Nociceptor neurons affect cancer immunosurveillance.

Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1-5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1-/- CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.

Pt-Cu@Bi2MoO6/TiO2 Photocatalyst for CO2 Reduction.

Bi2MoO6/TiO2 heterojunction photocatalysts were constructed by depositing Bi2MoO6 nanosheets on TiO2 nanobelts' surface using a solvothermal method, and the surface of the optimum Bi2MoO6/TiO2 composite was decorated with copper and/or platinum nanoparticles. The synthesized samples were investigated for the CO2 photocatalytic reduction. The structural and optical properties of synthesized photocatalysts were characterized by XRD, FESEM, EDX, N2-physisorption, Raman, TPD-CO2, DRS, and PL analysis. The Bi2MoO6/TiO2 composite with different molar ratios of Bi2MoO6 to TiO2 (1, 1/2, 1/3, 1/4, 1/5, and 1/6) showed enhanced photocatalytic activity compared to pure Bi2MoO6 and TiO2. In comparison to bulk Bi2MoO6 and TiO2, the formation of a heterojunction between Bi2MoO6 and TiO2 leads to enhanced CO2 adsorption capacity. The enhanced performance of composites can be ascribed to the improved efficiency of light harvesting in the visible light range and suppressing charge recombination. The composite photocatalytic activity indicated that the ratio of Bi2MoO6 to TiO2 in the composite samples influenced the photocatalytic performance. The Bi2MoO6/TiO2 composite with 1/4 molar ratio had the best performance in 8 h (36.4 µmol/gcat), which was about 10 and 3 times higher than TiO2 and Bi2MoO6 photocatalysts, respectively. Under UV-visible light irradiation, the Pt-Cu@BMT4 sample produced the highest amount of methane (83.6 µmol/gcat) during CO2 photoreduction. During four irradiation cycles, the Pt-Cu@BMT4 sample exhibited superior stability with less than 5% decrease in methane production.

Social stigma and its relationship with quality of life in multiple sclerosis patients.

INTRODUCTION: Multiple sclerosis (MS) is the most prevalent disease of the central nervous system that affects the behavioral characteristics and lifestyle of patients. This study aimed to determine the social stigma and its relationship with quality of life in people with MS referring to the Jahrom MS Association. METHOD: This cross-sectional study was conducted on MS patients who are members of the MS Association of Jahrom City in Fars province, southern Iran in 2022. The samples were selected by census method. The number of participants remain 223 people. The data was collected using a standard two-part demographic and Multiple Sclerosis Quality of Life-54 (MSQOL-54) questionnaire and a researcher-made 20-question Social stigma questionnaire which validity and reliability were measured. Data analysis was done in a descriptive way (frequency, percentage, mean and standard deviation), univariate regression and multivariable linear regression. Data analysis was done using SPSS version 17 and at a significance level of less than 0.05. RESULT: Based on univariate regression, marriage [B = 0.2, p-value = 0.004], physical health [B = 0.4, p-value < 0.001], emotional well-being [B = 0.4, p-value = 0.001], cognitive functioning [B = 0.4, p-value < 0.001], health distress [B = 0.5, p-value < 0.001] had a positive and significant relationship with patients' quality of life. Duration of disease [B=-0.2, p-value < 0.001], physical role limitations [B=-0.4, p-value < 0.001], emotional role limitations [B=-0.5, p-value < 0.001], pain [B=-0.4, p-value < 0.001], energy [B=-0.3, p-value = 0.02], health perception [B=-0.3, p-value = 0.001], social functioning [B=-0.4, p-value < 0.001], sexual function [B=-0.3, p-value < 0.001], change in health [B=-0.3, p-value < 0.001], sexual function satisfaction [B=-0.3, p-value < 0.001] and social stigma [B=-0.3, p-value < 0.001] had a negative and significant relationship with patients' quality of life (p < 0.05). CONCLUSION: The study has emphasized the relationship between the extent and severity of symptoms and disorders with the quality of life of people with MS. The results of the study showed factors such as marriage, physical health and health distress have a positive relationship and factors like duration of disease, physical role limitations, and social stigma have a negative relationship with the quality of life of people with MS. The quality of life of people with MS is more influenced by mental and psychological factors than the physical limitations of these patients.

