High Numbers Of Memory T Cells Are Associated With Higher Risk Of Grade II-IV Acute Gvhd After Human Allogeneic Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2061-2061
Author(s):  
Michael Loschi ◽  
Régis Peffault de Latour ◽  
Raphael Porcher ◽  
Valerie Vanneaux ◽  
Marie Robin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Multivariate Analysis ◽  
T Cell ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Memory T Cells ◽  
Cytotoxic Lymphocytes ◽  
Memory T Cell ◽  
Grade Ii

Abstract Introduction Acute graft versus host disease is a frequent and life threatening complication following HSCT. Some predictive factors have been identified in the last decades. Experimental studies in mice suggest that the naïve cytotoxic T cells (CD3+/CD8+/CD45RA+/CD62L+) are the major mediators of acute GVHD and that removing this subset of the donor T cells, called ‘naïve T cells’, before transplant may reduce the frequency and intensity of GVHD. Detailed immunophenotyping of the graft including naïve and memory (CD3+/CD8+/CD45RA-/CD62L- ; CD3+/CD8+/CD45RA+/CD62L- ; CD3+/CD8+/CD45RA-/CD62L+ ) T-cell contents have never been explored in human GVHD. We studied the correlation between memory and naive T cell in bone marrow and peripheral blood grafts and development of acute GVHD after hematopoietic stem cell transplant. Methods We analyzed by detailed immunophenotyping, the grafts of a cohort of 210 patients among 402 patients who received an allogeneic stem cell transplantation from bone marrow and peripheral blood between January 2009 and June 2012 at a single center. There were no differences between the 210 studied patients and the other 192 in whom grafts were not studied. Characteristics of patients investigated for naïve and memory T cells were compared using Wilcoxon rank-sum tests and Fisher’s exact tests. The main outcome was occurrence of acute GVHD grade II – IV. Cumulating incidence of acute GVHD was estimated using usual methods and compared according to tertiles of T cytotoxic lymphocytes subpopulations using Gray’s test. Adjusted analyses were performed using Fine- Gray proportional hazards models. All tests were two - sided and p-values ≤ 0.05 were considered as indicating significant association. T cytotoxic lymphocytes were typed in all 210 grafts using CD3, CD8, CD45 RA and CD62L four colors immuphenotyping. Clinical and histological characteristics of patients were recorded. Including age, gender, ABO group and rhesus, viral serology of both the donor and the patient, characteristic of the grafts including HLA compatibility, bone marrow or peripheral blood, lymphocytes and nucleated cell and CD34 numeration, conditioning regimens, GVHD prophylaxis, characteristics of GVHD (date of onset, organs involved, stage and grade). Results Median follow up from transplant was 18 months. Cumulative incidence of acute GVHD was 59% (95% CI range 45 to 59) overall, and 49% (95% CI 42 to 56) at 100 days. In univariate analysis increased absolute counts of memory T cell subtypes were significantly correlated with the onset of an acute GVHD grade II – IV. Risk factors for acute GVHD (multivariate analysis) were use of an unrelated donor, positive CMV donor for a negative recipient, and use of TBI 12Gy. In a multivariate analysis the subtype CD3+/CD8+/CD45 RA-/CD62L- was associated with the onset of acute GVHD grade II-IV (adjusted Hazard Ratio = 1.26 and 1.98, p=0.02). Adjusting analysis on the total number of total nucleated cells infused did not affect the results. Restricting analyses to patients receiving peripheral blood stem cells also provided same conclusions. Conclusion This first study on the relation between rate of memory T cell and GVHD revealed that CD3+/CD8+/CD45 RA-/CD62 L- T-cells numbers and percentage were associated with acute GVHD grade II – IV. In contrast to murine models we did not find evidence for a link between naïve T-cells and GVHD risk Disclosures: Robin: novartis: Research Funding.

