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1.
Blood ; 125(15): 2381-5, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25733581

RESUMO

In follicular lymphoma (FL), follicular helper T cells (TFH) have been depicted as one of the main components of the malignant B-cell niche and a promising therapeutic target. Although defined by their capacity to sustain FL B-cell growth together with specific gene expression and cytokine secretion profiles, FL-TFH constitute a heterogeneous cell population. However, specific markers reflecting such functional heterogeneity are still lacking. In this study, we demonstrate that CD10 identifies a subset of fully functional germinal center TFH in normal secondary lymphoid organs. Importantly, this subset is amplified in the FL context, unlike in other B-cell lymphomas with a follicular growth pattern. Furthermore, whereas FL-TFH produce high levels of interleukin (IL)-21 and low levels of IL-17 irrespectively of their CD10 expression, CD10(pos) FL-TFH specifically exhibit an IL-4(hi)IFN-γ(lo)TNF-α(hi) cytokine profile associated with a high capacity to sustain directly and indirectly malignant B-cell survival. Altogether, our results highlight the important role of this novel functional subset in the FL cell niche.


Assuntos
Linfócitos B/patologia , Centro Germinativo/citologia , Interleucina-4/imunologia , Linfoma Folicular/imunologia , Neprilisina/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos B/imunologia , Sobrevivência Celular , Criança , Centro Germinativo/imunologia , Centro Germinativo/patologia , Humanos , Interferon gama/análise , Interferon gama/imunologia , Interleucina-4/análise , Linfoma Folicular/patologia , Neprilisina/análise , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/imunologia
2.
Front Immunol ; 15: 1391404, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38799444

RESUMO

Introduction: Follicular Lymphoma (FL) results from the malignant transformation of germinal center (GC) B cells. FL B cells display recurrent and diverse genetic alterations, some of them favoring their direct interaction with their cell microenvironment, including follicular helper T cells (Tfh). Although FL-Tfh key role is well-documented, the impact of their regulatory counterpart, the follicular regulatory T cell (Tfr) compartment, is still sparse. Methods: The aim of this study was to characterize FL-Tfr phenotype by cytometry, gene expression profile, FL-Tfr origin by transcriptomic analysis, and functionality by in vitro assays. Results: CD4+CXCR5+CD25hiICOS+ FL-Tfr displayed a regulatory program that is close to classical regulatory T cell (Treg) program, at the transcriptomic and methylome levels. Accordingly, Tfr imprinting stigmata were found on FL-Tfh and FL-B cells, compared to their physiological counterparts. In addition, FL-Tfr co-culture with autologous FL-Tfh or cytotoxic FL-CD8+ T cells inhibited their proliferation in vitro. Finally, although FL-Tfr shared many characteristics with Treg, TCR sequencing analyses demonstrated that part of them derived from precursors shared with FL-Tfh. Discussion: Altogether, these findings uncover the role and origin of a Tfr subset in FL niche and may be useful for lymphomagenesis knowledge and therapeutic management.


Assuntos
Linfoma Folicular , Linfócitos T Reguladores , Linfoma Folicular/imunologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Humanos , Linfócitos T Reguladores/imunologia , Perfilação da Expressão Gênica , Transcriptoma , Microambiente Tumoral/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células T Auxiliares Foliculares/imunologia , Células T Auxiliares Foliculares/metabolismo , Masculino , Feminino , Técnicas de Cocultura , Centro Germinativo/imunologia
3.
Hematol Transfus Cell Ther ; 45 Suppl 2: S131-S139, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37024424

