Antibody Response to Pneumococcal Conjugate Vaccine (PCV13) in Chronic Lymphocytic Leukemia Patients Receiving Ibrutinib

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5597-5597 ◽  
Author(s):  
Benjamin Andrick ◽  
Abulrahman Alwhaibi ◽  
David DeRemer ◽  
Sameera Quershi ◽  
Rahil Khan ◽  
...  
Keyword(s):  
Immune Response ◽  
Chronic Lymphocytic Leukemia ◽  
Pneumococcal Infection ◽  
Fold Increase ◽  
Lymphocytic Leukemia ◽  
Current Therapy ◽  
Control Group ◽  
Pneumococcal Serotypes ◽  
Post Vaccination ◽  
Increased Risk

Abstract Introduction Due to immune dysregulation and subsequent increased risk of infection associated with chronic lymphocytic leukemia (CLL), both the CDC and ACIP recommend patients with CLL receive the 13- valent pneumococcal conjugate vaccination (PCV13). The effect of ibrutinib, a selective inhibitor ofBruton'styrosine kinase (BTK) which effects B-antigen receptor (BCR) signaling, on IgG antibody responses to pneumococcal vaccination in patients with CLL has not been evaluated. The aim of this study was to evaluate the immune response to PCV13 in patients receiving in ibrutinib and CLL control patients (no active treatment). Methods Study patients were enrolled on an IRB approved protocol at Georgia Cancer Center. Specific inclusion criteria a) histological confirmed CLL as defined by WHO classification b) no current therapy (CLL control) c) ibrutinib 420 mg/day (active) d) ECOG ≤ 2. Exclusion criteria a) Previous vaccination with PCV13 within 2 years b) anti-CD20 therapy within last 6 months c) IVIG therapy within 6 weeks. Serum pneumococcal antibody assessment was performed by microsphere photometry on subjects at Day 0 and Day 30 days following vaccination. Antibody specific serotypes (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23) were determined by ELISA. Pre- and post- vaccination expression of BTK and HACS1 (hematopoietic adapter containing SH3 and SAM protein) of CD19+ lymphocytes was determined by Western Blot analysis. The primary objective was to determine whether concurrent administration of PCV13 in patients receiving ibrutinib generates a ≥ 2 fold increase in ≥ 3 of pneumococcal serotypes as compared to the control group. Secondary objectives were to evaluate expression BTK and HACS in both study groups. Results At interim analysis, 9 patients have been enrolled to date, with 8 patients (n=4 ibrutinib, n=4 CLL control) having completed pre and post-vaccination assessments. The median patient age was 69 yo(range: 53-77 yo) with 75% ≥ 65 yo. All CLL control patients (4/4) generated a ≥ 2 fold increase in ≥ 3 of pneumococcal serotypes, whereas (0/4) of ibrutinib patients generated an adequate immune response to PCV13 (p=0.029; Fisher exact). See Table 1 for mean serotype changes in both patient cohorts. Conclusions Preliminary data suggests that patients who are receiving ibrutinib group do not generate an effective immune response to PCV13 vaccination compared to untreated CLL controls. This may have an impact on susceptibility and response to infection with pneumococcal infection as well. Disclosures No relevant conflicts of interest to declare.

scholarly journals MicroRNA-196a2 single nucleotide polymorphism rs11614913 in Egyptian patients with chronic lymphocytic leukemia

2019 ◽  
Vol 7 (1) ◽  
pp. 17-20
Author(s):  
Akram Deghady ◽  
Reham Abo Elwafa ◽  
Manal AE Lsorady, ◽  
Darine Elbana
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Rna Molecules ◽  
Increased Risk ◽  
Egyptian Patients ◽  
Apoptosis Regulation

