analysis with constant comparison. RESULTS: Patients valued the nurses' work, particularly their advice on practical matters, information given about their disease, emotional support, advice on symptoms, and help with communication. They were glad that help was readily available. However, some patients who had been referred to the service did not realise that specialist palliative care nurses may be involved at a relatively early stage in a person's illness, and sometimes felt distressed by an early referral. One woman felt she had not had the emotional support she needed and another knew of women who had been upset because these nurses had discussed topics such as place of death 'too early'. However, people recognised the difficulties nurses faced in their work. CONCLUSIONS: Although our study differs from other studies, particularly in the way people were recruited, our findings support previous studies that have shown that specialist palliative care nurses are highly valued by those who have a terminal illness. It is important for people to understand that these nurses may be involved from the time of diagnosis and that roles have changed.

Qualitative study of men's perceptions of why treatment delays occur in the UK for those with testicular cancer.

BACKGROUND: Many studies (but not all) have shown that for men with testicular cancer a longer treatment delay is associated with additional treatments, greater morbidity, and shorter survival. AIM: This paper explores patients' perspectives on why treatment delays occur. DESIGN: Qualitative study using narrative interviews SETTING: Interviews in patient's homes throughout the United Kingdom (UK). METHOD: Interviews with a maximum variation sample of 45 men with testicular cancer, recruited through general practitioners (GPs), urologists, support groups, and charities. RESULTS: Those who sought help relatively quickly responded to symptoms, had heard about testicular cancer in the media, had seen leaflets in GPs' surgeries, or knew others with this disease. Men delayed because they did not recognise signs and symptoms; feared appearing weak, a hypochondriac, or lacking in masculinity; recalled past illness or painful examinations; were embarrassed; feared the consequences of treatment; or lacked time to consult their doctors. Beliefs about symptoms and pessimistic associations with cancer also led to delay. Treatment delays also resulted from misdiagnosis or waiting lists. CONCLUSION: Whether or not men should be taught to examine themselves routinely to check for testicular cancer is much debated. This study suggests that it is important that men are aware of the normal shape and feel of their testicles, and may benefit from information about signs and symptoms of testicular cancer and the excellent cure rate. Information, provided in surgeries where men feel welcome, might encourage men to seek help promptly when a problem arises. Our study also suggests that GPs may need to accept a low threshold for ultrasound investigation of testicular symptoms and that the ultrasound service needs to be improved. These measures may further reduce mortality and morbidity.

Lung cancer patients' perceptions of access to financial benefits: a qualitative study.

BACKGROUND: Financial worries may add to the stress experienced by patients and their families, but they are often not discussed with health professionals. People with lung cancer usually have to give up work, and many are terminally ill. AIM: To explore the financial concerns, perceptions and experiences of claiming benefits of people with lung cancer. DESIGN OF STUDY: Qualitative study using narrative interviews. SETTING: United Kingdom. METHOD: Interviews with a maximum variation sample of 45 people with lung cancer, recruited through general practitioners, consultants, nurses and support groups. RESULTS: Some people did not know that they could claim financial benefits, others found claim forms complicated, or were unaware that they had no legal right for important allowances to be backdated. Some people had to 'struggle' to obtain much needed benefits to which they were entitled. Patients below retirement age said that they would prefer to be working, and many were shocked by how hard it was to obtain the information needed to make claims. There was some evidence that even those who are seriously ill, and life-time tax payers, feel stigma in claiming financial help. Nurses, doctors and other patients sometimes offered valuable guidance, but many patients did not receive timely advice. The special social security rules (and DS1500 report form), which might have allowed them to claim benefits more rapidly than usual and at a higher rate, were not always understood. CONCLUSION: Many reasons were found as to why people with lung cancer have difficulty getting the benefits that they are entitled to. Hospital and primary care staff who handle the issue sensitively and help set claims in motion provide a valuable service that should be replicated throughout the National Health Service.

The use of patients' stories by self-help groups: a survey of voluntary organizations in the UK on the register of the College of Health.