Does motor control training improve pain and function in adults with symptomatic lumbar disc herniation? A systematic review and meta-analysis of 861 subjects in 16 trials.

OBJECTIVE: To evaluate the effectiveness of motor control training (MCT) compared with other physical therapist-led interventions, minimal/no intervention or surgery in patients with symptomatic lumbar disc herniation (LDH). DESIGN: Systematic review and meta-analysis. DATA SOURCES: Eight databases and the ClinicalTrials.gov were searched from inception to April 2021. ELIGIBILITY CRITERIA: We included clinical trial studies with concurrent comparison groups which examined the effectiveness of MCT in patients with symptomatic LDH. Primary outcomes were pain intensity and functional status which were expressed as mean difference (MD) and standardised mean difference (SMD), respectively. RESULTS: We screened 6695 articles, of which 16 clinical trials (861 participants) were eligible. Fourteen studies were judged to have high risk of bias and two studies had some risk of bias. In patients who did not undergo surgery, MCT resulted in clinically meaningful pain reduction compared with other physical therapist-led interventions (ie, transcutaneous electrical nerve stimulation (TENS)) at short-term (MD -28.85, -40.04 to -17.66, n=69, studies=2). However, the robustness of the finding was poor. For functional status, a large and statistically significant treatment effect was found in favour of MCT compared with traditional/classic general exercises at long-term (SMD -0.83 to -1.35 to -0.31, n=63, studies=1) and other physical therapist-led interventions (ie, TENS) at short-term (SMD -1.43 to -2.41 to -0.46, n=69, studies=2). No studies compared MCT with surgery. In patients who had undergone surgery, large SMDs were seen. In favour of MCT compared with traditional/classic general exercises (SMD -0.95 to -1.32 to -0.58, n=124, studies=3), other physical therapist-led interventions (ie, conventional treatments; SMD -2.30 to -2.96 to -1.64, n=60, studies=1), and minimal intervention (SMD -1.34 to -1.87 to -0.81, n=68, studies=2) for functional improvement at short-term. The overall certainty of evidence was very low to low. CONCLUSION: At short-term, MCT improved pain and function compared with TENS in patients with symptomatic LDH who did not have surgery. MCT improved function compared with traditional/classic general exercises at long-term in patients who had undergone surgery. However, the results should be interpreted with caution because of the high risk of bias in the majority of studies. PROSPERO REGISTRATION NUMBER: CRD42016038166.

Clinical decision support system for quality of life among the elderly: an approach using artificial neural network.

BACKGROUND: Due to advancements in medicine and the elderly population's growth with various disabilities, attention to QoL among this age group is crucial. Early prediction of the QoL among the elderly by multiple care providers leads to decreased physical and mental disorders and increased social and environmental participation among them by considering all factors affecting it. So far, it is not designed the prediction system for QoL in this regard. Therefore, this study aimed to develop the CDSS based on ANN as an ML technique by considering the physical, psychiatric, and social factors. METHODS: In this developmental and applied study, we investigated the 980 cases associated with pleasant and unpleasant elderlies QoL cases. We used the BLR and simple correlation coefficient methods to attain the essential factors affecting the QoL among the elderly. Then three BP configurations, including CF-BP, FF-BP, and E-BP, were compared to get the best model for predicting the QoL. RESULTS: Based on the BLR, the 13 factors were considered the best factors affecting the elderly's QoL at P < 0.05. Comparing all ANN configurations showed that the CF-BP with the 13-16-1 structure with sensitivity = 0.95, specificity = 0.97, accuracy = 0.96, F-Score = 0.96, PPV = 0.95, and NPV = 0.97 gained the best performance for QoL among the elderly. CONCLUSION: The results of this study showed that the designed CDSS based on the CFBP could be considered an efficient tool for increasing the QoL among the elderly.

Flow injection chemiluminescence determination of ethion and computational investigation of the adsorption process on molecularly imprinted polymerized high internal phase emulsion.

