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1.
Clin Immunol ; 200: 31-34, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639166

RESUMO

This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.


Assuntos
Agamaglobulinemia/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Linfopenia/genética , /genética , Adulto , Agamaglobulinemia/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Feminino , Mutação com Ganho de Função , Humanos , Linfopenia/imunologia , Linfopoese , /imunologia
2.
J Allergy Clin Immunol ; 143(1): 266-275, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29778502

RESUMO

BACKGROUND: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined. OBJECTIVE: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. METHODS: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities. RESULTS: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. CONCLUSION: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Transtornos Linfoproliferativos , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/terapia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/terapia , Masculino , Taxa de Sobrevida
3.
J Allergy Clin Immunol ; 143(1): 276-291.e6, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29800648

RESUMO

BACKGROUND: Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K-AKT-mechanistic target of rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown. OBJECTIVE: Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies. METHODS: We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV. RESULTS: PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70. CONCLUSIONS: PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Classe I de Fosfatidilinositol 3-Quinases , Infecções por Vírus Epstein-Barr , Mutação com Ganho de Função , Doenças Genéticas Inatas/imunologia , Herpesvirus Humano 4/imunologia , Células Matadoras Naturais/imunologia , Adolescente , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/genética , Senescência Celular/genética , Senescência Celular/imunologia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Vigilância Imunológica/genética , Células Matadoras Naturais/patologia , Masculino , Pessoa de Meia-Idade
4.
J Clin Invest ; 129(1): 122-136, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30457982

RESUMO

Targeted therapy with small molecules directed at essential survival pathways in leukemia represents a major advance, including the phosphatidylinositol-3'-kinase (PI3K) p110δ inhibitor idelalisib. Here, we found that genetic inactivation of p110δ (p110δD910A/D910A) in the Eµ-TCL1 murine chronic lymphocytic leukemia (CLL) model impaired B cell receptor signaling and B cell migration, and significantly delayed leukemia pathogenesis. Regardless of TCL1 expression, p110δ inactivation led to rectal prolapse in mice resembling autoimmune colitis in patients receiving idelalisib. Moreover, we showed that p110δ inactivation in the microenvironment protected against CLL and acute myeloid leukemia. After receiving higher numbers of TCL1 leukemia cells, half of p110δD910A/D910A mice spontaneously recovered from high disease burden and resisted leukemia rechallenge. Despite disease resistance, p110δD910A/D910A mice exhibited compromised CD4+ and CD8+ T cell response, and depletion of CD4+ or CD8+ T cells restored leukemia. Interestingly, p110δD910A/D910A mice showed significantly impaired Treg expansion that associated with disease clearance. Reconstitution of p110δD910A/D910A mice with p110δWT/WT Tregs reversed leukemia resistance. Our findings suggest that p110δ inhibitors may have direct antileukemic and indirect immune-activating effects, further supporting that p110δ blockade may have a broader immune-modulatory role in types of leukemia that are not sensitive to p110δ inhibition.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Tolerância Imunológica , Leucemia Linfoide/imunologia , Mutação de Sentido Incorreto , Neoplasias Experimentais/imunologia , Linfócitos T Reguladores/imunologia , Substituição de Aminoácidos , Animais , Linfócitos T CD8-Positivos/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Leucemia Linfoide/genética , Leucemia Linfoide/patologia , Leucemia Linfoide/terapia , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Linfócitos T Reguladores/patologia
5.
J Clin Immunol ; 38(8): 854-863, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30499059

RESUMO

PURPOSE: We aimed to report the clinical manifestations and immunological features of activated phosphatidylinositol 3-kinase δ syndrome 1 (APDS1) in a Chinese cohort. Moreover, we investigated the efficacy and safety of rapamycin therapy for Chinese patients with APDS1. METHODS: Fifteen Chinese patients with APDS1 from 14 unrelated families were enrolled in this study. These patients were diagnosed based on clinical features, immunological phenotype, and whole-exome sequencing. Four patients were treated with rapamycin, and the clinical efficacy and safety of rapamycin were observed. The changes of phosphorylation of Akt and mammalian target of rapamycin (mTOR) signaling pathway after rapamycin treatment were detected by flow cytometry and real-time PCR. RESULTS: The common clinical manifestations of the patients included lymphadenopathy (93%), recurrent sinopulmonary infections (93%), hepatosplenomegaly (93%), and diarrhea (78%). Epstein-Barr virus (EBV) (80%) and fungus (Aspergillus) (47%) were the most common pathogens. Immunological phenotype included elevated Immunoglobulin (Ig) M levels (100%), decreased naive T cells, increased senescent T cells, and expanded transitional B cells. Whole-exome sequencing indicated that 13 patients had heterogeneous PIK3CD E1021K mutations, 1 patient had heterogeneous E1025G mutation and 1 patient had heterogeneous Y524N mutation. Gain-of-function (GOF) PIK3CD mutations increased the phosphorylation of the Akt-mTOR signaling pathway. Four patients underwent rapamycin therapy, experiencing substantial improvement in clinical symptoms and immunological phenotype. Rapamycin inhibited the activated Akt-mTOR signaling pathway. CONCLUSIONS: We described 15 Chinese patients with APDS1. Treatment with the mTOR inhibitor rapamycin improved patient outcomes.