Background: MicroRNAs are recently identified class of small single stranded RNA molecules of 21-23 nucleotides that regulate gene expression at the posttranscriptional level. Chronic lymphocytic leukemia (CLL) is characterized by a typical defect in apoptosis resulting in accumulation of mature resting B cells within the peripheral blood, bone marrow and lymphoid organs. One of the relevant microRNAs to CLL is microRNA-196a2, as its potential targets of action include genes involved in apoptosis regulation. The single nucleotide polymorphism (SNP) in microRNA-196a2 rs11614913 C/T has been implicated as possible biomarker associated with multiple kinds of cancers. While multiple recent studies showed that genetic polymorphisms play an influential role in CLL susceptibility, the role of microRNA-196a2 SNP rs11614913in CLL remains elusive. Patients and methods: The present study was conducted on 40 newly diagnosed Egyptian CLL patients and 40 control subjects. Genotyping of microRNA-196a2 SNP rs11614913 was performed by real-time PCR. Results: The CC genotype was found in 55% of CLL patients versus 12.5% of the controls.On the other handthe TT and TC genotypes were significantly predominant in the control group compared to CLL patients with frequencies of 25% and 62.5% versus 10% and 35% respectively (p<0.001). The C allele carriers were found to have 3.38 fold increased risk for development of CLL (OR=3.38, CI=1.75–6.56) while the T allele seems to be protective against CLL (OR=0.29, CI=0.15–0.57). Conclusion: We could conclude that the CC genotype and the C allele of miR-1962a SNP rs3217927are implicated in the risk of CLL development in Egyptian patients while the T allele has a protective effect. However, additional well-designed large studies are required for the validation of these associations

scholarly journals Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with B-cell chronic lymphocytic leukemia (CLL)???. A double edged sword

2021 ◽  
Author(s):  
Mahmoud Ramadan Elkazzaz ◽  
Yousry Esam-Eldin Abo-Amer ◽  
Tamer Haydara ◽  
Aziz Rodan Sarohan ◽  
Amr Ahmed
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Retinoic Acid ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Risk Allele ◽  
Lymphocytic Leukemia ◽  
Trans Retinoic Acid ◽  
Increased Risk ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Patients with B-cell chronic lymphocytic leukemia (CLL) have an increased risk of severe infections due to disease- and treatment-related immunodeficiency. As a result, patients with hematologic malignancies have been given priority for primary COVID-19 vaccination. Unfortunately, many studies have suggested that patients with B-cell chronic lymphocytic leukemia (CLL) who have been fully vaccinated can develop severe and often fatal complications. Therefore, adjuvants that can induce mRNA vaccine efficacy are desperately needed for this category of patients with haematological malignancies. A recent, study by Oxford University scientists showed that leucine zipper transcription factor-like 1(LZTFL1), as a candidate causal gene and its enhancer the rs17713054 A risk allele was significantly responsible for the twofold increased risk of respiratory failure from COVID-19 associated with 3p21.31.By using sequence analysis, the risk allele generates a second CCAAT/enhancer binding protein beta (CEBPB) motif in the enhancer. Moreover, neither LZTFL1 variants found in T cells nor B cells are responsible for increasing death risk from COVID-19 infection according to oxford study. Here, we propose attestable hypothesis that trans retinoic acid could enhance the immune response in vaccinated patients with B-cell chronic lymphocytic leukemia (CLL) according to the recent findings of Oxford scientists by inducing the casual gene(LZTFL1) in CD4 T cells and inhibiting (CEBPB) motif.Conclusions Haematological malignancies (blood cancers) patients are more vulnerable to COVID-19 disuse severity and mortality. Un fortunately mRNA vaccine seem to be less effective with weak immune response and insufficient level of generated antibodies in this category of patients. Therefore we suggest all trans retinoic acid is a good candidate as mRNA COVID-19 vaccine adjuvant via inducing LZTFL1 gene in CD4Tcells and this activation could improve the immune response and increase the level of the generated antibodies. Moreover LZTFL1 gene in CD4 T cells is not associated with increasing risk of COVID-19 infection because of absence of its enhancer(The risk allele of the SNP, rs17713054 A) in immune cells according to oxford recent study. In addition to all trans retinoic acid could inhibit CCAAT/enhancer binding protein beta motif that is generated by The risk allele of the SNP, rs17713054 A

scholarly journals Glycobiom Lymphocytes Surface Study of Patients with B-Cell Chronic Lymphocytic Leukemia

