Supplementary Data from Plasma CD27, a Surrogate of the Intratumoral CD27–CD70 Interaction, Correlates with Immunotherapy Resistance in Renal Cell Carcinoma
Both human and mouse cytomegaloviruses (CMVs) encode proteins that inhibit the activation of NK cells by down-regulating cellular ligands for the activating NK cell receptor NKG2D. Up to now, three ligands for the NKG2D receptor, named RAE-1, H60, and MULT-1, have been identified in mice. The resistance of mouse strains to murine CMV (MCMV) infection is determined by their ability to generate an effective NK cell response. The MCMV gene m152, a member of the m145 gene family, down-regulates the expression of RAE-1 in order to avoid NK cell control in vivo. Here we report that the m155 gene, another member of the m145 gene family, encodes a protein that interferes with the expression of H60 on the surfaces of infected cells. Deletion of the m155 gene leads to an only partial restoration of H60 expression on the cell surface, suggesting the involvement of another, so far unknown, viral inhibitor. In spite of this, an m155 deletion mutant virus shows NK cell-dependent attenuation in vivo. The acquisition of endo-beta-N-acetylglucosaminidase H resistance and the preserved half-life of H60 in MCMV-infected cells indicate that the m155-mediated effect must take place in a compartment after H60 exits from the ERGIC-cis-Golgi compartment.
Bacground: In Bangladesh conventionally CHOP therapy is widely practiced for the treatment of NHL patient. But refractory/ relapse case is highly observed in CHOP therapy. Reports of different clinical trials showed that addition of Rituximab with CHOP therapy dramatically increase the progression free survival (PFS) and overall survival (OS) of patients.Methodology: To analyze the response and toxicities of NHL patients treated with Rituximab in combination with other chemotherapy regimen admitted in Anwer Khan Modern Hospital, City Hospital and United Hospital in Dhaka, Bangladesh. Response and toxicities of patients admitted to three institutions between May 2003 to December 2006 were analyzed. A total of 30 patients were observed in this study. Patients received up to 6-8 cycles of Rituximab in combination with CHOP for every 3 weeks as an induction therapy. Maintenance therapy was given to 6 patients at 3 months interval for up to 2 years.Result: After a median follow up period of 6 years patients were evaluated on the basis of response criteria. Out of the 30 patients 3 patients did not completed 6 cycle R-CHOP treatment regimen. 13% of the patients were refractory and died before completing therapy. With R-CHOP combination 47% of the patients experienced complete response. Partial response was observed in 20% of the patients. In this study 6% of the patients did not get response from the therapy. Haematological toxicity included grade 3-4 neutropenia 13%, anaemic 4%, febrile neutropenia 17% and thrombocytopenia 11%. Non-haematological toxicity included grade 2-3 nausea or vomiting 18%, grade 3 fatigue 12%.Conclusion: Addition of Rituximab as an immunotherapy option with chemotherapy regimen provides excellent response to Bangladeshi patients diagnosed for Diffused Large B Cell Lymphoma (DLBCL). Further study needs to be done to evaluate efficacy and toxicity profiles of patients treated with other chemotherapy regimen who were not eligible for CHOP regimen.Anwer Khan Modern Medical College Journal Vol. 6, No. 1: January 2015, Pages 28-34
Human immune responses are highly variable from one individual to another, with these differences determined by both genetic and environmental factors. We previously established the Milieu Interieur cohort to define the boundaries of healthy immune responses and identify and quantify its different determinants. From this cohort of 1,000 well-defined healthy donors, we have identified multiple genetic and environmental factors that are associated with variable immune phenotypes. Crucially, these associations were observed in a healthy context, as defined by strict inclusion and exclusion criteria. To assess how such immune responses may vary over time, we initiated a 10-year follow-up clinical study of the cohort. From the original 1,000 donors, we identified and recruited 415 donors from whom we assessed recent medical history and lifestyle factors, in addition to collecting samples for measurement of diverse immune phenotypes. A comparison of 107 laboratory and serological measures over the 10-year period showed significant correlations, highlighting the quality of the data collected. By accounting for potential batch effects, our analyses revealed the profound effects of aging on health-related biomarkers and antibody levels against common pathogens. We determined that a significant proportion of the donors no longer meet the initial definition of good health, due to either physiological changes associated with aging, or disease incidence including cancer, autoimmune and cardiovascular diseases. We found that disease development over the past 10 years is associated with a biological aging score, assessed at the time of the initial recruitment. In summary, the Milieu Interieur follow-up study will provide new opportunities for studying biological mechanisms of immunosenescence and identifying factors associated with accelerated immune aging and poor health outcomes.
