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2.
Nat Commun ; 10(1): 3106, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308374

RESUMO

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+ vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.

3.
Sci Immunol ; 4(34)2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979797

RESUMO

Autoimmune regulator (AIRE) mutations result in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome characterized by defective central T cell tolerance and the production of many autoantibodies targeting tissue-specific antigens and cytokines. By studying CD3- and AIRE-deficient patients, we found that lack of either T cells or AIRE function resulted in the peripheral accumulation of autoreactive mature naïve B cells. Proteomic arrays and Biacore affinity measurements revealed that unmutated antibodies expressed by these autoreactive naïve B cells recognized soluble molecules and cytokines including insulin, IL-17A, and IL-17F, which are AIRE-dependent thymic peripheral tissue antigens targeted by autoimmune responses in APECED. AIRE-deficient patients also displayed decreased frequencies of regulatory T cells (Tregs) that lacked common TCRß clones found instead in their conventional T cell compartment, thereby suggesting holes in the Treg TCR repertoire of these patients. Hence, AIRE-mediated T cell/Treg selection normally prevents the expansion of autoreactive naïve B cells recognizing peripheral self-antigens.

4.
Artigo em Inglês | MEDLINE | ID: mdl-29935219

RESUMO

BACKGROUND: The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy. OBJECTIVE: We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID-AIC). METHODS: We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID-AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID. RESULTS: We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID-AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID-AIC. Moreover, IgG+ B cells from patients with CVID+AIC expressed VH4-34-encoded antibodies with unmutated Ala-Val-Tyr and Asn-His-Ser motifs, which recognize both erythrocyte I/i self-antigens and commensal bacteria. CONCLUSIONS: Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG+ B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens.

5.
JCI Insight ; 3(5)2018 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-29515028

RESUMO

B cells play a central role in systemic lupus erythematosus (SLE) pathophysiology but dysregulated pathways leading to a break in B cell tolerance remain unclear. Since Toll-like receptor 9 (TLR9) favors the elimination of autoreactive B cells in the periphery, we assessed TLR9 function in SLE by analyzing the responses of B cells and plasmacytoid dendritic cells (pDCs) isolated from healthy donors and patients after stimulation with CpG, a TLR9 agonist. We found that SLE B cells from patients without hydroxychloroquine treatment displayed defective in vitro TLR9 responses, as illustrated by the impaired upregulation of B cell activation molecules and the diminished production of various cytokines including antiinflammatory IL-10. In agreement with CD19 controlling TLR9 responses in B cells, decreased expression of the CD19/CD21 complex on SLE B cells was detected as early as the transitional B cell stage. In contrast, TLR7 function was preserved in SLE B cells, whereas pDCs from SLE patients properly responded to TLR9 stimulation, thereby revealing that impaired TLR9 function in SLE was restricted to B cells. We conclude that abnormal CD19 expression and TLR9 tolerogenic function in SLE B cells may contribute to the break of B cell tolerance in these patients.

6.
Arthritis Rheumatol ; 70(2): 298-307, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29073352

RESUMO

OBJECTIVE: Patients with Sjögren's syndrome (SS) are prone to develop malignant lymphomas, and a correlation has been established between the lymphoproliferations occurring in these disorders and the presence in patients' blood of an unusual B cell population that down-regulates complement receptor 2/CD21. This study was undertaken to identify the B cell compartment from which these lymphoproliferations emerge and determine the mechanisms that promote clonal B cell expansion in patients with SS. METHODS: The reactivity of antibodies expressed by CD19+CD10-CD27-IgM+CD21-/low cells isolated from the blood of patients with SS was tested using a polymerase chain reaction-based approach that allows us to clone and express, in vitro, recombinant antibodies produced by single B cells. RESULTS: Clonal expansions were identified in CD21-/low B cells isolated from the peripheral blood of 3 patients with SS. These lymphoproliferations expressed B cell receptors (BCRs) that displayed somatic hypermutation lineage trees characteristic of a strong selection by antigens; one of these antigens was identified as a ribosomal self antigen. When the mutated BCR sequences expressed by the expanded CD21-/low B cell clones from patients with SS were reverted in vitro to their germline counterparts, one clone remained autoreactive. CONCLUSION: Clonal lymphoproliferations in patients with SS preferentially accumulate in the autoreactive CD21-/low B cell compartment often expanded in these subjects, and recognition of self antigens may drive the clonal B cell expansion while further refining BCR self-reactivity.