2021 ◽  
Vol 6 (6) ◽  
pp. 134-140
Author(s):  
G. S. Maslak ◽  
◽  
G. P. Chernenko ◽  
S. V. Abramov ◽  
I. Yu. Pismenetska ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Plasma Membranes ◽  
Polyclonal Antibodies ◽  
Fold Increase ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Quantitative Composition ◽  
Blood Lymphocytes ◽  
Cell Chronic Lymphocytic Leukemia

The purpose of the study was to investigate the intensity of exposure of peripheral blood lymphocyte surface glycans in patients with B-cell chronic lymphocytic leukemia by measuring the density of lectin- or antigen-positive epitopes under antitumor therapy in order to evaluate it for a more reasonable selection of qualitative and quantitative composition of therapy. Materials and methods. The objects of the study were blood lymphocytes of patients with chronic lymphocytic leukemia (n=15) aged 58-66 years before and after a course of standard chemotherapy according to the COP scheme. The control group consisted of healthy volunteers (n=15) aged 55 to 65 years. Isolation of lymphocytes was performed by a modified method of A. Boyum. Polyclonal antibodies to α1-acid glycoprotein and fibronectin were used. Exposure to Tn antigen and CD43 on blood lymphocytes was determined with secondary antibodies to mouse immunoglobulins conjugated to FITC (Millipore, USA). To study the exposure of glycans on the surface of lymphocytes, we used a set of seven lectins labeled with FITC. Data recording was performed on a Beckman Flower EPICS flow cytometer. Processing of the results was done using the program FCS3 Express. Results and discussion. Compared with the group of hematologically healthy donors on the surface of lymphocytes in patients with chronic lymphocytic leukemia, a 20-fold increase in the density of exposure to ConA epitopes, 10 times – UEAI- and SNA-positive epitopes were shown; MAA II epitope, Tn, and CD43 antigen densities were increased 100-fold (p <0.01). Exposure densities of MAA II-, Tn-, and CD43-positive epitopes on the plasma membrane of lymphocytes in patients with chronic lymphocytic leukemia receiving alkylation therapy decreased 10-fold relative to treatment data, but remained 10-fold higher than in the group of healthy hematologists. Conclusion. On the plasma membranes of lymphocytes in patients with chronic lymphocytic leukemia, the density of exposure of mannose and neuraminic acid residues was significantly increased. COP therapy reduced the density of these epitopes to control values. A significant increase in the density of carcinogenesis markers – Tn- and CD43-antigens on the plasma membranes of lymphocytes in patients with chronic lymphocytic leukemia has been shown. COP therapy provided only a partial decrease in their density, which indicates the insufficient effectiveness of COP therapy, its inability to completely stop the oncological process in patients with chronic lymphocytic leukemia

scholarly journals PD-1 inhibition in malignant melanoma and lack of clinical response in chronic lymphocytic leukemia in the same patients: a case series

2020 ◽  
Vol 27 (3) ◽  
Author(s):  
I. Landego ◽  
D. Hewitt ◽  
I. Hibbert ◽  
D. Dhaliwal ◽  
W. Pieterse ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Chronic Lymphocytic Leukemia ◽  
Meta Analysis ◽  
Case Series ◽  
Fold Increase ◽  
Lymphocytic Leukemia ◽  
Western World ◽  
Secondary Malignancy ◽  
Increased Risk ◽  
Adult Leukemia

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. Unfortunately these patients are often immunosuppressed and at increased risk of infection and secondary malignancy. Previous meta-analysis has found that patients with CLL are at a four-fold increase of melanoma compared to the general population. Recent advancements in our understanding of the programmed death (PD) receptor pathway have led to the advent of immunotherapies to target cancer cells. The use of PD-1 inhibitors is now considered first line treatment for BRAF wild-type metastatic melanoma. Interestingly, early pre-clinical data suggest that inhibition of this pathway may also be used in the treatment of CLL, however clinical trials now published were not successful. In this case series we highlight two cases where patients with CLL and concurrent malignant melanoma undergo treatment with PD-1 inhibitors, and were found to have reductions in their WBC counts but these were not sustained. These cases further illustrate that treatment of CLL with PD-1 inhibitors are ineffective treatment alone.