scholarly journals THE ROLE OF PREGNANCY-SPECIFIC GLYCOPROTEIN IN REGULATION OF MOLECULAR GENETIC DIFFERENTIATION MECHANISMS OF IMMUNE MEMORY T CELLS

2019 ◽  
Vol 21 (1) ◽  
pp. 49-58 ◽  
Author(s):  
M. B. Rayev ◽  
L. S. Litvinova ◽  
K. A. Yurova ◽  
O. G. Khaziakhmatova ◽  
V. P. Timganova ◽  
...  
Keyword(s):  
T Cells ◽  
Alternative Splicing ◽  
T Cell ◽  
Peripheral Blood ◽  
Functional Activity ◽  
Memory T Cells ◽  
Molecular Genetic ◽  
Immune Memory ◽  
Memory T Cell

The role of pregnancy-specific β1-glycoprotein (PSG) in the regulation of molecular genetic factors determining the functional activity of naїve T cells and T cells of immune memoryin vitrowas studied. Human PSG was isolated with a proprietary immuno-purification method using a biospecific sorbent followed by removing of immunoglobulin contamination with a HiTrapTMProtein G HP column. Physiological concentrations of PSG were used in the experiments. They corresponded to PSG levels in the peripheral blood of pregnant woman: 1, 10 and 100 μg/ml (I, II, III trimester, respectively). The objects of study were monocultures of naїve T cells (CD45RA+) and memory T cells (CD45R0+), obtained by immunomagnetic separation from the peripheral blood of women of reproductive age.It was established that at the level of naїve T cells (CD45RA+) PSG inhibited the expression of CD28 (1, 10, 100 μg/ml) and CD25 (100 μg/ml), without affecting the interleukin-2 (IL-2) production by these cells. At the same time, PSG in all concentrations studied suppressed the expression of CD25 at the immune memory T-cell (CD45R0+) surface but increased the IL-2 production. Expression ofU2af1l4, Gfi1, hnRNPLLgenes regulating the alternative splicing of the Ptprc gene encoding CD45 was also evaluated. It was found, that PSG reduced the expression of theGfi1(1, 10, 100 μg/ml),hnRNPLL(10, 100 μg/ml) genes, but increased the expression of theU2af1l4gene (1, 10, 100 μg/ml) in the naїve T cells. It was shown that at the immune memory T-cells’ level the effects were similar, with PSG rendering them in all concentrations used. The revealed changes in the mRNA transcription ofU2af1l4,Gfi1andhnRNPLLgenes in the studied T cell subsets may lead to the inhibition of CD45 “mature” isoform formation – CD45R0.Thus, PSG reduces the functional activity of naїve T cells and immune memory T cells associated with the expression of costimulation/activation molecules CD25 and CD28 and is involved in the regulation ofPtprcgene alternative splicing, which determines the ratio of CD45 molecule variants. Apparently, using these mechanisms, PSG regulates the functional activity of the memory T cell circulating pool, which is potentially capable of carrying out antigen-specific cytotoxic reactions against fetal antigens in vivo. In general, the data obtained broadens the notion of the PSG role in the regulation of molecular-genetic mechanisms of naїve T cells and immune memory T cells differentiation.

CXCR3 Is Required for the Efficient Recruitment of Bone Marrow-Resident Memory T Cells to Inflamed Tissues,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3242-3242
Author(s):  
Robbert van der Voort ◽  
Claudia Brandao ◽  
Thomas J. Volman ◽  
Viviènne Verweij ◽  
Klaas van Gisbergen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Memory T Cell

