Memory CD8+ T cell responses to cancer.

Long-lived memory CD8+ T cells play important roles in tumor immunity. Studies over the past two decades have identified four subsets of memory CD8+ T cells - central, effector, stem-like, and tissue resident memory - that either circulate through blood, lymphoid and peripheral organs, or reside in tissues where cancers develop. In this article, we will review studies from both pre-clinical mouse models and human patients to summarize the phenotype, distribution and unique features of each memory subset, and highlight specific roles of each subset in anti-tumor immunity. Moreover, we will discuss how stem-cell like and resident memory CD8+ T cell subsets relate to exhausted tumor-infiltrating lymphocytes (TIL) populations. These studies reveal how memory CD8+ T cell subsets together orchestrate durable immunity to cancer.

Conventional health care service utilization among cancer survivors that visit traditional and complementary providers in the Tromsø study: a cross-sectional study.

BACKGROUND: Traditional and complementary medicine (T&CM) is commonly used among cancer patients worldwide. Cancer patients in Norway mainly visit T&CM providers in addition to conventional health care services. It is not known how their utilization of T&CM providers influences their use of conventional health care services. The aim of this study was to investigate the difference between the utilization of conventional health care services among cancer survivors that visit T&CM providers and those that do not, and their associated factors. METHOD: Health care service utilization data were obtained from cancer survivors 40 years and above participating in the Tromsø Study: Tromsø 7 conducted in 2015-2016. Data were collected from self-administered questionnaires. Pearson chi-square tests, Fisher exact tests, t-test, and logistic regression were used, with the significance level considered at p < 0.05. RESULTS: Of 1553 individuals, 10% (n = 155) reported visiting T&CM providers in the past 12 months. As both cancer survivors visiting and not visiting T&CM providers were frequent users of conventional health care, no significant differences were found in the overall use of conventional health care (98.1vs.94.5%, p = .056). Users of T&CM providers were however more likely to visit physiotherapists (40.1% vs 25%, p < .001), emergency rooms (29.2% vs 16.5%, p < .001), chiropractors (17% vs 6%, p < .001), and psychologist/psychiatrist (8.9% vs 3.4%, p < .001). They also had more frequent visits to conventional health care (11.45 vs 8.31 yearly visits, p = 0.014), particularly to general practitioners (5.21 visits vs. 3.94 visits, p = .002). CONCLUSION: Results from this study show that visits to T&CM providers are associated with more visits to conventional health care services among cancer survivors. Further studies are needed to investigate the reasons for this high use behavior.

IL-15 Preconditioning Augments CAR T Cell Responses to Checkpoint Blockade for Improved Treatment of Solid Tumors.

Chimeric antigen receptor (CAR) T cell therapy has been highly successful in hematological malignancies leading to their US Food and Drug Administration (FDA) approval. However, the efficacy of CAR T cells in solid tumors is limited by tumor-induced immunosuppression, leading to the development of combination approaches, such as adjuvant programmed cell death 1 (PD-1) blockade. Current FDA-approved methods for generating CAR T cells utilize either anti-CD3 and interleukin (IL)-2 or anti-CD3/CD28 beads, which can generate a T cell product with an effector/exhausted phenotype. Whereas different cytokine preconditioning milieu, such as IL-7/IL-15, have been shown to promote T cell engraftment, the impact of this approach on CAR T cell responses to adjuvant immune-checkpoint blockade has not been assessed. In the current study, we reveal that the preconditioning of CAR T cells with IL-7/IL-15 increased CAR T cell responses to anti-PD-1 adjuvant therapy. This was associated with the emergence of an intratumoral CD8+CD62L+TCF7+IRF4- population that was highly responsive to anti-PD-1 therapy and mediated the vast majority of transcriptional and epigenetic changes in vivo following PD-1 blockade. Our data indicate that preservation of CAR T cells in a TCF7+ phenotype is crucial for their responsiveness to adjuvant immunotherapy approaches and should be a key consideration when designing clinical protocols.

Use of traditional and complementary medicine among Norwegian cancer patients in the seventh survey of the Tromsø study.