8.
Arthritis Rheumatol ; 69(11): 2203-2208, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28704602

RESUMO

OBJECTIVE: Central and peripheral B cell tolerance checkpoints are defective in many patients with autoimmune diseases, but the functionality of each discrete checkpoint has not been assessed in patients with Sjögren's syndrome (SS). We undertook this study to assess this functionality in SS patients. METHODS: Using a polymerase chain reaction-based approach that allows us to clone and express, in vitro, recombinant antibodies produced by single B cells, we tested the reactivity of recombinant antibodies cloned from single CD19+CD21low CD10+IgMhigh CD27- newly emigrant/transitional B cells and CD19+CD21+CD10-IgM+CD27- mature naive B cells from 5 SS patients. RESULTS: We found that the frequencies of newly emigrant/transitional B cells expressing polyreactive antibodies were significantly increased in SS patients compared to those in healthy donors, revealing defective central B cell tolerance in SS patients. Frequencies of mature naive B cells expressing autoreactive antibodies were also significantly increased in SS patients, thereby illustrating an impaired peripheral B cell tolerance checkpoint in these patients. CONCLUSION: Defective counterselection of developing autoreactive B cells observed in SS patients is a feature common to many other autoimmune diseases and may favor the development of autoimmunity by allowing autoreactive B cells to present self antigens to T cells.


Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Tolerância Imunológica/imunologia , Síndrome de Sjogren/imunologia , Adulto , Idoso , Anticorpos Antinucleares/imunologia , Diferenciação Celular , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Análise de Célula Única , Adulto Jovem
9.
Nat Genet ; 49(8): 1192-1201, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28628108

RESUMO

Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Dermatite Atópica/genética , Mutação em Linhagem Germinativa , Guanilato Ciclase/genética , Sistema ASC de Transporte de Aminoácidos/metabolismo , Estudos de Coortes , Análise Mutacional de DNA , Dermatite Atópica/imunologia , Feminino , Genes Dominantes , Glutamina/metabolismo , Humanos , Células Jurkat , Ativação Linfocitária , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Antígenos de Histocompatibilidade Menor/metabolismo , Complexos Multiproteicos/metabolismo , NF-kappa B/metabolismo , Linhagem , Linfócitos T/imunologia , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo
10.
J Exp Med ; 214(7): 1991-2003, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28500047

RESUMO

The germline immunoglobulin (Ig) variable heavy chain 4-34 (VH4-34) gene segment encodes in humans intrinsically self-reactive antibodies that recognize I/i carbohydrates expressed by erythrocytes with a specific motif in their framework region 1 (FWR1). VH4-34-expressing clones are common in the naive B cell repertoire but are rarely found in IgG memory B cells from healthy individuals. In contrast, CD27+IgG+ B cells from patients genetically deficient for IRAK4 or MYD88, which mediate the function of Toll-like receptors (TLRs) except TLR3, contained VH4-34-expressing clones and showed decreased somatic hypermutation frequencies. In addition, VH4-34-encoded IgGs from IRAK4- and MYD88-deficient patients often displayed an unmutated FWR1 motif, revealing that these antibodies still recognize I/i antigens, whereas their healthy donor counterparts harbored FWR1 mutations abolishing self-reactivity. However, this paradoxical self-reactivity correlated with these VH4-34-encoded IgG clones binding commensal bacteria antigens. Hence, B cells expressing germline-encoded self-reactive VH4-34 antibodies may represent an innate-like B cell population specialized in the containment of commensal bacteria when gut barriers are breached.


Assuntos
Linfócitos B/imunologia , Bactérias/imunologia , Imunoglobulina G/imunologia , Cadeias Pesadas de Imunoglobulinas/imunologia , Região Variável de Imunoglobulina/imunologia , Adolescente , Adulto , Sequência de Aminoácidos , Antígenos de Bactérias/imunologia , Autoanticorpos/genética , Autoanticorpos/imunologia , Linfócitos B/metabolismo , Criança , Pré-Escolar , Seleção Clonal Mediada por Antígeno , Feminino , Microbioma Gastrointestinal/imunologia , Humanos , Imunoglobulina G/genética , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Quinases Associadas a Receptores de Interleucina-1/deficiência , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/imunologia , Masculino , Mutação , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Homologia de Sequência de Aminoácidos , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto Jovem
12.
Blood Adv ; 1(23): 2007-2018, 2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-29296847