Abstract Abstract 3242 Although the importance of the bone marrow (BM) in hematopoiesis is well known, its function in adaptive immune responses has only recently been acknowledged. Currently it is known that the BM contains fully functional CD4+ and CD8+ T cells that can engage in both primary and secondary immune responses. Interestingly, most of these T cells belong to the memory T cell lineage, identifying the BM as one of the largest memory T cell reservoirs in the body. Since not much is known about the trafficking of BM T cells, we compared the homing phenotype and function of T cell subsets in the BM, blood, spleen and peripheral lymph nodes (pLN). In addition, we determined the expression of chemokine mRNA and protein levels in the BM and other lymphoid organs. We confirmed that at least 80% of the CD4+ and 60% of the CD8+ BM T cells have a memory phenotype, and that most CD4+ T cells belong to the effector memory lineage, while the CD8+ population predominantly consists of central memory T cells. Most BM T cells expressed the chemokine receptor CXCR3, the adhesion molecules P-selectin glycoprotein ligand 1 and VLA-4, and increased levels of CD44 and LFA-1, as compared to T cells from the spleen. In addition, L-selectin was absent from most CD4+ BM T cells, but present on virtually all CD8+ T cells. Notably, the percentage of CXCR3+ T cells within the effector memory and central memory subsets from BM was higher than within the same subsets from pLN. Furthermore, BM contained significant mRNA levels of the CXCR3 ligands CXCL9, CXCL10 and CXCL11. An in vivo migration assay using a mixture of fluorescent-labeled T cells from CXCR3-deficient mice and control mice indicated however that during homeostasis CXCR3 does not play a major role in BM entry or retention. These data suggest that CXCR3 expressed by memory T cells is rather involved in BM exit, than in BM entry. Indeed, we observed that, as compared to control mice, CXCR3−/− mice contained significantly more CD4+ and CD8+ T cells in their BM. Additional in vitro assays demonstrated that CD4+ and CD8+ BM T cells migrated vigorously in response to CXCL9 and CXCL10, generally released in high concentrations during inflammation. Finally, we demonstrate that CXCR3−/− effector/effector memory T cells, but not wild type T cells, accumulate in the BM of mice infected with lymphocytic choriomeningitis virus. Altogether, these data demonstrate that the BM is a major reservoir of memory T cells that employ CXCR3 to quickly respond to chemotactic signals from inflamed tissues. Disclosures: No relevant conflicts of interest to declare.

Use of Bone Marrow or Peripheral Blood Stem Cell Grafts in Non T Cell Depleted Haploidentical Transplants Using Post-Transplant Cyclophosphamide, an ALWP-EBMT Analysis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1165-1165 ◽  
Author(s):  
Annalisa Ruggeri ◽  
Myriam Labopin ◽  
Andrea Bacigalupo ◽  
Zafer Gülbas ◽  
Yener Koc ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Center Effect ◽  
Transplant Center ◽  
Grade Ii ◽  
Grade Iii