BACKGROUND: Traditional and complementary medicine (T&CM) is commonly used by cancer patients in Northern Norway, in particular spiritual forms like traditional healing. T&CM is mainly used complementary to conventional cancer treatment and is rarely discussed with conventional health care providers, increasing the risk of negative interaction with conventional cancer care. The aim of this study was to investigate the use of T&CM among cancer patients in Tromsø, and to investigate the differences in T&CM use between people living with cancer, people with cancer previously, and people without a history of cancer. METHOD: Data was drawn from the seventh survey of the Tromsø study conducted in 2015-2016. All inhabitants of Tromsø aged 40 and above were invited to participate (n = 32,591) of whom n = 21,083 accepted the invitation (response rate 65%). Data was collected thorough three self-administered questionnaires and a comprehensive clinical examination. Pearson chi-square tests, Fisher exact tests and one-way ANOVA tests were used to describe differences between the groups while binary logistic regressions were used for adjusted values. RESULTS: Eight percent of the participants (n = 1636) reported to have (n = 404) or have had (n = 1232) cancer. Of the participants with cancer at present 33.4% reported use of T&CM within the last year, 13.6% had consulted a T&CM provider, 17.9% had used herbal medicine/natural remedies and 6.4% had practiced self-help techniques. The participants with cancer at present were more likely to have visited a T&CM provider than participants with cancer previously (13.6% vs. 8.7%, p = 0.020). Among the participants with cancer at present, 6.4% reported to have consulted a TM provider, 5.8% had consulted an acupuncturist, while 4.7% had consulted other CM providers. Women were significantly more likely than men to have used acupuncture and self-help techniques. No significant gender differences were found regarding visits to other CM providers, TM providers nor use of herbal medicine/natural remedies. CONCLUSION: The findings are in line with previous research suggesting that both men and women use TM complementary to other CM modalities outside the official health care system. As herbal medicine might interact with conventional cancer treatment, health care providers need to discuss such use with their patients.

Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8(+) T-cell memory formation and function.

BACKGROUND: The capacity of CD8(+) T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8(+) T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8(+) T-cell immunity in human subjects is unknown. OBJECTIVE: We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8(+) T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. METHODS: Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8(+) T-cell differentiation in vivo and in vitro. RESULTS: Mutations in STAT3 and IL21R, but not STAT1, led to a decrease in multiple memory CD8(+) T-cell subsets in vivo, indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21-stimulated naive CD8(+) T cells. However, this defect was overcome by T-cell receptor engagement. CONCLUSION: The IL-21R/STAT3 pathway is required for many aspects of human CD8(+) T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R-deficient subjects.

A review of the WHO strategy on traditional, complementary, and integrative medicine from the perspective of academic consortia for integrative medicine and health.

Despite important progress in modern medicine, widely regarded as an indispensable foundation of healthcare in all highly advanced nations and regions, not all patients respond well to available treatments in biomedicine alone. Additionally, there are concerns about side effects of many medications and interventions, the unsustainable cost of healthcare and the low resolution of chronic non-communicable diseases and mental disorders whose incidence has risen in the last decades. Besides, the chronic stress and burnout of many healthcare professionals impairs the therapeutic relationship. These circumstances call for a change in the current paradigm and practices of biomedicine healthcare. Most of the world population (80%) uses some form of traditional, complementary, and integrative medicine (T&CM), usually alongside biomedicine. Patients seem equally satisfied with biomedicine and T&CM, but in the field of T&CM there are also many challenges, such as unsupported claims for safety and/or efficacy, contamination of herbal medicines and problems with regulation and quality standards. As biomedicine and T&CM seem to have different strengths and weaknesses, integration of both approaches may be beneficial. Indeed, WHO has repeatedly called upon member states to work on the integration of T&CM into healthcare systems. Integrative medicine (IM) is an approach that offers a paradigm for doing so. It combines the best of both worlds (biomedicine and T&CM), based on evidence for efficacy and safety, adopting a holistic personalized approach, focused on health. In the last decades academic health centers are increasingly supportive of IM, as evidenced by the foundation of national academic consortia for integrative medicine in Brazil (2017), the Netherlands (2018), and Germany (2024) besides the pioneering American consortium (1998). However, the integration process is slow and sometimes met with criticism and even hostility. The WHO T&CM strategies (2002-2005 and 2014-2023) have provided incipient guidance on the integration process, but several challenges are yet to be addressed. This policy review proposes several possible solutions, including the establishment of a global matrix of academic consortia for IM, to update and extend the WHO T&CM strategy, that is currently under review.