scholarly journals Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with B-cell chronic lymphocytic leukemia (CLL)???. A double edged sward

2021 ◽  
Author(s):  
Mahmoud Ramadan Elkazzaz ◽  
Yousry Esam-Eldin Abo-Amer ◽  
Amr Ahmed ◽  
Tamer Haydara
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Retinoic Acid ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Risk Allele ◽  
Lymphocytic Leukemia ◽  
Trans Retinoic Acid ◽  
Increased Risk ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Patients with B-cell chronic lymphocytic leukemia (CLL) have an increased risk of severe infections due to disease- and treatment-related immunodeficiency. As a result, patients with hematologic malignancies have been given priority for primary COVID-19 vaccination. Unfortunately, many studies have suggested that patients with B-cell chronic lymphocytic leukemia (CLL) who have been fully vaccinated can develop severe and often fatal complications. Therefore, adjuvants that can induce mRNA vaccine efficacy are desperately needed for this category of patients with haematological malignancies. A recent, study by Oxford University scientists showed that leucine zipper transcription factor-like 1(LZTFL1), as a candidate causal gene and its enhancer the rs17713054 A risk allele was significantly responsible for the twofold increased risk of respiratory failure from COVID-19 associated with 3p21.31.By using sequence analysis, the risk allele generates a second CCAAT/enhancer binding protein beta (CEBPB) motif in the enhancer. Moreover, neither LZTFL1 variants found in T cells nor B cells are responsible for increasing death risk from COVID-19 infection according to oxford study. Here, we propose attestable hypothesis that trans retinoic acid could enhance the immune response in vaccinated patients with B-cell chronic lymphocytic leukemia (CLL) according to the recent findings of Oxford scientists by inducing the casual gene(LZTFL1) in CD4 T cells and inhibiting (CEBPB) motif.Conclusions Haematological malignancies (blood cancers) patients are more vulnerable to COVID-19 disuse severity and mortality. Un fortunately mRNA vaccine seem to be less effective with weak immune response and insufficient level of generated antibodies in this category of patients. Therefore we suggest all trans retinoic acid is a good candidate as mRNA COVID-19 vaccine adjuvant via inducing LZTFL1 gene in CD4Tcells and this activation could improve the immune response and increase the level of the generated antibodies. Moreover LZTFL1 gene in CD4 T cells is not associated with increasing risk of COVID-19 infection because of absence of its enhancer(The risk allele of the SNP, rs17713054 A) in immune cells according to oxford recent study. In addition to all trans retinoic acid could inhibit CCAAT/enhancer binding protein beta motif that is generated by The risk allele of the SNP, rs17713054 A

Specific features of T- and NK-cellular immunity in chronic lymphocytic leukemia

2021 ◽  
Vol 66 (6) ◽  
pp. 345-352
Author(s):  
Evgeniy Vladimirovich Pochtar ◽  
S. A. Lugovskaya ◽  
E. V. Naumova ◽  
E. A. Dmitrieva ◽  
A. I. Kostin ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Lymphocytic Leukemia ◽  
Positive Trend ◽  
Functional Changes ◽  
Activated T Lymphocytes ◽  
T Helpers