Abstract The use of mobilized peripheral blood (PB) as stem cell source in allogeneic stem cell transplantation (HSCT) from sibling or unrelated donors is associated with higher incidence of chronic graft versus host disease (GVHD) as compared to HSCT with bone marrow (BM). The reported incidence of GVHD in the haploidentical transplants with PT-Cy with BM grafts is low, while GVHD incidence using PB grafts varied between studies between 30% to 40% in single center reports. With the aim to analyze the effect of stem cell (SC) source in the setting of non T cell depleted haploidentical transplant using post-transplant Cyclophosphamide (PT-Cy), we analyzed patients (pts) transplanted for AML or ALL in first or second complete remission (CR) and reported to the EBMT from 2010 to 2014. Four hundred fifty one pts were analyzed, the majority of the pts in both groups were transplanted for AML (73%) in CR1 (67%). BM was the source of SC for 260 pts and PB for 191. Median follow up was longer for pts receiving BM (22.8 vs 18.3 months) and those pts were more likely transplanted with a MAC (61% vs 49%, p=0.008). All pts received PT-Cy as GVHD prophylaxis and prophylaxis was mainly in combination to calcineurin inhibitor and MMF, according to transplant center policy. ATG use was not different for the 2 groups (5% vs 7%, p=0.41). Overall OS, LFS and GRF at 2 year were 55%, 51% and 43%. CI of grade II-IV acute GVHD, chronic GVHD, NRM and Relapse at 2 year were 18%, 35%, 23% and 24%, respectively. Pts transplanted with BM had a longer time to neutrophil engraftment (18 vs 17 days, p= <0.001). In the univariate analysis pts transplanted with BM had a lower incidence of grade II-IV and grade III-IV acute GVHD (12% vs 27%, p=<0.01; and 3%% vs 8%, p=<0.01, respectively). No difference in chronic GVHD (36% vs 32%, p=0.28) was reported according to the SC source (PB vs BM), nor in relapse (26% vs 22%, p=0.38) and NRM (23% vs 23%, p=0.60). At 2 year LFS was 49% vs 54%, p=074 and GRFS was 44% and 42%, p=0.59, for pts receiving BM and PB, respectively. LFS was 53% and 47% (p=0.31) for pts transplanted for AML and ALL, and 56% and 46% (p=0.004) for MAC vs RIC. In the multivariate analysis adjusted for age, diagnosis, disease status, CMV serostatus, conditioning regimen, center effect and SC source, the use of PB was the sole factor associated with an increased risk of grade II-IV acute GVHD (HR 2.2, 95%CI 1.27-3.9, p=0.005). The type of SC (PB vs BM) was not significant associated with grade III-IV aGVHD (HR 2.5, 95%CI 0.9-7.3, p=0.07), cGVHD (HR 1.0, 95%CI 0.57-1.9, p=0.88), relapse (HR 0.7, 95%CI 0.51-1.15, p=0.21), NRM (HR 0.80, 95%CI 0.49-1.32, p=0.4), GRFS (HR 0.90, 95%CI 0.65-1.25, p=0.56), LFS (HR 0.73, 95%CI 0.52-1.04, p=0.08) and OS (HR 0.79, 95%CI 0.54-1.15, p=0.23). For LFS and OS, the use of RIC regimen was the only factor associated with a higher risk of treatment failure, (LFS: HR 1.39, 95%CI 1.01-1.93, p=0.04; OS: HR 1.5, 95%CI 1.06-2.12, p=0.02) and higher risk of relapse (HR 1.61, 95%CI 1.06-2.44, p=0.02). Finally, a center effect was found to be significant for NRM, LFS, GRFS, OS and cGVHD , and entered a frailty variable in the multivariate model. In conclusion, our study indicates that in patients with acute leukemia in first or second CR receiving haploidentical transplant with PT-Cy, the outcomes according to the use of PB or BM are not different. The ultimate choice depends on transplant center experience and policy. Disclosures Bacigalupo: PIERRE FABRE: Speakers Bureau; SANOFI: Speakers Bureau. Ciceri:MolMed SpA: Consultancy.

scholarly journals OP0337 DIFFERENTIAL METHYLATION OF PERIPHERAL BLOOD ADAPTIVE IMMUNE CELLS IN INDIVIDUALS AT HIGH RISK FOR RA AND WITH EARLY RA COMPARED WITH CONTROLS IDENTIFIES PATHWAYS IMPORTANT IN TRANSITION TO ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 207.2-207
Author(s):  
R. Ai ◽  
D. Boyle ◽  
D. Hammaker ◽  
K. Deane ◽  
V. M. Holers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Memory T Cells ◽  
Research Support ◽  
Memory T Cell ◽  
Naïve T Cell ◽  
Naive T Cell