The lack of sufficient selectivity is the main limitation of chemiluminescence (CL) methods; because the CL reagent is not restricted to a specific analyte. This study investigated the preconcentration and determination of ethion using a flow injection CL (FIA-CL) method using a molecularly imprinted poly high internal phase emulsion (MIP-polyHIPE) adsorbent. Preliminary studies showed that ethion could be determined with high sensitivity in the Ru(bipy)3 2+ -acidic Ce(IV) CL system. A MIP-polyHIPE adsorbent was synthesized and used for preconcentration to increase the selectivity and sensitivity of the method. The adsorption of ethion on the adsorbent was investigated using density functional theory (DFT) and molecular dynamics (MD), UV-vis and FTIR spectrophotometry and liquid chromatography-tandem mass spectrometry (LC-MS-MS). Response surface methodology (RSM) and central composite design (CCD) were used to find optimized concentrations of variables. The linear dynamic range (LDR) and limit of detection (LOD) for ethion in the FIA-CL method were calculated 1.0 ⨯ 10-9 to 2.0 ⨯ 10-7 and 6.0 ⨯ 10-10  mol L-1 , respectively. The percentage of relative standard deviation for five repetitive measurements of 5.0 ⨯ 10-8  mol L-1 ethion was 4.2%. The proposed method was successfully used to separate and preconcentrate ethion from drinking and surface water sources.

Carbohydrate Intake, Glycemic Index, and Glycemic Load and the Risk of Breast Cancer among Iranian Women.

Limited studies have conducted on the association between carbohydrate intake, glycemic index (GI), glycemic load (GL), and BC risk among Middle Eastern women. Our objective was to examine whether intake of carbohydrates, GI and GL would lead to more risk of BC among Iranian women. In this case-control study, 136 women with histologically confirmed BC and 272 control women were recruited. Dietary intake was assessed using a validated 168-item food frequency questionnaire (FFQ) from which GI and GL were estimated. We calculated Odds ratios (OR) using logistic regression. The multivariate OR for the highest vs. the lowest quartile was 2.49 (95% CI 1.28-4.82; P trend = 0.005) for GI with a significant trend. OR for GI and GL among postmenopausal women were 4.45 (95% CI 1.59-12.47; P trend = 0.002) and 4.15 (95% CI 0.87-19.67; P trend = 0.03), respectively. OR for GI among women with reduced vegetable intake was 13.55 (95% CI 3.90-46.99; P trend <0.001). Our data suggest that high GI and GL play an important role in the risk of BC particularly among postmenopausal woman.

Does the reaction size of skin prick test associated with the allergic rhinitis symptom severity?

BACKGROUND: Skin prick test (SPT) has the best positive predictive value to diagnose respiratory atopic diseases, including allergic rhinitis (AR), but the association of severity of allergic symptom and SPT reaction size has not been clearly determined yet. METHODS: In this a cross- sectional investigation, the severity of disease is classified using a visual analog scale for main symptoms, and SPT was conducted according to the principles of the European Academy of Allergy and Clinical Immunology. RESULTS: Thirty seven percent of the participants had at least one severe symptom. Patients with sensitivity to Alternaria (common allergens in humans) or tree pollens had more severe symptoms. We found that in patients who had sensitivity to Russian thistle pollen, wheal size >6 mm, was associated with more severe symptoms. CONCLUSION: Despite previous conflicts to rely on SPT test for starting immunotherapy, we recommend this test especially for patients sensitive to Alternaria, weed pollens, and tree pollens, considering the size of wheal in association with AR symptom severity.

Quality and cost analysis of a wastewater treatment plant using GPS-X and CapdetWorks simulation programs.

Wastewater management is a significant challenge, especially for arid and semiarid countries due to the water scarcity crisis. Considering human health, environmental regulations, wastewater treatment plant expenses, and water reusability, this study aims to assist in designing an efficient and economical WWTP. Technical and economic simulation and modeling are important for designing, constructing, and predicting the requirements of wastewater treatment plant designs. Simulation of a project before its implementation, in the first place, reduces additional costs, and from another point of view, a project is examined and researched from different aspects. In this study, three wastewater treatment plants based on conventional activated sludge, contact stabilization, and step aeration were simulated and evaluated technically and economically using the Zargandeh treatment plant data in Tehran. In three scenarios, GPS-X software investigated the effect of raw wastewater variations between their minimum and maximum intervals on effluent quality, and because the range of inlet effluent was different, more precise results were obtained. Then, the economic costs of the project, including implementation, maintenance, and also energy use, were calculated by Capdetwork software, and contact stabilization was found to be more cost-effective.

