Low absolute CD4+ T cell counts in peripheral blood predict poor prognosis in patients with newly diagnosed multiple myeloma

Abstract Multiple myeloma patients are often treated with immunomodulatory drugs, proteasome inhibitors, or monoclonal antibodies until disease progression. Continuous therapy in combination with the underlying disease frequently results in severe humoral and cellular immunodeficiency, which often manifests in recurrent infections. Here, we report on the clinical management and immunological data of three multiple-myeloma patients diagnosed with COVID-19. Despite severe hypogammaglobulinemia, deteriorated T cell counts, and neutropenia, the patients were able to combat COVID-19 by balanced response of innate immunity, strong CD8+ and CD4+ T cell activation and differentiation, development of specific T-cell memory subsets, and development of anti-SARS-CoV-2 type IgM and IgG antibodies with virus-neutralizing capacities. Even 12 months after re-introduction of lenalidomide maintenance therapy, antibody levels and virus-neutralizing antibody titers remained detectable, indicating persisting immunity against SARS-CoV-2. We conclude that in MM patients who tested positive for SARS-CoV-2 and were receiving active MM treatment, immune response assessment could be a useful tool to help guide decision-making regarding the continuation of anti-tumor therapy and supportive therapy. Key messages Immunosuppression due to multiple myeloma might not be the crucial factor that is affecting the course of COVID-19. In this case, despite pre-existing severe deficits in CD4+ T-cell counts and IgA und IgM deficiency, we noticed a robust humoral and cellular immune response against SARS-CoV-2. Evaluation of immune response and antibody titers in MM patients that were tested positive for SARS-CoV-2 and are on active MM treatment should be performed on a larger scale; the findings might affect further treatment recommendations for COVID-19, MM treatment re-introduction, and isolation measures.

Download Full-text

Exploring T Cell Reactivity to Gliadin in Young Children with Newly Diagnosed Celiac Disease

Autoimmune Diseases ◽

10.1155/2014/927190 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Edwin Liu ◽

Kristen McDaniel ◽

Stephanie Case ◽

Liping Yu ◽

Bernd Gerhartz ◽

...

Keyword(s):

T Cells ◽

Celiac Disease ◽

T Cell ◽

Young Children ◽

Peripheral Blood ◽

T Cell Responses ◽

Cd4 T Cell ◽

Newly Diagnosed ◽

Cell Responses ◽

Gliadin Peptides

Class II major histocompatibility molecules confer disease risk in Celiac disease (CD) by presenting gliadin peptides to CD4 T cells in the small intestine. Deamidation of gliadin peptides by tissue transglutaminase creates immunogenic peptides presented by HLA-DQ2 and DQ8 molecules to activate proinflammatory CD4 T cells. Detecting gliadin specific T cell responses from the peripheral blood has been challenging due to low circulating frequencies and heterogeneity in response to gliadin epitopes. We investigated the peripheral T cell responses to alpha and gamma gliadin epitopes in young children with newly diagnosed and untreated CD. Using peptide/MHC recombinant protein constructs, we are able to robustly stimulate CD4 T cell clones previously derived from intestinal biopsies of CD patients. These recombinant proteins and a panel ofα- andγ-gliadin peptides were used to assess T cell responses from the peripheral blood. Proliferation assays using peripheral blood mononuclear cells revealed more CD4 T cell responses toα-gliadin thanγ-gliadin peptides with a single deamidatedα-gliadin peptide able to identify 60% of CD children. We conclude that it is possible to detect T cell responses without a gluten challenge or in vitro stimulus other than antigen, when measuring proliferative responses.

Download Full-text

Relation of CD4+CD25+ Regulatory T Cells to Immune Status in Patients with HIV Infection.

Blood ◽

10.1182/blood.v104.11.3106.3106 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3106-3106

Author(s):

Sachi Tsunemi ◽

Tsuyoshi Iwasaki ◽

Takehito Imado ◽

Satoshi Higasa ◽

Eizo Kakishita ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Hiv Infection ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Healthy Controls ◽