Background:The “Targeting Immune Responses for Prevention of RA” (TIP-RA) collaboration studies individuals at high risk for developing RA because of serum anti-citrullinated protein antibody positivity in absence of arthritis, and is focused on defining how they transition from at-risk to classifiable disease. One potential mechanism is through alterations in epigenetics patterns in adaptive immune cells.Objectives:Previous studies showed that DNA methylation patterns of early RA (ERA) synoviocytes differ from long-standing RA, suggesting that abnormal methylation occurs early in synovium and evolves over time. To extend these observations, we performed a cross-sectional analysis in TIP-RA of DNA methylation signatures in peripheral blood cells in ERA, at-risk anti-CCP3+ individuals and demographically matched CCP- controls.Methods:Genomic DNA was isolated from two independent cohorts of CCP- (cohorts 1 and 2, respectively: B cell: n = 17/34; memory T cell: n = 21/34; and naïve T cell: n = 21/33), CCP3+ (B cell: n = 18/37; memory T cell: n = 20/36; and naïve T cell: n = 20/35), and CCP3+ ERA (B cell: n = 4/18; memory T cell: n = 5/18; and naïve T cell: n = 5/18) after separating PBMCs using antibodies and magnetic beads. Methylation was measured by Illumina Infinium MethylationEPIC chip. Differentially methylated loci (DMLs) were identified using Welch’s t-test and mapped to gene promoter regions to define DM genes (DMGs). Principal component analysis (PCA) was used to represent relationship among groups. Pathway analysis was applied by Reactome.Results:For the initial cohort, 1494, 1097 and 1330 DMLs were identified among CCP+, CCP- and ERA in B cells, memory T cells and naïve T cells, respectively. For the confirmatory cohort, 523, 793 and 548 DMLs were found in corresponding cell populations. The DML overlap between the 2 cohorts was highly significant (p= 2.48E-77). The DMLs were combined for both groups and corresponded to 411, 412, and 351 DMGs in B cells, memory T cells and naïve T cells. Of these, we found 246, 198 and 195 DMGs between CCP3+ and ERA in each peripheral blood cell population, respectively. PCA showed separation of CCP+, CCP- and ERA in each of the three blood cell types by DMLs (Fig. 1). DMGs were mapped to biological pathways to identify DM pathways. Although most were not significant, there were several highly significant differences comparing CCP+, ERA and CCP- in memory T cells involving pathways, including “Interferon gamma signaling” (FDR 7.48E-14), “PD-1 signaling” (FDR 8.71E-10), “Translocation of ZAP-70 to Immunological synapse” (FDR 4.75E-10), and “Phosphorylation of CD3 and TCR zeta chains” (FDR 8.71E-10).Figure 1.PCA shows the separation of CCP+, CCP- and ERA patients in memory T cells in confirmatory cohort.Conclusion:We identified reproducible methylation signatures of CCP-, CCP+, and ERA in peripheral blood B cells, memory T cells and naïve T cells in initial and confirmatory cohorts. The methylome of ERA also demonstrated a distinctive pattern from CCP+, indicating that progression to RA is accompanied by epigenetic remodeling, especially in T cell signaling and interferon responses. These signatures identify critical pathways in CCP positivity and classifiable RA and could provide the basis of novel interventions to prevent disease.Disclosure of Interests:Rizi Ai: None declared, David Boyle: None declared, Deepa Hammaker: None declared, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Andre Matti: None declared, William Robinson: None declared, Jane Buckner Grant/research support from: Bristol-Myers Squibb, Janssen, Navin Rao Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Frederic Baribaud Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, Alyssa Johnsen Employee of: Janssen, Sunil Nagpal Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Wei Wang: None declared, Gary Firestein Grant/research support from: Lilly, Janssen, Abbvie

scholarly journals Detection of IFNγ-Secreting CD4+ and CD8+ Memory T Cells in COVID-19 Convalescents after Stimulation of Peripheral Blood Mononuclear Cells with Live SARS-CoV-2

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1490
Author(s):  
Victoria Matyushenko ◽  
Irina Isakova-Sivak ◽  
Igor Kudryavtsev ◽  
Arina Goshina ◽  
Anna Chistyakova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Natural Infection ◽  
Intracellular Cytokine Staining ◽  
T Cell Responses ◽  
Effector Memory ◽  
Memory T Cell ◽  
Cell Responses ◽  
Stimulation Of