OBJECTIVE: First-hand accounts of illness experience are believed to provide important insights for other patients and their carers. We report the results of a survey that explored how patients' stories are being collected and used by self-help and voluntary groups. METHODS: The annual College of Health survey contacts 2 458 addresses, which includes many self-help groups and voluntary associations. A brief questionnaire for the self-help groups on the register was attached to the summer 1999 survey on behalf of the DIPEx (database of individual patient experience) project. RESULTS: DIPEx received replies from 309 organizations representing a wide range of interests and conditions. These indicated that 202 (65%) of the groups currently use patients' stories in various ways. A further 59 (19%) of the groups reported that although they are not currently using them, they would like to in the future. Organizations that use patients' stories were invited to describe how they use them and provide examples, if applicable. Content analysis of the free text descriptions revealed 22 distinct uses among the 202 organizations using patient stories. The most frequent uses are the inclusion of patient stories in interviews or articles for the group newsletter (74 or 37%) and the use of stories for inclusion in newspaper articles or media broadcasts (31 or 15%). Some form of database of patients' stories was maintained by 23 groups (12%). CONCLUSIONS: These findings suggest that patients' stories are widely collected and used to support a wide range of the recognized functions of self-help and voluntary groups. This is encouraging to the DIPEx project's efforts to collect and analyse accounts of illness experience, which will be presented with evidence-based information about the effects of treatments.

Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection.

The signaling adaptor TNFR-associated factor 1 (TRAF1) is specifically lost from virus-specific CD8 T cells during the chronic phase of infection with HIV in humans or lymphocytic choriomeningitis virus (LCMV) clone 13 in mice. In contrast, TRAF1 is maintained at higher levels in virus-specific T cells of HIV controllers or after acute LCMV infection. TRAF1 expression negatively correlates with programmed death 1 expression and HIV load and knockdown of TRAF1 in CD8 T cells from viral controllers results in decreased HIV suppression ex vivo. Consistent with the desensitization of the TRAF1-binding co-stimulatory receptor 4-1BB, 4-1BBL-deficient mice have defects in viral control early, but not late, in chronic infection. TGFß induces the posttranslational loss of TRAF1, whereas IL-7 restores TRAF1 levels. A combination treatment with IL-7 and agonist anti-4-1BB antibody at 3 wk after LCMV clone 13 infection expands T cells and reduces viral load in a TRAF1-dependent manner. Moreover, transfer of TRAF1(+) but not TRAF1(-) memory T cells at the chronic stage of infection reduces viral load. These findings identify TRAF1 as a potential biomarker of HIV-specific CD8 T cell fitness during the chronic phase of disease and a target for therapy.

Patients with pancreatic cancer and relatives talk about preferred place of death and what influenced their preferences: a qualitative study.

OBJECTIVE: To explore reasons why people with pancreatic cancer, who are reaching the end of their lives, say they wish to die at home or elsewhere, and why preferences may change. DESIGN: Qualitative study using semistructured interviews followed by thematic analysis. SETTING: Respondents recruited from different parts of the UK during 2009/2010. PARTICIPANTS: 16 people with experience of pancreatic cancer (8 patients and 8 bereaved relatives) who discussed place of death in detail during an in-depth interview (from a total sample of 32 people with pancreatic cancer and eight relatives of others who had died of this disease). RESULTS: People's preferences were affected by their perceptions and previous experiences of care available at home, in a hospice or hospital. Preferences were also shaped by fears about possible loss of dignity, or fears of becoming a burden. Some people thought that a home death might leave bad memories for other members of the family. People with pancreatic cancer and their relatives were aware that preferences might change (or had changed) as death approached. CONCLUSIONS: The National Health Service End of Life Care Strategy for England seeks to meet the needs of people who are dying and promotes better support for home deaths. More information is needed about why patients hold different views about place of care and place of death, why patients' preferences change and what importance patients attach to place of death. Health professionals should bear this in mind if the subject is raised during advance care planning.