Assuntos
Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Síndromes de Imunodeficiência/imunologia , Células Precursoras de Linfócitos B/imunologia , Sirolimo/uso terapêutico , Linfócitos T/imunologia , Adolescente , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Estudos de Coortes , Feminino , Hepatomegalia , Humanos , Imunoglobulina M/sangue , Síndromes de Imunodeficiência/tratamento farmacológico , Lactente , Linfadenopatia , Masculino , Mutação/genética , Proteína Oncogênica v-akt/metabolismo , Fosforilação , Infecções Respiratórias , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
6.
J Exp Med ; 215(10): 2485-2496, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30194267

RESUMO

Activated PI3K-delta syndrome (APDS) is an immunodeficiency caused by gain-of-function mutations in PIK3CD. This disease exhibits complex immune phenotypes including increased IgM, recurrent infection, and impaired vaccine responses. To better understand the impact of B cells in this disease, we generated an inducible model of the common APDS mutation (hPIK3CD-E1021K; referred to as aPIK3CD) and intercrossed these mice with B cell-specific Cre models. Mb1-aPIK3CD mice exhibited bone marrow B lymphopenia and, conversely, expansion of the peripheral innate B1a and MZ B cell compartments. aPIK3CD B cells manifest increased pS6 and increased survival at several stages, without alterations in cycling, and baseline increases in plasma cells, natural IgM, and IgG3. Finally, Mb1-aPIK3CD mice exhibited blunted T cell-independent immune responses, and both AID- and CD21-aPIK3CD mice displayed reduced class-switched antibodies following T cell-dependent immunization. Thus, aPIK3CD alters B cell development and function and is counter-productive during immune responses, providing insight into B cell-intrinsic contributions to the APDS phenotype.


Assuntos
Mutação com Ganho de Função , Doenças Genéticas Inatas/imunologia , Imunidade Inata , Síndromes de Imunodeficiência/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Plasmócitos/imunologia , Animais , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/genética , Plasmócitos/patologia
7.
Front Immunol ; 9: 1758, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30116245

RESUMO

Activated phosphoinositide 3-kinase delta syndrome (APDS), also known as p110 delta-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI), is an autosomal dominant primary human immunodeficiency (PID) caused by heterozygous gain-of-function mutations in PIK3CD, which encodes the p110δ catalytic subunit of PI3K. This recently described PID is characterized by diverse and heterogeneous clinical manifestations that include recurrent respiratory infections, lymphoproliferation, progressive lymphopenia, and defective antibody responses. A major clinical manifestation observed in the NIH cohort of patients with PIK3CD mutations is chronic Epstein-Barr virus (EBV) and/or cytomegalovirus viremia. Despite uncontrolled EBV infection, many APDS/PASLI patients had normal or higher frequencies of EBV-specific CD8+ T cells. In this review, we discuss data pertaining to CD8+ T cell function in APDS/PASLI, including increased cell death, expression of exhaustion markers, and altered killing of autologous EBV-infected B cells, and how these and other data on PI3K provide insight into potential cellular defects that prevent clearance of chronic infections.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Infecções por Vírus Epstein-Barr/imunologia , Síndromes de Imunodeficiência/imunologia , Adolescente , Adulto , Animais , Diferenciação Celular , Sobrevivência Celular , Senescência Celular , Criança , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/imunologia , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/genética , Camundongos , Mutação , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Adulto Jovem
8.
Clin Immunol ; 197: 60-67, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30138677