CD45RA-Foxp3(high) activated/effector regulatory T cells in the CCR7 + CD45RA-CD27 + CD28+central memory subset are decreased in peripheral blood from patients with rheumatoid arthritis.

Human CD4+ T cells can be classified as either naïve, central memory (TCM), or effector memory (TEM) cells. To identify the CD4+ T cell subsets most important in the pathogenesis of rheumatoid arthritis (RA), we phenotypically defined human CD4+ T cells as functionally distinct subsets, and analyzed the distribution and characteristics of each subset in the peripheral blood. We classified CD4+ T cells into six novel subsets based on the expression of CD45RA, CCR7, CD27, and CD28. The CCR7 + CD45RA-CD27 + CD28+ TCM subset comprised a significantly smaller proportion of CD4+ T cells in RA patients compared to healthy controls. The frequency of TNF-α-producing cells in the CCR7-CD45RA-CD27 + CD28+ TEM subset was significantly increased in RA. Furthermore, within the CCR7 + CD45RA-CD27 + CD28+ TCM subset, which was decreased in periperal blood from RA, the proportions of total Foxp3+ Treg cells and CD45RA-Foxp3(high) activated/effector Treg cells were significantly lower in RA patients. Our findings suggest that the increased proportion of TNF-α-producing cells and the decreased proportion of CD45RA-Foxp3(high) activated/effector Treg cells in particular subsets may have critical roles in the pathogenesis of RA.

Clinical associations for traditional and complementary medicine use among norwegian cancer survivors in the seventh survey of the Tromsø study: a cross-sectional study.

BACKGROUND: Cancer survivors are a diverse group with varying needs that are patient-, disease-, and/or treatment-specific. Cancer survivors have reported supplementing conventional anti-cancer treatment with Traditional and Complementary Medicine (T&CM). Although female cancer survivors are reported to have more severe anticancer adverse effects, little is known about the association between anticancer treatment and T&CM use among Norwegian cancer survivors. The aims of this study are therefore to investigate (1) associations between cancer diagnosis characteristics and T&CM utilization and (2) associations between anticancer treatment and T&CM utilization among cancer survivors in the seventh survey of the Tromsø study. METHODS: Data was collected from the seventh survey of the Tromsø Study conducted in 2015-16 among all inhabitants of Tromsø municipality aged 40 and above (response rate 65%), where inhabitants received online and paper form questionnaires. Data from the data linkage to the Cancer Registry of Norway for cancer diagnosis characteristics was also used. The final study sample was made up of 1307 participants with a cancer diagnosis. Categorical variables were compared using Pearson's Chi-square test or Fisher's exact test while independent sample t-test was used to compare continuous variables. RESULTS: The use of T&CM the preceding 12 months was reported by 31.2% of the participants with natural remedies as the most reported modality of T&CM (18.2%, n = 238), followed by self-help practices of meditation, yoga, qigong, or tai chi, which was reported by 8.7% (n = 114). Users of T&CM were significantly younger (p = .001) and more likely to be female (p < .001) than the non-users, with higher use of T&CM among female survivors with poor self-reported health and being 1-5 years post-diagnosis. Lower use of T&CM was found among female survivors who received a combination of surgery with hormone therapy and those who received a combination of surgery with hormone therapy and radiotherapy. Similar usage was seen in male survivors, but not at a significant level. For both male and female survivors, T&CM was most frequently used by those with only one cancer diagnosis (p = .046). CONCLUSION: Our results indicate that the profile of the Norwegian cancer survivor who uses T&M is slightly changing compared to previous findings. Additionally, compared to male survivors, more clinical factors are associated with use of T&CM among female cancer survivors. These results should serve as a reminder to conventional health care providers to discuss the use of T&CM with patients across the entire cancer survivorship continuum to promote safe use, especially among female survivors.

Adherence to lifestyle recommendations among Norwegian cancer survivors and the impact of traditional and complementary medicine use: the Tromsø Study 2015-2016.