Cell Counts ◽

Hiv 1

Abstract Human immunodeficiency virus (HIV) infection is characterized by marked defects in CD4+ helper T cell (Th) functions that commonly progress to a substantial decline in peripheral CD4+ T cell counts. However, the mechanisms responsible for the loss of Th functions in HIV-infected patients independent of CD4+ T cell counts remains unclear. CD4+CD25+ regulatory T cells (T Reg) are essential for down-regulation of both autoreactive and alloreactive T cells. Therefore, we decided to investigate the role of T Reg in immune status of HIV-infected patients. We examined the expression of cell surface CD25, cytoplasmic IL-4 and cytoplasmic IFN-gamma in peripheral blood CD4+ T cells from both healthy controls (n=9) and HIV-infected patients (n=43). We also compared T Reg functions between the 2 groups. CD4+CD25+ T Reg isolated from both HIV-infected patients and healthy controls strongly expressed CD45RO, HLA-DR, and FoxP3, and suppressed the proliferation of CD4+CD25− T cells, suggesting that CD4+CD25+ T cells from both healthy controls and HIV-infected patients possess phenotypic and functional characteristics of Treg. CD4+CD25high T cells are a subset of circulating CD4+CD25+ T cells in normal humans and exhibit strong in vitro regulatory functions similar to those reported for murine CD4+CD25+ T Reg. We measured the frequency of CD4+CD25high T Reg by analysis of surface CD25 on CD4+ T cells in peripheral blood samples. We also examined Th1 and Th2 frequencies by analysis of cytoplasmic IFN-gamma and IL-4 levels in CD4+ T cells. T Reg from HIV-infected patients with detectable plasma HIV-1 RNA showed a statistically significant increase in CD4+CD25high cell frequency (p<0.05) compared to healthy controls, with T Reg frequencies inversely proportional to CD4+ T cell numbers (p<0.01). However, in HIV-infected patients with undetectable plasma HIV-RNA, frequencies of CD4+CD25high T Reg were not increased and not related to CD4+ T cell numbers. In both HIV-infected patient groups, T Reg frequency was inversely related to Th1 frequency (detectable: p<0.05, undetectable: p<0.001), but positively related to Th2 frequency (detectable: p<0.01, undetectable: p<0.001). Our results indicate that increased frequencies of peripheral blood T Reg were related to disease progression as measured by detectable plasma HIV-1 RNA, decreased peripheral blood CD4+ T cell counts, and polarization toward Th2 immune responses in HIV-infected patients. HIV infection may lead to induction of T reg that inhibit antiviral immune responses, resulting in the progression of the disease. Manipulation of T Reg could help restore antiviral immune responses in HIV infection, and prevent the progression of HIV infection.

Download Full-text

Low absolute CD4+ T cell counts in peripheral blood are associated with inferior survival in follicular lymphoma

Tumor Biology ◽

10.1007/s13277-016-5124-9 ◽

2016 ◽

Vol 37 (9) ◽

pp. 12589-12595 ◽

Cited By ~ 5

Author(s):

Lu He ◽

Jin-Hua Liang ◽

Jia-Zhu Wu ◽

Yue Li ◽

Shu-Chao Qin ◽

...

Keyword(s):

T Cell ◽

Follicular Lymphoma ◽

Peripheral Blood ◽

Cd4 T Cell ◽

Cell Counts

Download Full-text

Circulating Low Absolute CD4+ T Cell Counts May Predict Poor Prognosis in Extranodal NK/T-Cell Lymphoma Patients Treating with Pegaspargase-Based Chemotherapy

Cancer Research and Treatment ◽

10.4143/crt.2018.010 ◽

2019 ◽

Vol 51 (1) ◽

pp. 368-377 ◽

Cited By ~ 2

Author(s):

Ya-Ping Zhang ◽

Run Zhang ◽

Hua-Yuan Zhu ◽

Li Wang ◽

Yu-Jie Wu ◽

...

Keyword(s):

T Cell ◽

Poor Prognosis ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Cd4 T Cell ◽

Cell Counts ◽

Nk T Cell

Download Full-text

Evaluation of Baseline CD4 + T Cell Counts and ART Requirement in Newly Diagnosed HIV Seropositive Individuals in a Tertiary Care Hospital of Northern India

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2016/21595.8915 ◽

2016 ◽

Author(s):

Sonali Bhattar

Keyword(s):

T Cell ◽

Tertiary Care Hospital ◽

Tertiary Care ◽

Cd4 T Cell ◽

Care Hospital ◽

Newly Diagnosed ◽

Northern India ◽

Cell Counts ◽

Hiv Seropositive

Download Full-text

Decrease in CD4+ T-Cell Counts in Patients With Multiple Myeloma Treated With Bortezomib

Clinical Lymphoma Myeloma & Leukemia ◽

10.3816/clml.2010.n.019 ◽

2010 ◽

Vol 10 (2) ◽

pp. 134-137 ◽

Cited By ~ 23

Author(s):

Ulrike Heider ◽

Jessica Rademacher ◽

Martin Kaiser ◽

Lorenz Kleeberg ◽

Ivana von Metzler ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Cd4 T Cell ◽

Cell Counts

Download Full-text

Circulating Plasma Cells in Newly Diagnosed Symptomatic Multiple Myeloma As a Prognostic Marker for Patients with Standard-Risk Cytogenetics

Blood ◽

10.1182/blood.v124.21.3353.3353 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3353-3353

Author(s):

Davide Vagnoni ◽

Fosco Travaglini ◽

Stefano Angelini ◽

Alessia Dalsass ◽

Francesca Mestichelli ◽

...