RESUMO

Activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome is a newly defined and relatively common primary immunodeficiency, which is caused by heterozygous gain-of-function (GOF) mutations in PIK3CD or PIK3R1. Here, we report a novel de novo GOF mutation (c.1570 T > A, p.Y524N) in PIK3CD in a 6-year-old Chinese girl. The patient suffered recurrent sinopulmonary infection, bronchiectasis, lymphoproliferation, herpesvirus infection, and distinctive nodular lymphoid hyperplasia of mucosal surfaces. Immunological analysis revealed increased CD4+ T cell senescence and B cell immaturity. Further analysis revealed an increase in almost all CD4+ T cell subsets to varying degrees, including effector T cells and Treg cells. Increased levels of plasma T cell-related cytokines corroborated these results. Hyperactivation of the PI3Kδ-Akt-mTOR signaling pathway was also confirmed. Treatment with rapamycin ameliorated the lymphoproliferative immunodeficiency caused by hyperactivation of mTOR. These results expand genetic spectrum of APDS and will facilitate further study of the genotype-phenotype correlation in those with PIK3CD mutations.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/genética , Adolescente , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Senescência Celular , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Feminino , Mutação com Ganho de Função , Genótipo , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/imunologia , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Fenótipo , Análise de Sequência de DNA , Transdução de Sinais , Sirolimo/uso terapêutico , Subpopulações de Linfócitos T , Linfócitos T Reguladores/imunologia
10.
PLoS One ; 13(7): e0200163, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30001368

RESUMO

Precision cancer therapy requires on the one hand detailed knowledge about a tumor's driver oncogenes and on the other hand an effective targeted therapy that specifically inhibits these oncogenes. While the determination of genomic landscape of a tumor has reached a very precise level, the respective therapy options are scarce. The application of small inhibitory (si) RNAs is a promising field of investigation. Here, we present the effective in vivo-treatment of colorectal cancer (CRC) xenograft tumors with antibody-complexed, endoribonuclease-prepared small inhibitory (esi)RNAs. We chose heterogeneous endoribonuclease-prepared siRNA pools (esiRNAs) against the frequently mutated genes PIK3CA and KRAS and coupled them to the anti-EGFR antibody cetuximab, which was internalized specifically into the tumor cells. esiRNA pools have been shown to exhibit superior specificity in target gene knockdown compared to classic siRNAs. We identified a significant decrease in tumor growth upon this treatment due to decreased tumor cell proliferation. The ex vivo-analysis of the xenograft CRC tumors revealed the expected downregulation of the intended direct targets PIK3CA and KRAS on protein level. Moreover, known downstream targets for EGFR signaling such as p-ERK, p-AKT, and c-MYC were decreased as well. We therefore propose the use of antibody-esiRNA complexes as a novel experimental treatment option against key components of the EGFR signaling cascade.


Assuntos
Cetuximab/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Colorretais/terapia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Animais , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Terapia Combinada , Regulação para Baixo , Feminino , Células HT29 , Humanos , Camundongos , Camundongos Nus , Mutação , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nat Rev Clin Oncol ; 15(8): 510-527, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29777163

RESUMO

During the past 5 years, a number of highly active novel agents, including kinase inhibitors targeting BTK or PI3Kδ, an antagonist of the antiapoptotic protein BCL-2, and new anti-CD20 monoclonal antibodies, have been added to the therapeutic armamentarium for patients with chronic lymphocytic leukaemia (CLL). In these exciting times, care is needed to optimally integrate these novel agents into the traditional treatment algorithm without overlooking or compromising the benefits of established treatments, especially chemoimmunotherapy. A more personalized approach to CLL therapy that takes into account individual risk factors, patient characteristics, and their treatment preferences is now possible. Herein, we discuss the biological basis for the novel therapeutic agents and outline not only the major advantages of these agents over traditional therapies but also their adverse effects and the rationale for continued use of older versus newer types of therapy for selected patients with CLL. We conclude by providing recommendations for an individualized therapy approach for different populations of patients with CLL.


Assuntos
Imunoterapia/tendências , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Terapia de Alvo Molecular , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Medicina de Precisão , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Fatores de Risco
12.
Front Immunol ; 9: 568, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29675019

RESUMO

Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production. Heterozygous mutations in PIK3CD, PIK3R1, or PTEN, which are related to the hyperactive phosphoinositide 3-kinase (PI3K) signaling, were recently presented to cause APDS1 or APDS2 (APDSs), or APDS-like (APDS-L) disorder. In this study, we examined the AKT phosphorylation of peripheral blood lymphocytes and monocytes in patients with APDSs and APDS-L by using flow cytometry. CD19+ B cells of peripheral blood in APDS2 patients showed the enhanced phosphorylation of AKT at Ser473 (pAKT) without any specific stimulation. The enhanced pAKT in CD19+ B cells was normalized by the addition of a p110δ inhibitor. In contrast, CD3+ T cells and CD14+ monocytes did not show the enhanced pAKT in the absence of stimulation. These findings were similarly observed in patients with APDS1 and APDS-L. Among CD19+ B cells, enhanced pAKT was prominently detected in CD10+ immature B cells compared with CD10- mature B cells. Enhanced pAKT was not observed in B cells of healthy controls, patients with common variable immunodeficiency, and hyper IgM syndrome due to CD40L deficiency. These results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies.