Pressure Pain Threshold in Subjects With Piriformis Syndrome: Test-Retest, Intrarater, and Interrater Reliability, and Minimal Detectible Changes.

OBJECTIVE: This study aimed to assess the test-retest, intrarater, and interrater reliability of using the pressure pain threshold (PPT) in healthy and affected piriformis muscles and to estimate its absolute reliability. As a secondary objective, the degree of tenderness of the affected piriformis muscles was compared with healthy piriformis muscles. STUDY DESIGN: This study used a comparative and reliability-based design. SETTING: Rehabilitation clinic. PARTICIPANTS: Patients (N=30) with unilateral piriformis muscle syndrome (30 affected and 30 healthy piriformis muscles) were recruited, and the PPT of both the healthy and affected piriformis muscles was recorded using digital algometry. Measurements of PPT were done by 2 raters (rater 1 and 2), which were selected at random order. Rater 1 repeated the PPT measurements 24-72 hours after initial assessment. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: PPT. RESULTS: Excellent intrarater intraclass correlation coefficient (ICC) values were observed for the PPT of the affected piriformis (ICC: 0.86-0.96) and the healthy piriformis (ICC: 0.88-0.96) in the same session. The PPT measurements using digital algometry showed good-to-excellent interrater reliability (ICC: 0.64-0.92) and test-retest reliability (ICC: 0.72-0.95) in both the healthy and affected piriformis muscles. The findings revealed a significant decrease in the PPT of the affected piriformis muscle in comparison to the healthy piriformis muscle (mean difference 12.76; 95% confidence interval, 15.69-9.82; P<.001). CONCLUSIONS: Digital algometry is a reliable tool for measuring piriformis PPT, regardless of the testing session and the rater. Patients with unilateral piriformis muscle syndrome have increased tenderness and decreased PPT in the affected piriformis muscle in comparison to the healthy piriformis muscle.

Ultrasound-guided dry needling decreases pain in patients with piriformis syndrome.

INTRODUCTION: Piriformis muscle syndrome (PMS) is a disorder that can lead to symptoms of buttock pain and limited hip-joint mobility, and may have an impact on quality of life. METHODS: Thirty-two patients with PMS were randomized to the treatment group, which included three sessions of ultrasound-guided dry needling (DN) of the piriformis muscle (n = 16), or a waitlist control group (n = 16). The primary outcome was pain intensity measured on the visual analog scale recorded at baseline and then at 72 hours and 1 week after treatment. RESULTS: At 1-week follow-up, pain intensity was significantly less in the DN group than in the waitlist control group (-2.16 [-1.01 to -3.32], P = .007) by an amount consistent with clinically meaningful improvement. DISCUSSION: The findings suggest that DN resulted in clinically meaningful short-term improvement in pain intensity of patients with PMS.

Efficacy of a written prayer technique on the anxiety of mothers of children with cancer.

OBJECTIVE: To investigate the effect of a written prayer technique on the anxiety of mothers of children with cancer. METHOD: This clinical trial recruited 90 mothers of children with cancer admitted to the Medical Centre of Tehran. Using a convenience sampling method, we randomly assigned the participants to two groups: control (n = 45) and intervention (n = 45). Data were collected through the Spielberger's anxiety scale and a demographic questionnaire. Maternal anxiety was measured before the intervention, immediately after the three-day intervention, and five weeks after the intervention. We used a writing technique in the intervention and control groups for 20 minutes over three consecutive days. In the intervention group, participants wrote down their sincere desires and wishes that they demanded from God without any worry or stress. The control group spent 20 minutes writing their normal daily schedules; for example, feeding their children or changing their children's clothes. During the three consecutive days of intervention, we asked both groups not to worry about grammar or spelling errors. Finally, the data were analyzed using descriptive and analytical statistical methods.ResultA statistically significant difference was observed between the two groups (intervention and control mean, 34.9 ± 9.9 and 47.9 ± 16.2, respectively) relative to anxiety after the intervention (p < 0.001). After five weeks, the intervention group continued to exhibit significantly reduced anxiety compared with the control group (intervention and control mean, 34.7 ± 9.6 and 48.5 ± 16.4; p < 0.001).Significance of resultsThe written prayer technique appears to be an effective, efficient, cost-effective, and practical method for reducing anxiety in mothers of children with cancer.

