Effects of Chronic Exposure of PCB (Aroclor 1254) on Specific and Nonspecific Immune Parameters in the Rhesus (Macaca mulatta) Monkey. Tryphonas, H., Luster, M. I., Schiffman, G., Dawson, L.-L., Hodgen, M., Germolec, D., Hayward, S., Bryce, F., Loo, J. C. K., Mandy, F., and Arnold, D. L. (1991). Fundam. Appl. Toxicol. 16, 773–786. The immunomodulatory effects of low-level, chronic polychlorinated biphenyl PCB; (Aroclor 1254) exposure were investigated in female rhesus (Macaca mulatta) monkeys. Five groups of monkeys (initially 16 monkeyS/group) were orally administered PCB at levels of 0, 5, 20, 40, or 80 μg/kg body wt/day. Tests for immunomodulation were initiated after 55 months of exposure to PCBs. Statistically significant observed immune changes included a dose-related decrease in the anamnestic (IgM and IgG) response to sheep red blood cells. Conversely, the antibody response to pneumococcus antigen did not differ significantly across the test groups. A statistically significant dose-related decrease in lymphoproliferation was noted with increasing doses of PCBs when phytohemagglutinin and Concanavalin A, but not when pokeweed mitogen, were used as mitogens. A trend toward reduced peak chemiluminescence (mV/min) was observed in zymosan-activated peripheral blood monocytes. The time to peak chemiluminescence of phorbol myristate acetate activation was statistically increased in a dose-response fashion. Flow cytometric analysis results of peripheral blood lymphocytes using the markers CD4, CD8, and CD20 were similar across the test groups. The mean percentage levels for the CD2 marker in the treated groups were statistically lower than the mean in the control, while absolute numbers for CD2 were similar across the test groups. Serum hydrocortisone levels did not differ among the test groups. Taken together these results indicate that low-level, chronic PCB exposure alters a number of rhesus monkey immune system components and that these effects may be due to altered T-cell and/or macrophage function. These data may be of use in extrapolating potential human health effects following chronic PCB exposure.
Frank Mandy [Color figure can be viewed at wileyonlinelibrary.com] During the past decade, we have seen steady progress in the fight against cancer with the flow cytometry (FC) platform. Some types of malignancies which previously were often undetected until it was too late are presently detected earlier, so treatment in many cases are more effective. We are introducing 10 communications in this issue, and they are all about supporting the arduous task of ultimately eradicating cancer. These efforts are further challenged with Covid-19. Our relentless pursuit reminds me of the 19th century philosopher Arthur Schopenhauer who said “Talent hits a target no one else can hit; Genius hits a target no one else can see.” As we are well into the second decade of a new century, our remarkable FC platform continues to push boundaries forward in cell analysis. In 2003, two medical/social historians, Peter Keating and Alberto Cambrosio from Montreal, wrote a book about FC with the title: “Biomedical Platforms,” which is about “realigning the normal and the pathological in the late-twentieth-century medicine (Mandy & Gratama, 2009). It is interesting to note that Montreal is a city, where from November to April the streets are usually covered in a hiemal monochromatic blanket. It exists as shades of gray, frequently sprinkled with fresh white snow, but only to revert back in days to a filthy gray. Contrasting such a bleak image, in clinical laboratories the FC platforms generate brilliant fluorescent fluorophore tags permitting our visualization of more membrane receptors associated with pathological findings. These continuous immunophenotyping efforts lead to steady improvements in oncological outcomes. No doubt that our celebrated platform continues to inspire talented scientists to ask critical questions and design clever experiments, to find targets that were until now “invisible.” Innovative new polychromatic protocols are constantly added to the FC platform. Two remarkable Individuals, who began their research carrier during the second half of the 20th century, such as Leonard Herzenberg (Roederer, 2013) and Howard Shapiro (Moore, 2021) have pushed the limits of the FC platform to beyond the imaginable. They focused monochromatic light from multiple wavelength to trigger on fluorescence emitted from poly-fluorophore tags. Today, it is possible to perform complex multiparametric analysis, to measure cell associated proteins, report antigen-specific T-cell receptor clonotypes and design immunotherapies to deal with specific malignancies. Our magnificent analytical platform continues to deliver progress on the ardours path to obliterate cancer. In this issue, there are five Original Articles, one Review Article, two Case Reports, one Brief Communication and a Letter to the Editor. Two of the Original Articles focused on new diagnostics protocols for Waldenström Macroglobulinemia (WM), a disease first described almost 80 years