Assuntos
Linfócitos B/imunologia , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Síndromes de Imunodeficiência/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Adolescente , Adulto , Sequência de Aminoácidos , Linfócitos B/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Mutação , Linhagem , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Células Precursoras de Linfócitos B/imunologia , Células Precursoras de Linfócitos B/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adulto Jovem
13.
Nat Rev Clin Oncol ; 15(5): 273-291, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29508857

RESUMO

The PI3K-AKT-mTOR pathway is one of the most frequently dysregulated pathways in cancer and, consequently, more than 40 compounds that target key components of this signalling network have been tested in clinical trials involving patients with a range of different cancers. The clinical development of many of these agents, however, has not advanced to late-phase randomized trials, and the antitumour activity of those that have been evaluated in comparative prospective studies has typically been limited, or toxicities were found to be prohibitive. Nevertheless, the mTOR inhibitors temsirolimus and everolimus and the PI3K inhibitors idelalisib and copanlisib have been approved by the FDA for clinical use in the treatment of a number of different cancers. Novel compounds with greater potency and selectivity, as well as improved therapeutic indices owing to reduced risks of toxicity, are clearly required. In addition, biomarkers that are predictive of a response, such as PIK3CA mutations for inhibitors of the PI3K catalytic subunit α isoform, must be identified and analytically and clinically validated. Finally, considering that oncogenic activation of the PI3K-AKT-mTOR pathway often occurs alongside pro-tumorigenic aberrations in other signalling networks, rational combinations are also needed to optimize the effectiveness of treatment. Herein, we review the current experience with anticancer therapies that target the PI3K-AKT-mTOR pathway.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Proteína Oncogênica v-akt/imunologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Everolimo/uso terapêutico , Humanos , Terapia de Alvo Molecular , Neoplasias/imunologia , Proteína Oncogênica v-akt/antagonistas & inibidores , Purinas/uso terapêutico , Pirimidinas/uso terapêutico , Quinazolinas/uso terapêutico , Quinazolinonas/uso terapêutico , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/imunologia
14.
Front Immunol ; 9: 446, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29563914

RESUMO

Pathogenic gain-of-function mutations in the gene encoding phosphoinositide 3-kinase delta (PI3Kδ) cause activated PI3Kδ syndrome (APDS), a disease characterized by humoral immunodeficiency, lymphadenopathy, and an inability to control persistent viral infections including Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. Understanding the mechanisms leading to impaired immune response is important to optimally treat APDS patients. Immunosenescence of CD8+ T cells was suggested to contribute to APDS pathogenesis. However, the constitutive activation of T cells in APDS may also result in T cell exhaustion. Therefore, we studied exhaustion of the CD8+ T cell compartment in APDS patients and compared them with healthy controls and HIV patients, as a control for exhaustion. The subset distribution of the T cell compartment of APDS patients was comparable with HIV patients with decreased naive CD4+ and CD8+ T cells and increased effector CD8+ T cells. Like in HIV+ patients, expression of activation markers and inhibitory receptors CD160, CD244, and programmed death receptor (PD)-1 on CD8+ T cells was increased in APDS patients, indicating exhaustion. EBV-specific CD8+ T cells from APDS patients exhibited an exhausted phenotype that resembled HIV-specific CD8+ T cells in terms of inhibitory receptor expression. Inhibition of PD-1 on EBV-specific CD8+ T cells from APDS patients enhanced in vitro proliferation and effector cytokine production. Based on these results, we conclude that total and EBV-specific CD8+ T cells from APDS patients are characterized by T cell exhaustion. Furthermore, PD-1 checkpoint inhibition may provide a possible therapeutic approach to support the immune system of APDS patients to control EBV and CMV.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/imunologia , Mutação/genética , Subpopulações de Linfócitos T/imunologia , Viroses/imunologia , Adolescente , Adulto , Proliferação de Células , Células Cultivadas , Senescência Celular , Criança , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Citocinas/metabolismo , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Imunofenotipagem , Ativação Linfocitária , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Viroses/genética , Adulto Jovem
15.
Front Immunol ; 9: 237, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29599765