INTRODUCTION: Adherence to healthy lifestyle recommendations has positive effects on cancer outcomes yet adherence is low among cancer survivors. Differences in adherence between women and men, phase of survivorship, and other factors that might increase adherence, like the use of traditional and complementary medicine (T&CM), need to be explored. We aimed to study the adherence to national recommendations for a healthy diet (daily intake of ≥ 5 portions of fruit/vegetables), physical activity (150 min of moderate-intensity or 75 min of high-intensity/week), normal body mass index (BMI) (18.5-24.9 kg/m2), non-smoking, and low-risk alcohol consumption (women ≤ 10 g/day, men ≤ 20 g/day) among Norwegian cancer survivors and their associations with sex, the use of T&CM, and survivorship phase. METHODS: We used logistic regression, independent sample t-test, and chi-square test to study self-reported (diet, physical activity, smoking, alcohol consumption) and measured (BMI) adherence in 1530 cancer survivors (40 years and above, participating in the population-based Tromsø Study conducted in 2015-2016 (65% attendance). We dichotomized all assessed lifestyle recommendations (adherence = 1 point, non-adherence = 0 points), and created a score for every recommendation (0-5 points). Adherence to individual lifestyle recommendations and the use of T&CM as well as the phase of survivorship was adjusted for sex, age, income, and living with a partner. RESULTS: Adherence to recommendations was 7.5% for diet, 85.3% for physical activity, 30.5% for BMI, 89.3% for non-smoking, and 87.6% for alcohol consumption. In total 2.3% adhered to all five recommendations concurrently (mean score 2.96 [SD = 0.86]). Women adhered to more recommendations concurrently compared to men (3.03 [SD = 0.90] vs. 2.89 [SD = 0.80] points respectively, [p = .012]). In total, 31% reported the use of T&CM and there were no differences in adherence to individual lifestyle recommendations or concurrent adherence in overall T&CM use compared to non-use. Users of self-help techniques were more likely to adhere to the recommendations of diet (aOR 2.69, 95% CI 1.45-4.98) and physical activity (aOR 6.26, 95% CI 1.51-25.92). Users of traditional healers and users of more than one T&CM modality were less likely to adhere to the low-risk alcohol consumption recommendation, (aOR 0.32, 95% CI 0.13-0.77, and aOR 0.53, 95% CI 1.08-2.17, respectively) compared to T&CM non-users. Survivors with cancer previously (1162) had higher odds of adhering to the recommendation of diet (aOR 2.66, 95% CI 1.36-5.19) than survivors with cancer presently (n = 368), but not to other recommendations. CONCLUSION: The health of cancer survivors can be improved through adherence to lifestyle recommendations, yet our study found partial adherence among survivors in Norway, in accordance with findings from other countries. Although overall T&CM use was not associated with higher adherence to lifestyle recommendations, differences in adherence were seen among individual modalities like the use of self-help techniques and traditional healers. Our results suggest the need for intensified follow-up of lifestyle with attention to male survivors and diet among all survivors throughout the cancer survivorship continuum.

Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model.

Introduction: The discovery of immune checkpoints and the development of their specific inhibitors was acclaimed as a major breakthrough in cancer therapy. However, only a limited patient cohort shows sufficient response to therapy. Hence, there is a need for identifying new checkpoints and predictive biomarkers with the objective of overcoming immune escape and resistance to treatment. Having been associated with both, treatment response and failure, LDL seems to be a double-edged sword in anti-PD1 immunotherapy. Being embedded into complex metabolic conditions, the impact of LDL on distinct immune cells has not been sufficiently addressed. Revealing the effects of LDL on T cell performance in tumor immunity may enable individual treatment adjustments in order to enhance the response to routinely administered immunotherapies in different patient populations. The object of this work was to investigate the effect of LDL on T cell activation and tumor immunity in-vitro. Methods: Experiments were performed with different LDL dosages (LDLlow = 50 µg/ml and LDLhigh = 200 µg/ml) referring to medium control. T cell phenotype, cytokines and metabolism were analyzed. The functional relevance of our findings was studied in a HCT116 spheroid model in the context of anti-PD-1 blockade. Results: The key points of our findings showed that LDLhigh skewed the CD4+ T cell subset into a central memory-like phenotype, enhanced the expression of the co-stimulatory marker CD154 (CD40L) and significantly reduced secretion of IL-10. The exhaustion markers PD-1 and LAG-3 were downregulated on both T cell subsets and phenotypical changes were associated with a balanced T cell metabolism, in particular with a significant decrease of reactive oxygen species (ROS). T cell transfer into a HCT116 spheroid model resulted in a significant reduction of the spheroid viability in presence of an anti-PD-1 antibody combined with LDLhigh. Discussion: Further research needs to be conducted to fully understand the impact of LDL on T cells in tumor immunity and moreover, to also unravel LDL effects on other lymphocytes and myeloid cells for improving anti-PD-1 immunotherapy. The reason for improved response might be a resilient, less exhausted phenotype with balanced ROS levels.