ago. The first Original Article's tile: “Flow cytometry detection of CD138 expression continuum between monotypic B and plasma cells is associated with both high IgM peak levels and MYD88 mutation and contributes to diagnosis of Waldenström Macroglobulinemia.” It has been previously established that FC can identify and characterize distinct immunophenotypic profiles of neoplastic plasma cells (Wang & Lin, 2019). Also, some of the challenges related to diagnosing T-cell neoplasms have been addressed, with overlapping features including reactive T-cells (Shi et al., 2020). The authors deal with FC analysis of both B-cells and PC from patients with IgM peaks. MYD88 and CXCR4 mutations studies are presented using an allele-specific PCR and with high throughput sequencing. The study is an exploration with FC to identify a CD138 expression continuum as a marker of ongoing plasma cell differentiation of WM tumors. The second Original Article's title is “VS38 staining presents a novel gating strategy in flow cytometry for small B cell lymphoma, especially in lympho-plasmacytic lymphoma/Waldenström macroglobulinemia.” In the past, CD5+ chronic B-cells have been reported in lymphoproliferative disorders (Dronca et al., 2010). Determination of CD43 and CD200 surface expressions to improve the accuracy of B-cell lymphoma immuno-phenotyping has been previously reported (Hoffmann et al., 2020). Also, FC analysis of diagnostic and prognostic value of plasma cell neoplasms have been reviewed elsewhere (Wang & Lin, 2019). The authors evaluated the stainability of VS38, which is used for multiple myeloma, in normal and abnormal B cells with FC in order to develop a new strategy to detect lymphoma associated with WM. The third Original Article's title is “Malignant PCs in bone marrow detected by flow cytometry as a predictor for the risk stratification system of multiple myeloma.” With an FC protocol, it is possible to quantify plasma cells and the ratio of malignant PCs. They are strongly associated with unfavorable clinical-pathology. It is a sensitive method for multiple myeloma (MM) patient's and is used for risk stratification. In this study, malignant PCs in MM bone marrow was detected with FC. A literature review reveals CD20-positive cells exists in primary nasal peripheral T-cell lymphoma (Dronca et al., 2010). The authors data demonstrates that malignant PCs can be detected with FC and is elevated in MM patients with negative pathological features. The authors conclude that multiparameter FC evaluation of BMPC for diagnosis is valuable. The fourth Original Article covers “Time point-dependent concordance and prognostic significance of flow cytometry and real time quantitative PCR for measurable/minimal residual disease detection in acute myeloid leukemia with t(8;21) (q22;q22.1).” In a recent publication, the prognostic significance of the presence of hematogones after autologous stem cell transplantation in patients with multiple myeloma was discussed (Sorigue et al., 2020). Validation of a modified pre-lysis sample preparation for FC for minimal residual disease assessment in multiple myeloma was presented elsewhere (Göçer & Kurtoglue, 2021) also, in a case report, MM with CD138 changed from positive to negative (Bayly et al., 2020; Yu et al., 2021). According to the authors, FC alone does not provide accurate prognoses. However, sequential monitoring with PCR is a significant step to more dependable prognosis. The title of the fifth Original Article is “Log reduction of leukemic cells and minimal residual disease by flow cytometry represent effective predictors of clinical outcome in elderly patients with acute myeloid leukemia.” Minimal residual disease (MRD) and log-reduction of leukemic cells are poorly investigated in elderly patients with acute myeloid leukemia (AML) treated with hypometilating agents (HMAs). It has been previously established that with 11-markers, using 10-color FC assessment, it is possible to measure residual disease for T-cell acute lymphoblastic leukemia using an exclusion approach (Soh et al., 2020). The authors focused on MRD in elderly AML patients who received HMAs. After comparing the times of assessment with 4 and 6-cycles, the later was considered optimal. Patients who achieved MRD negativity or 2-log-reduction of leukemic cells with 6-cycles had a significantly longer disease-free survival. The Review Article's title is “A comparison and review of the flow cytometric findings in classic Hodgkin lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, T cell/histiocyte rich large B cell lymphoma and primary mediastinal large B cell lymphoma.” Traditionally, distinguishing these entities are difficult with FC. There are insufficient immuno-phenotypic guidelines for the investigation of certain lymphomas (Tsagarakis et al., 2022). Multicentric efforts have been made to standardize FC analysis of CD30 expression in non-Hodgkin lymphoma (Debliquis et al., 2021). There is also a report on using CD43 and CD200 surface expression they do improve accuracy of B-cell lymphoma immunophenotyping (Dronca