Background: New coronavirus SARS-CoV-2, a causative agent of the COVID-19 pandemic, has been circulating among humans since November 2019. Multiple studies have assessed the qualitative and quantitative characteristics of virus-specific immunity in COVID-19 convalescents, however, some aspects of the development of memory T-cell responses after natural SARS-CoV-2 infection remain uncovered. Methods: In most of published studies T-cell immunity to the new coronavirus is assessed using peptides corresponding to SARS-CoV-1 or SARS-CoV-2 T-cell epitopes, or with peptide pools covering various parts of the viral proteins. Here, we determined the level of CD4+ and CD8+ memory T-cell responses in COVID-19 convalescents by stimulating PBMCs collected 1 to 6 months after recovery with sucrose gradient-purified live SARS-CoV-2. IFNγ production by the central and effector memory helper and cytotoxic T cells was assessed by intracellular cytokine staining assay and flow cytometry. Results: Stimulation of PBMCs with live SARS-CoV-2 revealed IFNγ-producing T-helper effector memory cells with CD4+CD45RA−CCR7− phenotype, which persisted in circulation for up to 6 month after COVID-19. In contrast, SARS-CoV-2-specific IFNγ-secreting cytotoxic effector memory T cells were found at significant levels only shortly after the disease, but rapidly decreased over time. Conclusion: The stimulation of immune cells with live SARS-CoV-2 revealed a rapid decline in the pool of effector memory CD8+, but not CD4+, T cells after recovery from COVID-19. These data provide additional information on the development and persistence of cellular immune responses after natural infection, and can inform further development of T cell-based SARS-CoV-2 vaccines.

scholarly journals The impact of body mass index on adaptive immune cells in the human bone marrow

2020 ◽  
Author(s):  
Luca Pangrazzi ◽  
Erin Naismith ◽  
Carina Miggitsch ◽  
Jose’ Antonio Carmona Arana ◽  
Michael Keller ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Bone Marrow ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Immune Cells ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Adaptive Immune ◽  
Adaptive Immune Cells

Abstract Background. Obesity has been associated with chronic inflammation and oxidative stress. Both conditions play a determinant role in the pathogenesis of age-related diseases, such as immunosenescence. Adipose tissue can modulate the function of the immune system with the secretion of molecules influencing the phenotype of immune cells. The importance of the bone marrow (BM) in the maintenance of antigen-experienced adaptive immune cells has been documented in mice. Recently, some groups have investigated the survival of effector/memory T cells in the human BM. Despite this, whether high body mass index (BMI) may affect immune cells in the BM and the production of molecules supporting the maintenance of these cells it is unknown.Methods. Using flow cytometry, the frequency and the phenotype of immune cell populations were measured in paired BM and PB samples obtained from persons with different BMI. Furthermore, the expression of BM cytokines was assessed. The influence of cytomegalovirus (CMV) on T cell subsets was additionally considered, dividing the donors into the CMV- and CMV+ groups.Results. Our study suggests that increased BMI may affect both the maintenance and the phenotype of adaptive immune cells in the BM. While the BM levels of IL-15 and IL-6, supporting the survival of highly differentiated T cells, and oxygen radicals increased in overweight persons, the production of IFNγ and TNF by CD8+ T cells was reduced. In addition, the frequency of B cells and CD4+ T cells positively correlated with BMI in the BM of CMV- persons. Finally, the frequency of several T cell subsets, and the expression of senescence/exhaustion markers within these subpopulations, were affected by BMI. In particular, the levels of bona fide memory T cells may be reduced in overweight persons.Conclusion. Our work suggests that, in addition to aging and CMV, obesity may represent an additional risk factor for immunosenescence in adaptive immune cells. Metabolic interventions may help in improving the fitness of the immune system in the elderly.

scholarly journals Anti-CD19 Chimeric Antigen Receptor T Cell Treatment of Relapsed /Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Resistant to Bruton's Tyrosine Kinase (BTK) Inhibitor

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-36
Author(s):  
Weihong Chen ◽  
Xin Du ◽  
Wenyujing Zhou ◽  
Changru Luo ◽  
Xiaoqing LI
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Lymph Nodes ◽  
Peripheral Blood ◽  
Serum Levels ◽  
Car T Cell ◽  
Car T ◽  
Btk Inhibitor