Profound immunological dysfunction is the key factor determining the development of infectious complications in chronic lymphocytic leukemia (CLL). The aim of this work is to assess the features of the subpopulation composition of T-lymphocytes (T-helpers (Th), cytotoxic T-lymphocytes (Tcyt), T regulatory cells (Treg), T-NK cells, naive Th, Th-memory, activated T-lymphocytes, TCRγδ cells) and NK cells in peripheral blood of patients with newly diagnosed chronic lymphocytic leukemia (CLL) and receiving ibrutinib therapy. Hematological and immunophenotypic studies have been performed in 30 patients with previously untreated CLL, 122 patients on ibrutinib therapy and 20 healthy donors. The subpopulation composition of T-lymphocytes (Th, Tcyt, Treg, T-NK, naive T-helpers, memory T-helpers, TCRγδ cells, activated T-lymphocytes) and NK cells has been assessed on flow cytometer (FACSCanto II (BD)) using the following panel of monoclonal antibodies: CD45, CD19, CD3, CD4, CD5, CD8, TCRγδ, CD127, CD16, CD56, CD57 CD45RA, CD45R0, HLA-DR, CD25. Compared to controls all CLL samples were found to have higher the absolute number of T-lymphocytes, NK cells and their subpopulations, T-helpers (especially of memory T-cells), cytotoxic T-cells, regulatory T-cells, TCRγδ T-cells, activated T-lymphocytes, increased cytotoxic potential of NK cells in previously untreated CLL patients. Patients who received ibrutinib therapy have registered a positive trend towards recovery of the subpopulation composition of T-lymphocytes and NK-cells. CLL patients have been found to have quantitative and functional changes in the subpopulations of T-lymphocytes and NK cells, indicating dysregulation of the immune response, and a high risk of developing infections. Monitoring of immunological parameters for ibrutinib therapy make possible to estimate impact of ibrutinib on the adaptive anti-CLL immune response.

scholarly journals Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with B-cell chronic lymphocytic leukemia (CLL)???. A double edged sward

2021 ◽  
Author(s):  
Mahmoud Ramadan Elkazzaz ◽  
Yousry Esam-Eldin Abo-Amer ◽  
Amr Ahmed ◽  
Tamer Haydara
Keyword(s):  
Respiratory Failure ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Risk Allele ◽  
Lymphocytic Leukemia ◽  
Causal Gene ◽  
Oxford University ◽  
Increased Risk ◽  
University Scientists ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Patients with B-cell chronic lymphocytic leukemia (CLL) have an increased risk of severe infections due to disease- and treatment-related immunodeficiency. As a result, patients with hematologic malignancies have been given priority for primary COVID-19 vaccination. Unfortunately, many studies have suggested that patients with B-cell chronic lymphocytic leukemia (CLL) who have been fully vaccinated can develop severe and often fatal complications. Therefore, adjuvants that can induce mRNA vaccine efficacy are desperately needed for this category of patients with haematological malignancies. A recent, study by Oxford University scientists showed that leucine zipper transcription factor-like 1(LZTFL1), as a candidate causal gene and its enhancer the rs17713054 A risk allele was significantly responsible for the twofold increased risk of respiratory failure from COVID-19 associated with 3p21.31.By using sequence analysis, the risk allele generates a second CCAAT/enhancer binding protein beta (CEBPB) motif in the enhancer. Moreover, neither LZTFL1 variants found in T cells nor B cells are responsible for increasing death risk from COVID-19 infection according to oxford study. Here, we propose attestable hypothesis that trans retinoic acid could enhance the immune response in vaccinated patients with B-cell chronic lymphocytic leukemia (CLL) according to the recent findings of Oxford scientists by inducing the casual gene(LZTFL1) in CD4 T cells and inhibiting (CEBPB) motif.

scholarly journals Role of interleukin-10 and interleukin-24 in the pathogenesis of В-cell chronic lymphocytic leukemia

2018 ◽  
pp. 56-61
Author(s):  
Т.Н. Жевак ◽  
Н.П. Чеснокова ◽  
Т.В. Шелехова ◽  
О.Е. Царева ◽  
И.А. Будник ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Serum Level ◽  
B Cell ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Patient Groups ◽  
Cell Chronic Lymphocytic Leukemia