RESUMO

B cells play a major role in antigen presentation and antibody production in the development of autoimmune diseases, and some of these diseases disproportionally occur in females. Moreover, immune responses tend to be stronger in female vs male humans and mice. Because it is challenging to distinguish intrinsic from extrinsic influences on human immune responses, we used a personalized immune (PI) humanized mouse model, in which immune systems were generated de novo from adult human hematopoietic stem cells (HSCs) in immunodeficient mice. We assessed the effect of recipient sex and of donor autoimmune diseases (type 1 diabetes [T1D] and rheumatoid arthritis [RA]) on human B-cell development in PI mice. We observed that human B-cell levels were increased in female recipients regardless of the source of human HSCs or the strain of immunodeficient recipient mice. Moreover, mice injected with T1D- or RA-derived HSCs displayed B-cell abnormalities compared with healthy control HSC-derived mice, including altered B-cell levels, increased proportions of mature B cells and reduced CD19 expression. Our study revealed an HSC-extrinsic effect of recipient sex on human B-cell reconstitution. Moreover, the PI humanized mouse model revealed HSC-intrinsic defects in central B-cell tolerance that recapitulated those in patients with autoimmune diseases. These results demonstrate the utility of humanized mouse models as a tool to better understand human immune cell development and regulation.

13.
J Clin Invest ; 126(11): 4219-4236, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27760045

RESUMO

Alterations in the apoptosis of immune cells have been associated with autoimmunity. Here, we have identified a homozygous missense mutation in the gene encoding the base excision repair enzyme Nei endonuclease VIII-like 3 (NEIL3) that abolished enzymatic activity in 3 siblings from a consanguineous family. The NEIL3 mutation was associated with fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function in these individuals. The same homozygous NEIL3 mutation was also identified in an asymptomatic individual who exhibited elevated levels of serum autoantibodies and defective peripheral B cell tolerance, but normal B cell function. Further analysis of the patients revealed an absence of LPS-responsive beige-like anchor (LRBA) protein expression, a known cause of immunodeficiency. We next examined the contribution of NEIL3 to the maintenance of self-tolerance in Neil3-/- mice. Although Neil3-/- mice displayed normal B cell function, they exhibited elevated serum levels of autoantibodies and developed nephritis following treatment with poly(I:C) to mimic microbial stimulation. In Neil3-/- mice, splenic T and B cells as well as germinal center B cells from Peyer's patches showed marked increases in apoptosis and cell death, indicating the potential release of self-antigens that favor autoimmunity. These findings demonstrate that deficiency in NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies, and predisposition to autoimmunity.


Assuntos
Doenças Autoimunes , Linfócitos B/imunologia , Endodesoxirribonucleases/deficiência , Predisposição Genética para Doença , N-Glicosil Hidrolases/deficiência , Linfócitos T/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/imunologia , Autoanticorpos/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos B/patologia , Endodesoxirribonucleases/imunologia , Feminino , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Knockout , N-Glicosil Hidrolases/imunologia , Poli I-C/farmacologia , Linfócitos T/patologia
14.
J Clin Invest ; 126(11): 4289-4302, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27701145

RESUMO

Patients with mutations in AICDA, which encodes activation-induced cytidine deaminase (AID), display an impaired peripheral B cell tolerance. AID mediates class-switch recombination (CSR) and somatic hypermutation (SHM) in B cells, but the mechanism by which AID prevents the accumulation of autoreactive B cells in blood is unclear. Here, we analyzed B cell tolerance in AID-deficient patients, patients with autosomal dominant AID mutations (AD-AID), asymptomatic AICDA heterozygotes (AID+/-), and patients with uracil N-glycosylase (UNG) deficiency, which impairs CSR but not SHM. The low frequency of autoreactive mature naive B cells in UNG-deficient patients resembled that of healthy subjects, revealing that impaired CSR does not interfere with the peripheral B cell tolerance checkpoint. In contrast, we observed decreased frequencies of SHM in memory B cells from AD-AID patients and AID+/- subjects, who were unable to prevent the accumulation of autoreactive mature naive B cells. In addition, the individuals with AICDA mutations, but not UNG-deficient patients, displayed Tregs with defective suppressive capacity that correlated with increases in circulating T follicular helper cells and enhanced cytokine production. We conclude that SHM, but not CSR, regulates peripheral B cell tolerance through the production of mutated antibodies that clear antigens and prevent sustained interleukin secretions that interfere with Treg function.