et al., 2010). However, this review includes fluorochrome tagged antibody combinations, which provide accurate resolution using an immunoprofile method. An algorithm with characterization of the background reactive B-cell and T-cell populations also helps to narrow the differential diagnosis. The first Case Report is about “Peripheral T-cell lymphoma immunophenotype in a patient with a history of Muromonab-CD3 therapy: A case report and a diagnostic dilemma.” A dilemma exists when using peripheral T-cell lymphoma immunophenotyping in a patient after Muromonab-2 CD3 therapy. The authors describe a case with peripheral blood sample having a false-negative staining for CD3 cell surface because of endogenous anti-CD3 antibodies present 20 years after Muromonab-CD3 therapy. The second Case Report's title is “Lymphoid blasts with aberrant myeloid marker expression and BCR/ABL1: is it mixed phenotype acute leukemia or B lymphoblastic leukemia?” There is a single-cell profiling report in pediatric T-cell acute lymphoblastic leukemia (Bonaccorso et al., 2020). There is also a report about residual disease assessment of B-cell precursor acute lymphoblastic leukemia, where the CD304/neuropilin-1 is a useful marker (Gudapati et al., 2020). Also, there is a report about leukemia-associated immunophenotypes subdivided in “categories of specificity” which may attribute to the dilemma (Rossi et al., 2020). The authors are asking a rhetorical question, they highlight the signature inverse expression characteristic using a case of MPAL B/myeloid with BCR/ABL1. They further make the point that, BCR/ABL1 in a case such as this one presented may create more ambiguity since it is known to be associated with aberrant myeloid expression in BALL. The title of the Brief Communication is: “Bone marrow follicular-like T cells in monoclonal gammopathies.” The authors findings point to a possible impairment of CD4+ Treg follicular-like cells in regulating antibody production. It is unlikely but there is a report of malignant plasmacytes in bone marrow detected by FC as a predictor for the risk stratification of multiple myeloma (Tian et al., 2022). There are some questions about proper validation of pre-lysis sample preparation technique for FC (Sorigue et al., 2020). There was an article published on the significance of method selection for sensitivity during multiple myeloma residual disease (Soh et al., 2020). The Letter to the Editor is focused on a publication entitled “Automated leukocyte parameters are useful in the assessment of myelodysplastic syndromes.” (Shestakova et al., 2021) The authors suggest that Cytometry B readers should be made aware of two additional studies which strengthens the message about additional features available on some automated white blood cell counters. They explain that such additional features are of interest when evaluating elderly patients for MDS. There are more publications covering improved diagnostic options for MDS such as exploring blast composition in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms with CD45RA and CD371 to improve diagnostic value of FC (Barreau et al., 2020). FC phenotypic evaluation of granulocytes and monocytes with 1-tube panel for diagnosis of patients w3th MDS (Gardikas et al., 2019). There is also an article on immunophenotypic profile of CD34+ subpopulation for detecting low-grade MDS (Shameli et al., 2020). Let me circle back to the Schopenhauer analogy, among the communications outlined, if you have identified some new tools while browsing through the reports, perhaps some of them will help you to visualize targets that were not visible to you. It is possible that Len's and Howard's eternal resting in peace will be perhaps a bit sweeter.
Objective: Because effective antiretroviral therapy (ART) reduces immune activation, we hypothesize that early changes in immune activation are associated with subsequent virologic response to therapy. Design: Observational cohort study. Setting: Institutional HIV clinic. Subjects: Thirty-four adult HIV patients with virologic failure on their current antiretroviral regimen. Intervention: Change to salvage regimen selected by patient's physician. Main Outcome Measures: Measures of immune activation at baseline and at 2, 4, 8, and 24 weeks after enrollment. Data were analyzed by proportional hazards (PH) models. Results: PH models showed that reductions between baseline and week 2 in expression of CD38 (P = 0.02) or CD95 (P = 0.02) on CD4+ T cells were associated with increased likelihood of achieving virologic suppression. Kaplan-Meier analysis demonstrated that patients who had reductions within the first 2 weeks of therapy in CD4+ T-cell expression of CD38 (P = 0.003) or CD95 (P = 0.08) were more likely to achieve viral suppression than those who did not. Conclusions: Reduced CD4+ T-cell expression of CD38 and CD95 occurring within 2 weeks of salvage therapy is associated with subsequent viral suppression. Monitoring CD38 and CD95 may allow earlier assessment of the response to ART.
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