The LabEx Milieu Interieur ( MI ) project is a clinical study centered on the detailed characterization of the baseline and induced immune responses in blood samples from 1,000 healthy donors. Analyses of these samples has lay ground for seminal studies on the genetic and environmental determinants of immunologic variance in a healthy cohort population. In the current study we developed in vitro methods enabling standardized quantification of MI-cohort-derived primary fibroblasts responses. Our results show that in vitro human donor cohort fibroblast responses to stimulation by different MAMPs analogs allows to characterize individual donor immune-phenotype variability. The results provide proof-of-concept foundation to a new experimental framework for such studies. A bio-bank of primary fibroblast lines was generated from 323 out of 1,000 healthy individuals selected from the MI-study cohort. To study inter-donor variability of innate immune response in primary human dermal fibroblasts we chose to measure the TLR3 and TLR4 response pathways, both receptors being expressed and previously studied in fibroblasts. We established high-throughput automation compatible methods for standardized primary fibroblast cell activation, using purified MAMPS analogs, poly I:C and LPS that stimulate TLR3 and TLR4 pathways respectively. These results were in turn compared with a stimulation method using infection by HSV-1 virus. Our “Add-only” protocol minimizes high-throughput automation system variability facilitating whole process automation from cell plating through stimulation to recovery of cell supernatants, and fluorescent labeling. Images were acquired automatically by high-throughput acquisition on an automated high-content imaging microscope. Under these methodological conditions standardized image acquisition provided for quantification of cellular responses allowing biological variability to be measured with low system noise and high biological signal fidelity. Optimal for automated analysis of immuno-phenotype of primary human cell responses our method and experimental framework as reported here is highly compatible to high-throughput screening protocols like those necessary for chemo-genomic screening. In context of primary fibroblasts derived from donors enrolled to the MI-clinical-study our results open the way to assert the utility of studying immune-phenotype characteristics relevant to a human clinical cohort.
Multiple stress pathways result in the induction of autophagy and apoptosis. Current methods (e.g., protein gel blot, microscopy) do not offer quantitative single-cell resolution, thus making it difficult to discern if these pathways are mutually exclusive or, in some situations, cooperative in executing cell death. We report a novel method that enables high-throughput, high-content assessment of LC3 puncta and caspase-3 cleavage at the single cell level.
Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
HIV elite controllers maintain a population of CD4 + T cells endowed with high avidity for Gag antigens and potent effector functions. How these HIV-specific cells avoid infection and depletion upon encounter with the virus remains incompletely understood. Ex vivo characterization of single Gag-specific CD4 + T cells reveals an advanced Th1 differentiation pattern in controllers, except for the CCR5 marker, which is downregulated compared to specific cells of treated patients. Accordingly, controller specific CD4 + T cells show decreased susceptibility to CCR5-dependent HIV entry. Two controllers carried biallelic mutations impairing CCR5 surface expression, indicating that in rare cases CCR5 downregulation can have a direct genetic cause. Increased expression of β-chemokine ligands upon high-avidity antigen/TCR interactions contributes to autocrine CCR5 downregulation in controllers without CCR5 mutations. These findings suggest that genetic and functional regulation of the primary HIV coreceptor CCR5 play a key role in promoting natural HIV control.