Gender Differences in the Publication Rate Among Breast Imaging Radiologists in the United States and Canada.

OBJECTIVE: The purpose of this study is to determine whether academic achievement differs by gender among breast imaging radiologists. MATERIALS AND METHODS: We examined the gender disparity in academic breast radiology using several parameters, including the h-index, the number of publications, and the number of citations. We also inspected gender disparity in academic ranks and leadership ranks. RESULTS: The research productivity of female breast imagers was found to be significantly lower than that of male colleagues across all academic ranks (p < 0.001). In addition, no correlation was noted between female gender and leadership positions (p = 0.57), despite the fact that women dominate the specialty of breast imaging. CONCLUSION: The number of publications by female radiologists has risen steadily over time; however, a significant gender disparity is seen in scholarly productivity.

Trends of infodemiology studies: a scoping review.

INTRODUCTION: The health care industry is rich in data and information. Web technologies, such as search engines and social media, have provided an opportunity for the management of user generated data in real time in the form of infodemiology studies. The aim of this study was to investigate infodemiology studies conducted during 2002-2016, and compare them based on developed, developing and in transition countries. METHODS: This scoping review was conducted in 2017 with the help of the PRISMA guidelines. PubMed, Scopus, Science Direct, Web of Knowledge, Google Scholar, Wiley and Springer databases were searched between the years 2002 and 2016. Finally, 56 articles were included in the review and analysed. RESULTS: The initial infodemiology studies pertain to the quality assessment of the hospital's websites. Most of the studies were on developed countries, based on flu, and published in the Journal of Medical Internet Research. CONCLUSION: The infodemiology approach provides unmatched opportunities for the management of health data and information generated by the users. Using this potential will provide unique opportunities for the health information need assessment in real time by health librarians and thereby provide evidence based health information to the people.

Genetic diversity and structure of Capparis spinosa L. in Iran as revealed by ISSR markers.

Capparis spinosa L. (caper bush) is an economically and ecologically important perennial shrub that grows across different regions of Iran. In this study, the genetic diversity and population structure of Iranian genepool of C. spinosa is evaluated using Inter Simple Sequence Repeat (ISSR) markers. Using 10 ISSR primers, 387 DNA fragments (bands) were amplified from the genomic DNA of 92 individuals belonging to twenty-one populations of C. spinosa, of which 378 (97.7%) were polymorphic. High level of genetic diversity (percentage of polymorphic loci = 98.2%, h = 0.1382, I = 0.243), high genetic differentiation (Gst = 0.5234) and low gene flow (Nm = 0.4553) among populations were observed. Caper bush populations were divided into 4 groups in the dendrogram, PCoA plot and Bayesian clustering results, mostly corresponded to their geographic regions. The results showed that there are value in sampling Iranian caper bush populations to look for valuable alleles for use in plant breeding programs.

Evaluating the expression profile and stability of different UCOE containing vector combinations in mAb-producing CHO cells.

BACKGROUND: As the demand for monoclonal antibodies (mAb) increases, more efficient expression methods are required for their manufacturing process. Transcriptional gene silencing is a common phenomenon in recombinant cell lines which leads to expression reduction and instability. There are reports on improved antibody expression in ubiquitous chromatin opening element (UCOE) containing both heavy and light chain gene constructs. Here we investigate the impact of having these elements as part of the light chain, heavy chain or both genes during cell line development. In this regard, non-UCOE and UCOE vectors were constructed and stable Chinese hamster ovary (CHO) cell pools were generated by different vector combinations. RESULTS: Expression analysis revealed that all UCOE cell pools had higher antibody yields compared to non-UCOE cells, Moreover the most optimal expression was obtained by cells containing just the UCOE on heavy chain. In terms of stability, it was shown that the high level of expression was kept consistence for more than four months in these cells whereas the expression titers were reduced in the other UCOE pools. CONCLUSIONS: In conclusion, UCOE significantly enhanced the level and stability of antibody expression and the use of this element with heavy chain provided more stable cell lines with higher production level.