RESUMO

INTRODUCTION: The remission induction treatment for acute myeloid leukemia (AML) has remained unchanged in the resource-limited setting in the Philippines. AML treatment consists of induction chemotherapy followed by high dose consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. In the Philippines, the Filipino household bears the burden of health care cost of hospitalization expenditure. Insights into the treatment costs becomes an essential requirement as these guides the allocation of resources to scheme health programs. METHOD: This study involved a retrospective cohort analysis of AML patients who underwent treatment for AML. Review of the statements of account per admission per patient during treatment for remission induction, consolidation, relapsed and refractory disease and best supportive care from 2017 to 2019. Of the 251 eligible patients, 190 patients were included. RESULT: The mean healthcare expenditure for remission induction chemotherapy (Phase 1) was US $2, 504.78 (Php 125,239.29). While 3 to 4 cycles of consolidation chemotherapy cost an average of US $3,222.72 (Php 162,103.20). For patients who had relapsed and refractory disease, an additional mean cost of US $3,163.32 (Php 159,115.28) and US $2, 914.72 (Php 146,610.55) were incurred, respectively. The average cost of palliative care was US $1,687.00 (Php 84,856.59). CONCLUSION: The cost of chemotherapy and other therapeutics bear most of the weight of the direct healthcare cost. The cost of AML treatment represents a significant economic burden for patients and the institution. The cost increases as patients proceed through subsequent lines of treatment for induction failure. Existing subsidy for health insurance benefits could still be improved for appropriate source allocation of resources.

4.
Hematol Transfus Cell Ther ; 44(3): 307-313, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33431267

RESUMO

INTRODUCTION: Hematologic abnormalities are common in HIV and involve all blood cell lineages. A study on cytopenias, as correlated with disease progression, can be valuable in resource-limited settings. This study aimed to determine the hematologic profile of HIV patients and its association with CD4 count and antiretroviral (ARV) treatment. METHODS: This is a retrospective cohort study involving adult Filipino HIV patients with complete blood count (CBC) and CD4 count determinations prior to the initiation of ARV treatment and after ≥6 months of ARV treatment. Logistic regression was performed to determine the association between cytopenias and a CD4 count <200 cells/µL. RESULTS: The study included 302 patients. Anemia was the most common cytopenia. Anemia and leukopenia were associated with an increased likelihood of having a CD4 count <200 cells/µL in ARV-naïve patients. In ARV-treated patients, leukopenia was associated with an increased probability of having a CD4 count <200 cells/µL. An increase in hemoglobin, white blood cell (WBC) and platelet counts was observed after ≥6 months of ARV treatment. CONCLUSION: Anemia and leukopenia can be used as markers of immune status in HIV-infected individuals and improvement in the CBC parameters can be used to assess response to ARV treatment. Routine monitoring of hematologic parameters is recommended.

5.
Front Immunol ; 12: 653577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34017332

RESUMO

Multiple sclerosis (MS) is an immune-driven demyelinating disease of the central nervous system. Immune cell features are particularly promising as predictive biomarkers due to their central role in the pathogenesis but also as drug targets, even if nowadays, they have no impact in clinical practice. Recently, high-resolution approaches, such as mass cytometry (CyTOF), helped to better understand the diversity and functions of the immune system. In this study, we performed an exploratory analysis of blood immune response profiles in healthy controls and MS patients sampled at their first neurological relapse, using two large CyTOF panels including 62 markers exploring myeloid and lymphoid cells. An increased abundance of both a T-bet-expressing B cell subset and a CD206+ classical monocyte subset was detected in the blood of early MS patients. Moreover, T-bet-expressing B cells tended to be enriched in aggressive MS patients. This study provides new insights into understanding the pathophysiology of MS and the identification of immunological biomarkers. Further studies will be required to validate these results and to determine the exact role of the identified clusters in neuroinflammation.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Monócitos/imunologia , Esclerose Múltipla/imunologia , Adulto , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Biomarcadores/sangue , Separação Celular/métodos , Estudos de Coortes , Feminino , Citometria de Fluxo/métodos , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Monócitos/metabolismo , Esclerose Múltipla/sangue , Receptores Imunológicos/metabolismo , Proteínas com Domínio T/metabolismo , Adulto Jovem
6.
Front Immunol ; 11: 559866, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133070