CASE PRESENTATION: A 68-year-old male was diagnosed with CLL/SLL in November 2007. Bone marrow asp/bx: 36.5% lymphocytes, 78% CD19, 65% ATM (11q22 deleted) positive cells, 13.5% D13S25 (13q14.3 deleted). On December 10, 2009, the patient took FCR scheme for five cycles, followed by FR scheme for one cycle, and then a month of Chlorambucil. On September 5, 2013, the patient took BR scheme for four cycles with no effect. From March 2015 to Feb 2016, 420 mg of Ibrutinib was administered daily. On January 15, 2016, the patient developed swollen lymph nodes in his right neck with intermittent lumps, fever and nausea. He was admitted into the hospital at Feb 2, 2016. Test results: multiple swollen superficial lymph nodes over the body, with the biggest measuring 60×30mm on the right neck, with no tenderness. Supplementary tests: peripheral white blood cells (WBC) 11.94×10E9/L, lymphocyte 7.5×10E9/L, CD19 cells 6.73×10E9/L, bone marrow lymphocyte 62%, peripheral blood lymphocyte 52%. Immunophenotype: CD5, CD19, CD20dim, CD23, CD11b dim, HLA-DR expression, visible CD5+CD19+ cell clusters, and visible immunoglobulin cKappa with restricted expression. On March 10, 2016, peripheral blood platelet 60 × 10E9/L, CD19 cells 1.94×10E9/L, lactate dehydrogenase 460U/L, FER 115.6ng/ml, hepatitis B virus carrier. Diagnosis: CLL/SLL IV stage, ATM (11q22) deletion, D13S25 (13q14. 3) positive, CD19 positive. Relapse of CLL/SLL occurred again after four months and at this stage the patient was considered for therapy in a clinical trial of CD19-specific chimeric antigen receptor (CAR-) T cell therapy. Ethical approval and informed consent were obtained for anti-CD19 CAR T Cell treatment of ibrutinib resistance in relapsed/refractory CLL/SLL. We infused autologous T cells transduced with a CAR T 19 retroviral vector with CLL/SLL at doses of 3.3 × 10E8 CART19 cells on Mar. 16 2016. Patients were monitored for responses, toxic effects, and the expansion and persistence of circulating CART19 cells. After CART19 cells were infused, the patient experienced chills, fever, headache, weak, anorexia, nausea, shortness of breath, chest tightness, heart palpitation, hypotension and shock for 9 days. The serum levels of IFN-Υ were at their highest at day 7 after CAR T cells infusion. Serum interleukin 6 (IL-6) was at 680pg/ml and CD3+ cells were 97.5%, CD8+ cells 72.8% (18.7-32.8%), FER was 1529.5ng/ml (Normal No. 22-322ng/ml) 14 days after CAR-T cell infusion. The serum levels of IL-6 were at their highest at day14. The patient was diagnosed as having cytokine release syndrome. After the patient took the anti-IL-6R antibody and anti-TNF antibody, he began to recover gradually. Enlarge lymph nodes shrunk after being infused with CART19 cells for 7 days. The peripheral blood CD19 B lymphocytes were 0 on day 14 after infused with CAR T19 cells. Q-PCR was used to detect the amount of the peripheral blood CART19 cells, which stood at 5485 copies/μl, 924 copies/μl, 191 copies/μl respectively 2 weeks, 6 weeks and 3 months after infusing with CART19 cells. The peripheral blood CART 19 cells were not detectable 4 months after infusing with CART19 cells until present. The lymphadenopathy was decreased gradually after 14 days of infusion. The MRI test showed that lymphadenopathy reduced markedly or disappeared after 6 months of infusion. ATM (11q22 deleted) negative, D13S25 (13q14.3 deleted) negative. After treatment with CAR T 19 cell therapy for 53 months, the patient remained disease-free, the patient's lymph nodes, lymphocytes and I mmunoglobulins were normal. CONCLUSIONS : Cancer immunotherapy as a method of cancer treatment is the most effective after conventional treatments such as radiotherapy, chemotherapy, and surgery. For BTK Inhibitor resistance in relapsed and refractory CD19+ CLL/SLL, CD19 is a favorable target, because the expression of CD19 is limited to B cells and not present in other tissues or cells. Currently, the efficacy of this treatment in treating CLL/SLL remains to be seen. The effects of chemotherapy on the patient's B cell lymphoma are negligible, due to the fact that his CLL/SLL have become relapsed and refractory. As a result we chose the CAR T19 cell therapy genetic engineering technique as a method of treatment, to which the patient has responded well. Therefor, CAR T cell technology overcome the limitations of existing cancer therapies and has great potential for development and application. Disclosures No relevant conflicts of interest to declare.