The effect of sex and menstrual phase on memory formation during a nap.

Memory formation can be influenced by sleep and sex hormones in both men and women, and by the menstrual cycle in women. Though many studies have shown that sleep benefits the consolidation of memories, it is not clear whether this effect differs between men and women in general or according to menstrual phase in women. The present study investigated the effect of sex and menstrual cycle on memory consolidation of face-name associations (FNA) following a daytime nap. Recognition memory was tested using a face-name paired associates task with a polysomnographic nap between morning and evening testing. Seventeen healthy women (age: 20.75 (1.98) years) were studied at two time points of their menstrual cycles, defined from self-report and separated by 2weeks (perimenses: -5days to +6days from the start of menses, and non-perimenses: outside of the perimenses phase), and compared with eighteen healthy men (age: 22.01 (2.91) years). Regardless of menstrual phase, women had better pre-nap performance than men. Further, menstrual phase affected post-nap memory consolidation, with women showing greater forgetting in their perimenses phase compared with their non-perimenses phase and men. Interestingly, post-nap performance correlated with electrophysiological events during sleep (slow oscillations, spindles, and temporal coupling between the two), however, these correlations differed according to menstrual phase and sex. Men's performance improvement was associated with the temporal coupling of spindles and slow oscillations (i.e., spindle/SO coincidence) as well as spindles. Women, however, showed an association with slow oscillations during non-perimenses, whereas when they were in their perimenses phase of their cycle, women appeared to show an association only with sleep spindle events for consolidation. These findings add to the growing literature demonstrating sex and menstrual phase effects on memory formation during sleep.

PhiC31 integrase can improve the efficiency of different construct designs for monoclonal antibody expression in CHO cells.

OBJECTIVES: Several types of expression vectors have been used for recombinant protein expression in Chinese hamster ovary cells (CHO) which usually result in variable and unstable levels of expression. METHODS AND RESULTS: In this study, we have compared the mAb0014 expression level of single ORF/IRES vector and dual ORF vector in the presence and absence of phiC31 integrase targeting system. Both expression vectors contain an elongation factor 1α (EF1α) promoter upstream of LC and harboring an attB site. CHO-S cells were co-transfected with single ORF/IRES or dual ORF vectors along with a phiC31 integrase expression vector which can catalyze recombination between attB site and pseudo-attP sites presented in the mammalian genome. Our results demonstrated that dual ORF vector in the presence of phiC31 integrase expression vectors (+FC31 2P) generated more recombinant antibody in comparison to its negative control (-FC31 2P). Moreover, both of +FC31 2P and -FC31 2P cell pools yield higher recombinant protein in comparison to single ORF/IRES vector (FC31 IRES) cell pools. Stability of expression in phiC31 co-transfected cell pools (+FC31 2P and +FC31 IRES) had no considerable changes. CONCLUSIONS: Our results indicated that the dual ORF vector using integrase can support the generation of cell lines with stable transgene expression at an elevated mAb relative to single ORF/IRES vector.

CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor.

Ag receptors used for cancer immunotherapy are often directed against tumor-associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor-associated Ag that shows low expression in many normal tissues. Transfer of MDM2-TCR-engineered T cells into bone marrow chimeric mice revealed that Ag recognition in hematopoietic tissues maintained T cell function, whereas presentation of MDM2 in nonhematopoietic tissues caused reduced effector function. TCR-engineered CD8(+) T cells underwent rapid turnover, downmodulated CD8 expression, and lost cytotoxic function. We found that MDM2-TCR-engineered CD4(+) T cells provided help and restored cytotoxic function of CD8(+) T cells bearing the same TCR. Although the introduction of the CD8 coreceptor enhanced the ability of CD4(+) T cells to recognize MDM2 in vitro, the improved self-antigen recognition abolished their ability to provide helper function in vivo. The data indicate that the same class I-restricted TCR responsible for Ag recognition and tolerance induction in CD8(+) T cells can, in the absence of the CD8 coreceptor, elicit CD4 T cell help and partially reverse tolerance. Thus MHC class I-restricted CD4(+) T cells may enhance the efficacy of therapeutic TCR-engineered CD8(+) T cells and can be readily generated with the same TCR.