Cutting edge: unconventional CD8+ T cell recognition of a naturally occurring HLA-A*02:01-restricted 20mer epitope

Unconventional HLA class I-restricted CD8+ T cell epitopes, longer than 10 aa, have been implicated to play a role in human immunity against viruses and cancer. T cell recognition of long peptides, centrally bulging from the HLA cleft, has been described previously. Alternatively, long peptides can contain a linear HLA-bound core peptide, with a N- or C-terminal peptide "tail" extending from the HLA peptide binding groove. The role of such a peptide "tail" in CD8+ T cell recognition remains unclear. In this study, we identified a 20mer peptide (FLPTPEELGLLGPPRPQVLA [FLP]) derived from the IL-27R subunit α gene restricted to HLA-A*02:01, for which we solved the crystal structure and demonstrated a long C-terminal "tail" extension. FLP-specific T cell clones demonstrated various recognition modes, some T cells recognized the FLP core peptide, while for other T cells the peptide tail was essential for recognition. These results demonstrate a crucial role for a C-terminal peptide tail in immunogenicity. </p

Broadly applicable TCR-based therapy for multiple myeloma targeting the immunoglobulin J chain

Background: The immunoglobulin J chain (Jchain) is highly expressed in the majority of multiple myeloma (MM), and Jchain-derived peptides presented in HLA molecules may be suitable antigens for T-cell therapy of MM. Methods: Using immunopeptidomics, we identified Jchain-derived epitopes presented by MM cells, and pHLA tetramer technology was used to isolate Jchain-specific T-cell clones. Results: We identified T cells specific for Jchain peptides presented in HLA-A1, -A24, -A3, and -A11 that recognized and lysed JCHAIN-positive MM cells. TCRs of the most promising T-cell clones were sequenced, cloned into retroviral vectors, and transferred to CD8 T cells. Jchain TCR T cells recognized target cells when JCHAIN and the appropriate HLA restriction alleles were expressed, while JCHAIN or HLA-negative cells, including healthy subsets, were not recognized. Patient-derived JCHAIN-positive MM samples were also lysed by Jchain TCR T cells. In a preclinical in vivo model for established MM, Jchain-A1, -A24, -A3, and -A11 TCR T cells strongly eradicated MM cells, which resulted in 100-fold lower tumor burden in Jchain TCR versus control-treated mice. Conclusions: We identified TCRs targeting Jchain-derived peptides presented in four common HLA alleles. All four TCRs demonstrated potent preclinical anti-myeloma activity, encouraging further preclinical testing and ultimately clinical development.Proteomic

Improving cardiovascular risk management: A randomized, controlled trial on the effect of a decision support tool for patients and physicians

There is nonoptimal adherence of general practitioners (GPs) and patients to cardiovascular risk reducing interventions. GPs find it difficult to assimilate multiple risk factors into an accurate assessment of cardiovascular risk. In addition, communicating cardiovascular risk to patients has proved to be difficult. Improving primary prevention of cardiovascular disease (CVD) in primary care by enhancing patient involvement in the use of a decision support tool. Design Cluster randomized trial. Thirty-four GPs included patients (40-75 years old) without CVD. In an interactive, small group training session lasting 4h, the GPs in the intervention group were trained to use the guidelines on cardiovascular risk and a decision support tool. The control group received educational materials about the guidelines on paper. GPs’ clinical performance and patients' risk perception and self-reported lifestyles were measured at baseline and after 6 months. Results Thirty-four GPs recorded 490 consultations, 276 in the intervention and 214 in the control group. After 6 months, no significant effect of the intervention on the GPs’ performance or the patients' risk perception was found. There was only an effect on self-reported lifestyle, in that more men in the intervention group than in the control group increased their physical activity (odds ratio 3.8, 95% confidence interval 1.7–8.7). The 4-h interactive, small group training did not guarantee correct application of the decision support tool and as such failed to improve GPs’ performance or correct patients' risk perception. The positive effect on physical activity justifies further research on patient involvement

Therapeutic targeting of the BCR-associated protein CD79b in a TCR-based approach is hampered by aberrant expression of CD79b

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease

IMPORTANCE: Neurogranin (NGRN) seems to be a promising novel cerebrospinal fluid (CSF) biomarker for synaptic loss; however, clinical, and especially longitudinal, data are sparse. OBJECTIVE: To examine the utility of NGRN, with repeated CSF sampling, for diagnosis, prognosis, and monitoring of Alzheimer disease (AD). DESIGN, SETTING, AND PARTICIPANTS: Longitudinal study of consecutive patients who underwent 2 lumbar punctures between the beginning of 1995 and the end of 2010 within the memory clinic–based Amsterdam Dementia Cohort. The study included 163 patients: 37 cognitively normal participants (mean [SE] age, 64 [2] years; 38% female; and mean [SE] Mini-Mental State Examination [MMSE] score, 28 [0.3]), 61 patients with mild cognitive impairment (MCI) (mean [SE] age, 68 [1] years; 38% female; and mean [SE] MMSE score, 27 [0.3]), and 65 patients with AD (mean [SE] age, 65 [1] years; 45% female; and mean [SE] MMSE score, 22 [0.7]). The mean (SE) interval between lumbar punctures was 2.0 (0.1) years, and the mean (SE) duration of cognitive follow-up was 3.8 (0.2) years. Measurements of CSF NGRN levels were obtained in January and February 2014. MAIN OUTCOME AND MEASURE: Levels of NGRN in CSF samples. RESULTS: Baseline CSF levels of NGRN in patients with AD (median level, 2381 pg/mL [interquartile range, 1651-3416 pg/mL]) were higher than in cognitively normal participants (median level, 1712 pg/mL [interquartile range, 1206-2724 pg/mL]) (P = .04). Baseline NGRN levels were highly correlated with total tau and tau phosphorylated at threonine 181 in all patient groups (all P < .001), but not with Aβ42. Baseline CSF levels of NGRN were also higher in patients with MCI who progressed to AD (median level, 2842 pg/mL [interquartile range, 1882-3950 pg/mL]) compared with those with stable MCI (median level, 1752 pg/mL [interquartile range, 1024-2438 pg/mL]) (P = .004), and they were predictive of progression from MCI to AD (hazard ratio, 1.8 [95% CI, 1.1-2.9]; stratified by tertiles). Linear mixed-model analyses demonstrated that within-person levels of NGRN increased over time in cognitively normal participants (mean [SE] level, 90 [45] pg/mL per year; P < .05) but not in patients with MCI or AD. CONCLUSIONS AND RELEVANCE: Neurogranin is a promising biomarker for AD because levels were elevated in patients with AD compared with cognitively normal participants and predicted progression from MCI to AD. Within-person levels of NGRN increased in cognitively normal participants but not in patients with later stage MCI or AD, which suggests that NGRN may reflect presymptomatic synaptic dysfunction or loss

Generation of CD20-specific TCRs for TCR gene therapy of CD20(low) B-cell malignancies insusceptible to CD20-targeting antibodies

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological diseasesHematolog