Цель. Изучить закономерности изменения экспрессии интерлейкина-10 и интерлейкина-24, обладающих иммуномодулирующим эффектом, при развитии B-клеточного хронического лимфолейкоза. С учетом этого выявить информативные прогностические критерии развития гемобластоза и/или нового подхода к терапии заболевания. Методы. У 120 больных с разными стадиями В-клеточного хронического лимфолейкоза методом твердофазного иммуноферментного анализа исследована динамика уровней интерлейкина-10 и интерлейкина-24 в сыворотке крови. Результаты. Обнаружено закономерное повышение содержания интерлейкина-10 и интерлейкина-24 в сыворотке крови пациентов уже на начальной стадии B-клеточного хронического лимфолейкоза и сохранение их достоверно высоких уровней на последующих стадиях заболевания. Заключение. Обнаруженный нами факт повышения содержания интерлейкина-10 в сыворотке крови пациентов с В-клеточным хроническим лимфолейкозом является фактором риска снижения противоопухолевой защиты организма вследствие подавления им механизмов клеточного иммунитета и способности ингибировать апоптоз малигнизированных клеток. Напротив, повышение экспрессии интерлейкина-24, обладающего проапоптотической активностью и стимулирующего дифференцировку клеток, может способствовать повышению эффективности механизмов противоопухолевой резистентности организма. Устранение дисбаланса продукции и/или содержания указанных цитокинов в сыворотке крови может создать условия повышения эффективности терапии пациентов с В-клеточным хроническим лимфолейкозом. Aim. To study serum levels of immunosuppressive cytokines (interleukin (IL)-10 and IL-24) in patients with B-cell chronic lymphocytic leukemia for assessment of the disease progression and elaboration of a new treatment strategy. Methods. 120 patients with B-cell chronic lymphocytic leukemia were enrolled in the study and divided into four groups according to the disease stage (Rai stage I-IV). Control group included 30 healthy volunteers. Concentrations of IL-10 and IL-24 were measured in serum using the enzyme-linked immunosorbent assay (ELISA). Results. Serum levels of IL-10 and IL-24 levels were significantly increased in all patient groups compared to the control. No difference in the cytokines levels between the patient groups was observed. Conclusion. In patients with B-cell chronic lymphocytic leukemia, the increased serum level of IL-10 might impair the antitumor defence by inhibiting the cell immune response and preventing apoptosis of malignant lymphocytes. On the other hand, the increased serum level of IL-24 might oppose these effects by promoting cellular differentiation and inducing apoptosis in malignant cells. Therefore, correction of IL-10/IL-24 imbalance may be a beneficial therapeutic strategy for patients with B-cell chronic lymphocytic leukemia.

Lack of TIR8/SIGIRR triggers progression of chronic lymphocytic leukemia in mouse models

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 660-669 ◽  
Author(s):  
Maria Teresa Sabrina Bertilaccio ◽  
Giorgia Simonetti ◽  
Antonis Dagklis ◽  
Martina Rocchi ◽  
Tania Veliz Rodriguez ◽  
...  
Keyword(s):  
Immune Response ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Adaptive Immune Response ◽  
Lymphocytic Leukemia ◽  
Fine Tuning ◽  
Terminal Phase ◽  
Lymphoid Malignancies ◽  
History Of ◽  
Molecular Patterns

Abstract Inflammation is involved in the initiation and progression of several chronic lymphoid malignancies of B-cell type. Toll-like receptors (TLR) are transmembrane inflammatory receptors that on recognition of pathogen-associated molecular patterns trigger an innate immune response and bridge the innate and adaptive immune response by acting as costimulatory signals for B cells. Fine tuning of TLR and IL-1R–like (ILR) activity is regulated by TIR8 (SIGIRR), a transmembrane receptor of the TLR/ILR family which inhibits other family members. To test the hypothesis that TLR and/or ILR may play a role in the natural history of chronic B-cell tumors, we crossed Eμ-TCL1 transgenic mice, a well established model of chronic lymphocytic leukemia (CLL), with mice lacking the inhibitory receptor TIR8 that allow an unabated TLR-mediated stimulation. We here report that in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened. The morphology and phenotype of the mouse leukemic expansions reproduce the progression of human CLL into an aggressive and frequently terminal phase characterized by the appearance of prolymphocytes. This study reveals an important pathogenetic implication of TLR in CLL development and progression.

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