Safety and use of complementary and alternative medicine in Norway during the first wave of the COVID-19 pandemic using an adapted version of the I-CAM-Q; a cross-sectional survey.

BACKGROUND: The COVID-19 pandemic lockdown has had a profound impact on physical and mental well-being throughout the world. Previous studies have revealed that complementary and alternative medicine (CAM) is frequently used for, and can be potential beneficial for strengthening physical mental resilience. The aims of this study were therefore to determine the prevalence and reasons for use of CAM during the first wave of the COVID-19 pandemic among a representative sample of the Norwegian population, and further determine self-reported effects and adverse effects of the CAM modalities used. METHODS: Computer assisted telephone interviews using a COVID-adapted I-CAM-Q questionnaire were conducted with 1008 randomly selected Norwegians aged 16 and above using multistage sampling during April and May 2020 applying age and sex quotas for each area. Frequencies, Pearson's chi-square tests, Fisher exact tests, and independent sample t-test were used to identify the users of CAM, what they used, why they used it and whether they experienced effect and/or adverse effects of the modalities used, and further to describe differences in sociodemographic factors associated with CAM use. Cronbach's alpha tests were used to test for internal consistency in the different groups of CAM. Significance level was set to p < 0.05. RESULTS: The study revealed that two thirds of the respondents (67%) had used CAM within the first 3 months of the COVID-19 pandemic, in particular CAM modalities that did not involve a provider. Most used were natural remedies and dietary supplement (57%, mainly vitamins and minerals), but self-help practices like yoga and meditation were also widely used (24%). Women used CAM modalities significantly more than men (77% vs. 58%). Most of the respondents found the modalities they used beneficial, and few reported adverse effects of the treatments. CONCLUSIONS: A large proportion of the Norwegian population used CAM during the first wave of the COVID-19 pandemic with high satisfaction and few reported adverse effects. CAM was rarely used to prevent or treat COVID-19, but rather to treat a long-term health condition, and to improve well-being.

Current status and future prospects of research and development operations in traditional and complementary and alternative medicine manufacturing small- and medium-sized enterprises: a 2014 company-based survey.

BACKGROUND: Small- and medium-sized enterprises (SMEs) have played key roles in the economic growth and technical innovation of traditional and complementary and alternative medicine (T&CM). Research and development (R&D) are critical activities for industrial progress. This study aimed to characterize the current status of SME R&D activities and to explore manufacturers' perceptions of R&D expansion. METHODS: Records of the distribution of T&CM SMEs and R&D resources detailed in the 2014 Statistics of Korea T&CM Industries survey, a previously conducted survey on the industrial status of the T&CM field, were reviewed. Data on the perceptions of R&D activities were investigated through a company-based survey covering 285 T&CM-manufacturing SMEs. RESULTS: Greater than 99% of the 13,636 T&CM manufacturers at the time of the study were SMEs employing less than 50 workers. Natural cosmetics manufacturing SMEs (NC SMEs) had the highest R&D expenditures. NC SMEs rely heavily on internal R&D operations, which may contribute to their strong need for R&D collaboration with public research institutions and expanded T&CM-promoted R&D programs. "Digestive system disorders" are the main target diseases for current herbal and dietary supplement manufacturing SMEs and herbal medicine manufacturing SMEs. These SMEs tend to view their own product-related business as a priority for future R&D investment. CONCLUSION: This study represents the first attempt to assess SME perceptions of R&D activities. The findings herein can inform the design of sustainable programs that support R&D by reducing the gaps between the perspectives of T&CM product makers and policymakers.

Study protocol of a pragmatic, randomised controlled pilot trial: clinical effectiveness on smoking cessation of traditional and complementary medicine interventions, including acupuncture and aromatherapy, in combination with nicotine replacement therapy.