scholarly journals Imbalances within the peripheral blood T-helper (CD4+) and T-suppressor (CD8+) cell populations in the reconstitution phase after human bone marrow transplantation

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1196-1200 ◽  
Author(s):  
A Velardi ◽  
A Terenzi ◽  
S Cucciaioni ◽  
R Millo ◽  
CE Grossi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Peripheral Blood ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
T Cell Subsets ◽  
Allogeneic Bone ◽  
T Helper

Abstract Peripheral blood T cell subsets were evaluated in 11 patients during the reconstitution phase after allogeneic bone marrow transplantation and compared with 11 age-matched controls. The proportion of cells coexpressing Leu7 and CD11b (C3bi receptor) markers was determined within the CD4+ (T-helper) and the CD8+ (T-suppressor) subsets by two- color immunofluorescence analysis. CD4+ and CD8+ T cells reached normal or near-normal values within the first year posttransplant. In contrast to normal controls, however, most of the cells in both subsets coexpressed the Leu7 and CD11b markers. T cells with such phenotype display the morphological features of granular lymphocytes (GLs) and a functional inability to produce interleukin 2 (IL 2). These T cell imbalances were not related to graft v host disease (GvHD) or to clinically detectable virus infections and may account for some defects of cellular and humoral immunity that occur after bone marrow transplantation./

scholarly journals Impact of multiple hits with cognate antigen on memory CD8+ T-cell fate

2020 ◽  
Vol 32 (9) ◽  
pp. 571-581 ◽  
Author(s):  
Shiki Takamura
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Primary Immune Response ◽  
Memory T Cell ◽  
Cognate Antigen ◽  
Memory Cd8 T Cell

Abstract Antigen-driven activation of CD8+ T cells results in the development of a robust anti-pathogen response and ultimately leads to the establishment of long-lived memory T cells. During the primary response, CD8+ T cells interact multiple times with cognate antigen on distinct types of antigen-presenting cells. The timing, location and context of these antigen encounters significantly impact the differentiation programs initiated in the cells. Moderate re-activation in the periphery promotes the establishment of the tissue-resident memory T cells that serve as sentinels at the portal of pathogen entry. Under some circumstances, moderate re-activation of T cells in the periphery can result in the excessive expansion and accumulation of circulatory memory T cells, a process called memory inflation. In contrast, excessive re-activation stimuli generally impede conventional T-cell differentiation programs and can result in T-cell exhaustion. However, these conditions can also elicit a small population of exhausted T cells with a memory-like signature and self-renewal capability that are capable of responding to immunotherapy, and restoration of functional activity. Although it is clear that antigen re-encounter during the primary immune response has a significant impact on memory T-cell development, we still do not understand the molecular details that drive these fate decisions. Here, we review our understanding of how antigen encounters and re-activation events impact the array of memory CD8+ T-cell subsets subsequently generated. Identification of the molecular programs that drive memory T-cell generation will advance the development of new vaccine strategies that elicit high-quality CD8+ T-cell memory.

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