Keyword(s):

Multiple Myeloma ◽

Flow Cytometry ◽

Peripheral Blood ◽

Poor Prognosis ◽

Plasma Cells ◽

Cox Model ◽

Significant Proportion ◽

Newly Diagnosed ◽

Operating Characteristics ◽

Standard Risk

Abstract Multiple Myeloma (MM) is a clonal B-cell disorder characterized by accumulation of malignant plasma cells (PCs) in the bone marrow (BM). Circulating PCs can be detected in the peripheral blood of a significant proportion of patients with MM and their presence is a well-known prognostic factor. Indeed, the appearance of circulating PCs in the blood could indicate relative indipendence from adhesion to the microenvironment, thus implying more aggressive disease. In this study, we examined the relationship between the number of PCs and citogenetic risk in patients with newly diagnosed MM. We analyzed peripheral blood from patients with Monoclonal Gammopathy of Undetermined Significance (MGUS; n=15), Smoldering Myeloma (SM; n=28), Solitary Plasmacytomas (SP; n=3) and active Multiple Myeloma (MM; n=105). These patients were followed by the U.O.C. Ematologia at the "Mazzoni" Hospital from January 2006 to December 2013, with a median follow-up of 25 months. We analyzed clinical, laboratory and cytogenetic data of patients with active MM. However, cytogenetic analysis was not evaluable for 15 patients. The number of circulating PCs was detected by flow cytometry using a simple two-colours approach. Cells were stained with fluorescence-labeled CD38 and CD45 antibodies and 50,000 events were acquired and analyzed for each patient. PCs were identified by gating on CD38bright+/CD45- cells. Using a receiver operating characteristics (ROC) analysis, we assessed that ³41circulating PCs is the optimal cut-off for defining poor prognosis. The 8-years probability of Overall Survival (OS) and Progression-Free Survival (PFS) in patients with <41 and ³41circulating PCs, was 32% vs 8% (p=0.017) and 29% vs 0% (p=0.0008), respectively. Patients with high-risk cytogenetics (n=24) had poor prognosis, independently of circulating PCs (PC<41 vs PC³41: OS=0% vs OS=16%, p=n.s.; PFS=0% vs 17%, p=n.s.). Patients with standard-risk cytogenetics (n=66) showed a better prognosis associated to a lower number of circulating PCs (PC<41 vs PC³41: OS=36% vs 10%, p=0.026; PFS=37% vs 0%, p=0.0001). These data were confirmed by multivariate analysis (Cox model) for the subgroup with standard-risk cytogenetics, in which the presence of ³41 circulating PCs, older age, DS stage >I and lack of maintenance therapy, adversely affected OS and PFS. All patients with SP showed no circulating PCs. In all cases of MGUS or SM, circulating PCs, when detected, were <20. In summary, our results suggest that the quantification of circulating PCs by flow cytometry could provide useful prognostic information in newly diagnosed MM patients with standard-risk cytogenetics. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Rapid Increase of CD8+ T Cell Count in Peripheral Blood of Pediatric Patients After HLA-Identical Stem Cell Transplantation for African Sickle Cell Anemia

Blood ◽

10.1182/blood.v120.21.4769.4769 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4769-4769

Author(s):

Antonella Isgrò ◽

Marco Marziali ◽

Pietro Sodani ◽

Javid Gaziev ◽

Daniela Fraboni ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cd4 T Cell ◽

Myeloablative Conditioning ◽

Cell Counts

Abstract Abstract 4769 Background. Sickle Cell anemia (SCA) remain a disease with high risk of morbidity and early death, especially in African patients. Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCA. To analyze immunohematological reconstitution after transplant, we report our experience concerning 12 geno-identical HSCT for SCA-patients prepared with the same myeloablative conditioning regiment consisting of Busulfan and Cyclophosphamide. Patients and Methods. Twelve patients with a median age of 12 years (range, 2–16), affected by sickle cell anemia (SCA), received hematopoietic stem cell transplantations from HLA-identical, related donors following a myeloablative conditioning regimen. To analyze the mechanisms involved in immunological reconstitution post transplant, we analyzed T cell subsets by flow cytometry at + 60 post transplant. Results. All patients had sustained engraftment and remained free of any SCA-related events after transplantation. Sixty days after the transplant, the patients had significantly lower CD4+ T cells in comparison to the controls (15.6 ± 5.9 % vs. 47.5 ± 6% respectively), whereas CD8+ T cells were the first lymphocytes to repopulate the peripheral blood with up to 45% of these cells being CD8+ T cells (in mean 48.5 ± 14.3 % vs. 20 ± 7%). All patients displayed reduced numbers of B cells versus normal value, and 10/12 patients had only 0% to 1% of control levels of CD19+ cells. CD3-CD56+bright NK cells were 18.6 ± 12.2 %, whereas CD3-CD16+ (with cytotoxic functions) were 16.7 ± 11.8 %. Conclusion. Our primary finding include the following: 1) rapid increase of lymphocytes in peripheral blood after transplant; 2) rapid expansion of CD8+ T cell but not CD4 T cell counts. Probably reactivation of cytomegalovirus (CMV) infection, observed in 11/12 patients on the early stages of T-lymphocyte recovery after transplant, might induce a dramatic increase in CD8 but not in CD4 T-cell counts. Disclosures: No relevant conflicts of interest to declare.

Download Full-text