INTRODUCTION: Nicotine dependence is a disease, and tobacco use is related to 6 million deaths annually worldwide. Recently, in many countries, there has been growing interest in the use of traditional and complementary medicine (T&CM) methods, especially acupuncture, as therapeutic interventions for smoking cessation. The aim of this pilot study is to investigate the effectiveness of T&CM interventions on smoking cessation. METHODS AND ANALYSIS: The STOP (Stop Tobacco Programme using traditional Korean medicine) study is designed to be a pragmatic, open-label, randomised pilot trial. This trial will evaluate whether adding T&CM methods (ie, ear and body acupuncture, aromatherapy) to conventional cessation methods (ie, nicotine replacement therapy (NRT), counselling) increases smoking cessation rates. Forty participants over 19 years old who are capable of communicating in Korean will be recruited. They will be current smokers who meet one of the following criteria: (1) smoke more than 10 cigarettes a day, (2) smoke less than 10 cigarettes a day and previously failed to cease smoking, or (3) smoke fewer than 10 cigarettes a day and have a nicotine dependence score (Fagerstrom Test for Nicotine Dependence) of 4 points or more. The trial will consist of 4 weeks of treatment and a 20 week follow-up period. A statistician will perform the statistical analyses for both the intention-to-treat (all randomly assigned participants) and per-protocol (participants who completed the trial without any protocol deviations) data using SAS 9.1.3. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board (IRB) of the Dunsan Korean Medicine Hospital of Daejeon University (IRB reference no: DJDSKH-15-BM-11-1, Protocol No. version 4.1.).The protocol will be reapproved by IRB if it requires amendment. The trial will be conducted according to the Declaration of Helsinki, 7th version (2013). This study is designed to minimise the risk to participants, and the investigators will explain the study to the participants in detail. As an ethical clinical trial, the control group will also be given conventional cessation treatments, including NRT and counselling. Participants will be screened and provided with a registration number to protect their personal information. Informed consent will be obtained from the participants prior to enrolling them in the trial. Participants will be allowed to withdraw at anytime without penalty. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT02768025); pre-results.

IL-7 promotes long-term in vitro survival of unique long-lived memory subset generated from mucosal effector memory CD4+ T cells in chronic colitis mice.

Colitogenic memory CD4(+) T cells are important in the pathogenesis of inflammatory bowel disease (IBD). Although memory stem cells with high survival and self-renewal capacity were recently identified in both mice and humans, it is unclear whether a similar subset is present in chronic colitis mice. We sought to identify and purify a long-lived subset of colitogenic memory CD4(+) T cells, which may be targets for treatment of IBD. A long-lived subset of colitogenic memory CD4(+) T cells was purified using a long-term culture system. The characteristics of these cells were assessed. Interleukin (IL)-7 promoted the in vitro survival for >8 weeks of lamina propria (LP) CD4(+) T cells from colitic SCID mice previously injected with CD4(+)CD45RB(high) T cells. These cells were in a quiescent state and divided a maximum of 5 times in 4 weeks. LP CD4(+) T cells expressed higher levels of Bcl-2, integrin-α4ß7, CXCR3 and CD25 after than before culture, as well as secreting high concentrations of IL-2 and low concentrations of IFN-γ and IL-17 in response to intestinal bacterial antigens. LP CD4(+) T cells from colitic mice cultured with IL-7 for 8 weeks induced more severe colitis than LP CD4(+) T cells cultured for 4 weeks. We developed a novel culture system to purify a long-lived, highly pathogenic memory subset from activated LP CD4(+) T cells. IL-7 promoted long-term in vitro survival of this subset in a quiescent state. This subset will be a novel, effective target for the treatment of IBD.

Human effector T cells derived from central memory cells rather than CD8(+)T cells modified by tumor-specific TCR gene transfer possess superior traits for adoptive immunotherapy.