RESUMO

Fibroblastic reticular cells (FRCs) are the specialized lymphoid stromal cells initially identified as triggering T-cell recruitment and dynamic motion in secondary lymphoid organs. Interestingly, FRCs also display antigen presentation capacities and support lymphocyte survival. CXCR5+CD4+ follicular T cells are important players of B-cell maturation and antibody response. Our study reported that in vitro-differentiated FRC-like cells enhanced the growth of the whole CXCR5+CD4+ T-cell compartment, while enhancing IL-4 secretion specifically by the PD1dimCXCR5+CD4+ cell subset, in a Notch- and ICAM1/LFA1-dependent manner. In addition, we revealed that in follicular lymphoma (FL) tissues, previously identified as enriched for PD1hiCXCR5hiCD4+ mature follicular helper T cells, PD1dimCXCR5+CD4+ T cells displayed an enrichment for Notch and integrin gene signatures, and a Notch and ICAM-1-dependent overexpression of IL-4 compared to their non-malignant counterparts. These findings suggest that the crosstalk between FRCs and CXCR5+PD1dimCD4+ T cells may contribute to the FL IL-4 rich environment, thus providing new insights in FL lymphomagenesis.


Assuntos
Interleucina-4/biossíntese , Ativação Linfocitária/imunologia , Tecido Linfoide/citologia , Tecido Linfoide/fisiologia , Células Estromais/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Biomarcadores , Comunicação Celular , Proliferação de Células , Sobrevivência Celular , Citocinas/biossíntese , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Molécula 1 de Adesão Intercelular/metabolismo , Ativação Linfocitária/genética , Receptores CXCR5/metabolismo , Receptores Notch/metabolismo , Transcriptoma
7.
Hematol., Transfus. Cell Ther. (Impr.) ; 45(supl.2): S131-S139, July 2023. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1514198

RESUMO

ABSTRACT Introduction: The remission induction treatment for acute myeloid leukemia (AML) has remained unchanged in the resource-limited setting in the Philippines. AML treatment consists of induction chemotherapy followed by high dose consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. In the Philippines, the Filipino household bears the burden of health care cost of hospitalization expenditure. Insights into the treatment costs becomes an essential requirement as these guides the allocation of resources to scheme health programs. Method: This study involved a retrospective cohort analysis of AML patients who underwent treatment for AML. Review of the statements of account per admission per patient during treatment for remission induction, consolidation, relapsed and refractory disease and best supportive care from 2017 to 2019. Of the 251 eligible patients, 190 patients were included. Result: The mean healthcare expenditure for remission induction chemotherapy (Phase 1) was US $2, 504.78 (Php 125,239.29). While 3 to 4 cycles of consolidation chemotherapy cost an average of US $3,222.72 (Php 162,103.20). For patients who had relapsed and refractory disease, an additional mean cost of US $3,163.32 (Php 159,115.28) and US $2, 914.72 (Php 146,610.55) were incurred, respectively. The average cost of palliative care was US $1,687.00 (Php 84,856.59). Conclusion: The cost of chemotherapy and other therapeutics bear most of the weight of the direct healthcare cost. The cost of AML treatment represents a significant economic burden for patients and the institution. The cost increases as patients proceed through subsequent lines of treatment for induction failure. Existing subsidy for health insurance benefits could still be improved for appropriate source allocation of resources.

8.
Hematol., Transfus. Cell Ther. (Impr.) ; 44(3): 307-313, July-Sept. 2022. tab
Artigo em Inglês | LILACS | ID: biblio-1404986

RESUMO

ABSTRACT Introduction: Hematologic abnormalities are common in HIV and involve all blood cell lineages. A study on cytopenias, as correlated with disease progression, can be valuable in resource-limited settings. This study aimed to determine the hematologic profile of HIV patients and its association with CD4 count and antiretroviral (ARV) treatment. Methods: This is a retrospective cohort study involving adult Filipino HIV patients with complete blood count (CBC) and CD4 count determinations prior to the initiation of ARV treatment and after ≥6 months of ARV treatment. Logistic regression was performed to determine the association between cytopenias and a CD4 count <200 cells/μL. Results: The study included 302 patients. Anemia was the most common cytopenia. Anemia and leukopenia were associated with an increased likelihood of having a CD4 count <200 cells/μL in ARV-naïve patients. In ARV-treated patients, leukopenia was associated with an increased probability of having a CD4 count <200 cells/μL. An increase in hemoglobin, white blood cell (WBC) and platelet counts was observed after ≥6 months of ARV treatment. Conclusion: Anemia and leukopenia can be used as markers of immune status in HIV-infected individuals and improvement in the CBC parameters can be used to assess response to ARV treatment. Routine monitoring of hematologic parameters is recommended.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Infecções por HIV , Terapia Antirretroviral de Alta Atividade , Leucopenia , Antígenos CD4 , Anemia
9.
Cancer Res ; 69(7): 3228-37, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19276371