Assuntos
Linfócitos B/imunologia , Pontos de Checagem do Ciclo Celular/imunologia , Citidina Desaminase/deficiência , Tolerância Imunológica , Memória Imunológica , Mutação , Hipermutação Somática de Imunoglobulina/imunologia , Linfócitos B/patologia , Pontos de Checagem do Ciclo Celular/genética , Citidina Desaminase/imunologia , Feminino , Humanos , Masculino , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
15.
Exp Hematol ; 44(9): 811-816.e3, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27321893

RESUMO

Lymphoid-committed CD34(+)lin(-)CD10(+)CD24(-) progenitors undergo a rebound at month 3 after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the absence of acute graft-versus-host disease (aGVHD). Here, we analyzed transcriptional programs of cell-sorted circulating lymphoid-committed progenitors and CD34(+)Lin(-)CD10(-) nonlymphoid progenitors in 11 allo-HSCT patients who had (n = 5) or had not (n = 6) developed grade 2 or 3 aGVHD and in 7 age-matched healthy donors. Major upregulated pathways include protein synthesis, energy production, cell cycle regulation, and cytoskeleton organization. Notably, genes from protein biogenesis, translation machinery, and cell cycle (CDK6) were overexpressed in progenitors from patients in the absence of aGVHD compared with healthy donors and patients affected by aGVHD. Expression of many genes from the mitochondrial oxidative phosphorylation metabolic pathway leading to ATP production were more specifically increased in lymphoid-committed progenitors in the absence of aGVHD. This was also the case for genes involved in cell mobilization such as those regulating Rho GTPase activity. In all, we found that circulating lymphoid-committed progenitors undergo profound changes in metabolism, favoring cell proliferation, energy production, and cell mobilization after allo-HSCT in humans. These mechanisms are abolished in the case of aGVHD or its treatment, indicating a persistent cell-intrinsic defect after exit from the bone marrow.


Assuntos
Metabolismo Energético , Transplante de Células-Tronco Hematopoéticas , Células Progenitoras Linfoides/metabolismo , Adulto , Biomarcadores , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Transplante Homólogo , Adulto Jovem
16.
J Clin Invest ; 125(10): 3941-51, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26368308

RESUMO

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and high susceptibility to developing tumors and autoimmunity. Recent evidence suggests that B cells may be key players in the pathogenesis of autoimmunity in WAS. Here, we assessed whether WAS protein deficiency (WASp deficiency) affects the establishment of B cell tolerance by testing the reactivity of recombinant antibodies isolated from single B cells from 4 WAS patients before and after gene therapy (GT). We found that pre-GT WASp-deficient B cells were hyperreactive to B cell receptor stimulation (BCR stimulation). This hyperreactivity correlated with decreased frequency of autoreactive new emigrant/transitional B cells exiting the BM, indicating that the BCR signaling threshold plays a major role in the regulation of central B cell tolerance. In contrast, mature naive B cells from WAS patients were enriched in self-reactive clones, revealing that peripheral B cell tolerance checkpoint dysfunction is associated with impaired suppressive function of WAS regulatory T cells. The introduction of functional WASp by GT corrected the alterations of both central and peripheral B cell tolerance checkpoints. We conclude that WASp plays an important role in the establishment and maintenance of B cell tolerance in humans and that restoration of WASp by GT is able to restore B cell tolerance in WAS patients.


Assuntos
Linfócitos B/imunologia , Terapia Genética , Vetores Genéticos/uso terapêutico , Tolerância Imunológica , Proteína da Síndrome de Wiskott-Aldrich/uso terapêutico , Síndrome de Wiskott-Aldrich/terapia , Adulto , Sequência de Aminoácidos , Medula Óssea/patologia , Criança , Pré-Escolar , Deleção Clonal , Células Clonais/imunologia , Humanos , Lentivirus/genética , Masculino , Dados de Sequência Molecular , Receptores de Antígenos de Linfócitos B/imunologia , Proteínas Recombinantes de Fusão , Linfócitos T Reguladores/imunologia , Síndrome de Wiskott-Aldrich/imunologia , Proteína da Síndrome de Wiskott-Aldrich/deficiência , Proteína da Síndrome de Wiskott-Aldrich/genética
17.
Blood ; 124(15): 2459-62, 2014 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-25185266

RESUMO

Using B-cell rearrangement excision circle measurements, we analyzed B-cell reconstitution in a cohort of 243 patients who underwent allogeneic stem cell transplantation. Acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) transiently increased B-cell replication but decreased overall B-cell neogenesis with a clear difference in terms of kinetics. Moreover, the impact of aGVHD in the absence of cGVHD was transient, recovering at month 6 similar values as in patients who did not suffer from GVHD. Conversely, impact of cGVHD at month 12 in multivariate analysis was independent of the previous aGVHD effect on B-cell output. Finally, we showed in patients affected with cGVHD a higher B-cell division rate that correlates with an elevated BAFF/CD19(+) B-cell ratio, supporting a B-cell hyperactivation state in vivo.