Adoptive cell therapy provides an attractive treatment of cancer, and our expanding capacity to target tumor antigens is driven by genetically engineered human T lymphocytes that express genes encoding tumor-specific T cell receptors (TCRs). The intrinsic properties of cultured T cells used for therapy were reported to have tremendous influences on their persistence and antitumor efficacy in vivo. In this study, we isolated CD8(+) central memory T cells from peripheral blood lymphocytes of healthy donors, and then transferred with the gene encoding TCR specific for tumor antigen using recombinant adenovirus vector Ad5F35-TRAV-TRBV. We found effector T cells derived from central memory T cells improved cell viability, maintained certain level of CD62L expression, and reacquired the CD62L(+)CD44(high) phenotype of central memory T cells after effector T cells differentiation. We then compared the antitumor reactivity of central memory T cells and CD8(+)T cells after TCR gene transferred. The results indicated that tumor-specific TCR gene being transferred to central memory T cells effectively increased the specific killing of antigen positive tumor cells and the expression of cytolytic granule protein. Furthermore, TCR gene transferred central memory T cells were more effective than TCR gene transferred CD8(+)T cells in CTL activity and effector cytokine secretion. These results implicated that isolating central memory T cells rather than CD8(+)T cells for insertion of gene encoding tumor-specific TCR may provide a superior tumor-reactive T cell population for adoptive transfer.

Cell-mediated immune responses in the head-associated lymphoid tissues induced to a live attenuated avian coronavirus vaccine.

Humoral immunity is important for controlling viral diseases of poultry, but recent studies have indicated that cytotoxic T cells also play an important role in the immune response to infectious bronchitis virus (IBV). To better understand the cell mediated immune responses to IBV in the mucosal and systemic immune compartments chickens were ocularly vaccinated with IBV. This induced a lymphocyte expansion in head-associated lymphoid tissues (HALT) and to a lesser extent in the spleen, followed by a rapid decline, probably due to homing of lymphocytes out of these organs and contraction of the lymphocyte population. This interpretation was supported by observations that changes in mononuclear cells were mirrored by that in CD3(+)CD44(+) T cell abundance, which presumably represent T effector cells. Increased interferon gamma (IFN-γ) expression was observed in the mucosal immune compartment, i.e., HALT, after primary vaccination, but shifted to the systemic immune compartment after boosting. In contrast, the expression of cytotoxicity-associated genes, i.e., granzyme A (GZMA) and perforin mRNA, remained associated with the HALT after boosting. Thus, an Ark-type IBV ocular vaccine induces a central memory IFN-γ response in the spleen while the cytotoxic effector memory response, as measured by GZMA and perforin mRNA expression, remains associated with CALT after boosting.

A myriad of functions and complex regulation of the CCR7/CCL19/CCL21 chemokine axis in the adaptive immune system.

The chemokine receptor CCR7 and its ligands CCL19 and CCL21 control a diverse array of migratory events in adaptive immune function. Most prominently, CCR7 promotes homing of T cells and DCs to T cell areas of lymphoid tissues where T cell priming occurs. However, CCR7 and its ligands also contribute to a multitude of adaptive immune functions including thymocyte development, secondary lymphoid organogenesis, high affinity antibody responses, regulatory and memory T cell function, and lymphocyte egress from tissues. In this survey, we summarise the role of CCR7 in adaptive immunity and describe recent progress in understanding how this axis is regulated. In particular we highlight CCX-CKR, which scavenges both CCR7 ligands, and discuss its emerging significance in the immune system.

Preferences For Traditional & Complementary Medicine Among Malaysian Hospitalised Patients In Ukm Medical Centre 2012

The uprising needs of traditional & complementary medicine (T&CM) despite the availability of conventional medical (CVM) treatments has gained a serious concern to the authorities in hospital care delivery systems. It was about suffices the supply and demand for T&CM and its absence may interfere the quality of patient care. Malaysia was not exempted of this phenomenon. Moreover, its rich tropical biodiversity and multi-ethnical medical systems promoted T&CM usage. This research was aimed to determine the overall T& CM preferences, the preferred future patient care services (FPCS) and its socio-demographic and warding characteristics. Using a self-administered standardised questionnaire, instrumented by cross sectional study, a total 132 warded patients in a UKM Medical Center (UKMMC) were interviewed. T&CM preferences were the composite of seven domains. The finding revealed that the T&CM preference was 64.4%, dominated by older age (66.2%), women (68.2%), low education (66.0%), employed (66.7%), high income (67.5%) and married (66.0%). Oncology (81.3%) and orthopaedic (75.7%) ward patients were more in preference compared to other wards. When asked about the FPCS preference, about 80.3% expected integrative medicine services to be provided, whereas the remaining were still exclusively preferred modern medicine (15.2%) and alternative medicine (4.5%) respectively. As conclusion, this study has affirmed that there is a great need towards T&CM among hospitalized patients who are accessible to modern CVM.