RESUMO

Human mesenchymal stem cells (MSC) strongly repress activated T-cell proliferation through the production of a complex set of soluble factors, including the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO), which is induced by IFN-gamma. Conversely, MSCs support survival of follicular lymphoma (FL) B cells, in particular after exposure to tumor necrosis factor-alpha (TNF) and lymphotoxin-alpha1beta2 (LT). The role of MSCs on normal and malignant B-cell growth in steady-state and inflammatory conditions remains to be fully explored. We show here that resting MSCs sustain activated normal B-cell proliferation and survival, whereas IFN-gamma-conditioned MSCs mediate IDO-dependent B-cell growth arrest and apoptosis. IFN-gamma, TNF, and LT are significantly overexpressed by the microenvironment of invaded FL-lymph nodes, but their relative expression patterns are highly heterogeneous between samples. In vitro, IFN-gamma abrogates the B-cell supportive phenotype induced by TNF and LT on MSCs. Moreover, IFN-gamma overrules the growth promoting effect of MSCs on primary purified FL B cells. Altogether, these results underline the crucial role of the cytokine context in the local crosstalk between malignant cells and their microenvironment and provide new insights into our knowledge of the FL cell niche that emerges as a new promising target for innovative therapeutic strategies.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Interferon gama/farmacologia , Linfoma Folicular/enzimologia , Linfoma Folicular/patologia , Mesoderma/enzimologia , Mesoderma/patologia , Linfócitos B/enzimologia , Linfócitos B/imunologia , Linfócitos B/patologia , Sobrevivência Celular/imunologia , Criança , Humanos , Interferon-alfa/imunologia , Interferon-alfa/farmacologia , Interferon gama/imunologia , Ativação Linfocitária , Linfoma de Células B/enzimologia , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Linfoma Folicular/imunologia , Mesoderma/imunologia , Células Estromais/enzimologia , Células Estromais/imunologia , Células Estromais/patologia
10.
Blood ; 109(2): 693-702, 2007 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-16985173

RESUMO

Accumulating evidence indicates that the cellular microenvironment plays a key role in follicular lymphoma (FL) pathogenesis, both within tumor lymph nodes (LNs) and in infiltrated bone marrow where ectopic LN-like reticular cells are integrated within malignant B-cell nodular aggregates. In normal secondary lymphoid organs, specific stromal cell subsets provide a highly specialized microenvironment that supports immune response. In particular, fibroblastic reticular cells (FRCs) mediate immune cell migration, adhesion, and reciprocal interactions. The role of FRCs and their postulated progenitors, that is, bone marrow mesenchymal stem cells (MSCs), in FL remains unexplored. In this study, we investigated the relationships between FRCs and MSCs and their capacity to sustain malignant B-cell growth. Our findings strongly suggest that secondary lymphoid organs contain MSCs able to give rise to adipocytes, chondrocytes, osteoblasts, as well as fully functional B-cell supportive FRCs. In vitro, bone marrow-derived MSCs acquire a complete FRC phenotype in response to a combination of tumor necrosis factor-alpha and lymphotoxin-alpha1beta2. Moreover, MSCs recruit primary FL cells that, in turn, trigger their differentiation into FRCs, making them able to support malignant B-cell survival. Altogether, these new insights into the cross talk between lymphoma cells and their microenvironment could offer original therapeutic strategies.


Assuntos
Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Células Estromais/fisiologia , Células da Medula Óssea/citologia , Separação Celular/métodos , Células Cultivadas , Humanos , Tecido Linfoide/citologia , Tonsila Palatina/citologia , Células Estromais/citologia
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