Assuntos
Linfócitos B/imunologia , Linfócitos B/patologia , Divisão Celular , Doença Enxerto-Hospedeiro/imunologia , Doença Aguda , Adulto , Fator Ativador de Células B/sangue , Proliferação de Células , Doença Crônica , Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante Homólogo
18.
PLoS One ; 9(3): e91492, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24621606

RESUMO

Immune recovery after profound lymphopenia is a major challenge in many clinical situations, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recovery depends, in a first step, on hematopoietic lymphoid progenitors production in the bone marrow (BM). In this study, we characterized CD34+Lin-CD10+ lymphoid progenitors in the peripheral blood of allo-HSCT patients. Our data demonstrate a strong recovery of this population 3 months after transplantation. This rebound was abolished in patients who developed acute graft-versus-host disease (aGVHD). A similar recovery profile was found for both CD24+ and CD24- progenitor subpopulations. CD34+lin-CD10+CD24- lymphoid progenitors sorted from allo-HSCT patients preserved their T cell potentiel according to in vitro T-cell differentiation assay and the expression profile of 22 genes involved in T-cell differentiation and homing. CD34+lin-CD10+CD24- cells from patients without aGVHD had reduced CXCR4 gene expression, consistent with an enhanced egress from the BM. CCR7 gene expression was reduced in patients after allo-HSCT, as were its ligands CCL21 and CCL19. This reduction was particularly marked in patients with aGVHD, suggesting a possible impact on thymic homing. Thus, the data presented here identify this population as an important early step in T cell reconstitution in humans and so, an important target when seeking to enhance immune reconstitution.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Receptores CXCR4/metabolismo , Linfócitos T/citologia , Adolescente , Adulto , Idoso , Antígenos CD34/metabolismo , Células da Medula Óssea/imunologia , Quimiocina CXCL12/metabolismo , Criança , Regulação para Baixo/imunologia , Feminino , Reação Hospedeiro-Enxerto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/metabolismo , Receptores CXCR4/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timo/imunologia , Transplante Homólogo/efeitos adversos , Adulto Jovem
19.
Leuk Lymphoma ; 55(8): 1788-95, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24237448

RESUMO

Whether the efficacy of lenalidomide in the treatment of multiple myeloma (MM) is due to direct tumor toxicity only or to additional immunomodulatory effects is unclear. We studied the effect of lenalidomide treatment on T-cell immune reconstitution in patients with MM who had undergone autologous peripheral blood stem cell transplant (ASCT). Twenty-nine newly diagnosed patients with MM received induction therapy followed by high-dose melphalan and ASCT. After ASCT, 11 patients received lenalidomide consolidation therapy for 2 months followed by maintenance therapy until disease progression. The remaining 18 patients received no treatment. Serial analysis of thymic output, as given by numbers of T-cell receptor excision circles (sjTRECs), and T-cell phenotyping was performed until 18 months post-ASCT. Lenalidomide impaired long-term thymic T-cell reconstitution, decreased CD4 + and CD8 + CD45RA + CCR7 - effector-terminal T-cell absolute counts and increased CD4 + CD25 + CD127 - /low regulatory T-cells. Lenalidomide consolidation and long-term maintenance therapy, administered post-ASCT, may have a potentially negative impact on immune surveillance.


Assuntos
Antineoplásicos/uso terapêutico , Homeostase/imunologia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Subpopulações de Linfócitos T/imunologia , Talidomida/análogos & derivados , Adulto , Antígenos de Superfície/metabolismo , Antineoplásicos/farmacologia , Estudos de Casos e Controles , Quimioterapia de Consolidação , Transplante de Células-Tronco Hematopoéticas , Homeostase/efeitos dos fármacos , Humanos , Imunofenotipagem , Lenalidomida , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Talidomida/farmacologia , Talidomida/uso terapêutico , Timo/imunologia , Transplante Autólogo , Resultado do Tratamento
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