RESUMO

The phosphatidylinositol-3-kinase (PI3K)/Akt pathway is important for multiple stages of herpesvirus replication including virus entry, replication, latency, and reactivation. Recently, patients with gain-of-function mutations in the p110δ-catalytic subunit of PI3K or in the p85-regulatory subunit of PI3K have been reported. These patients have constitutively active PI3K with hyperactivation of Akt. They present with lymphoproliferation and often have infections, particularly recurrent respiratory infections and/or severe virus infections. The most frequent virus infections are due to Epstein-Barr virus (EBV) and cytomegalovirus (CMV); patients often present with persistent EBV and/or CMV viremia, EBV lymphoproliferative disease, or CMV lymphadenitis. No patients have been reported with CMV pneumonia, colitis, or retinitis. Other herpesvirus infections have included herpes simplex pneumonia, recurrent zoster, and varicella after vaccination with the varicella vaccine. Additional viral infections have included adenovirus viremia, severe warts, and extensive Molluscum contagiosum virus infection. The increased susceptibility to virus infections in these patients is likely due to a reduced number of long-lived memory CD8 T cells and an increased number of terminally differentiated effector CD8 T cells.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Síndromes de Imunodeficiência/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Viremia/imunologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Citomegalovirus/imunologia , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Mutação com Ganho de Função , Predisposição Genética para Doença , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/virologia , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Viremia/tratamento farmacológico , Viremia/genética , Viremia/virologia
16.
Front Immunol ; 9: 338, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29556229

RESUMO

The activated phosphoinositide 3-kinase δ syndrome (APDS), also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI), is a combined immunodeficiency syndrome caused by gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (encoding p110δ: APDS1 or PASLI-CD) and PIK3R1 (encoding p85α: APDS2 or PASLI-R1). While the disease is clinically heterogeneous, respiratory symptoms and complications are near universal and often severe. Infections of the ears, sinuses, and upper and lower respiratory tracts are the earliest and most frequent manifestation of APDS, secondary to both respiratory viruses and to bacterial pathogens typical of defective B cell function. End organ damage in the form of small airways disease and bronchiectasis frequently complicates APDS, but despite documented T cell defects, opportunistic infections have rarely been observed. Antimicrobial (principally antibiotic) prophylaxis and/or immunoglobulin replacement have been widely used to reduce the frequency and severity of respiratory infection in APDS, but outcome data to confirm the efficacy of these interventions are limited. Despite these measures, APDS patients are often afflicted by benign lymphoproliferative disease, which may present in the respiratory system as tonsillar/adenoidal enlargement, mediastinal lymphadenopathy, or mucosal nodular lymphoid hyperplasia, potentially causing airways obstruction and compounding the infection phenotype. Treatment with rapamycin and PI3Kδ inhibitors has been reported to be of benefit in benign lymphoproliferation, but hematopoietic stem cell transplantation (ideally undertaken before permanent airway damage is established) remains the only curative treatment for APDS.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases , Inibidores Enzimáticos/uso terapêutico , Síndromes de Imunodeficiência , Mutação , Infecções Respiratórias , Sirolimo/uso terapêutico , Transplante de Células-Tronco , Aloenxertos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/terapia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/terapia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Infecções Respiratórias/patologia , Infecções Respiratórias/terapia
17.
Front Immunol ; 9: 332, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535720

RESUMO

Class IA phosphatidylinositol 3-kinase (PI3K) catalytic subunits p110α and p110δ are targets in cancer therapy expressed at high levels in T lymphocytes. The role of p110δ PI3K in normal or pathological immune responses is well established, yet the importance of p110α subunits in T cell-dependent immune responses is not clear. To address this problem, mice with p110α conditionally deleted in CD4+ and CD8+ T lymphocytes (p110α-/-ΔT) were used. p110α-/-ΔT mice show normal development of T cell subsets, but slightly reduced numbers of CD4+ T cells in the spleen. "In vitro," TCR/CD3 plus CD28 activation of naive CD4+ and CD8+ p110α-/-ΔT T cells showed enhanced effector function, particularly IFN-γ secretion, T-bet induction, and Akt, Erk, or P38 activation. Tfh derived from p110α-/-ΔT cells also have enhanced responses when compared to normal mice, and IL-2 expanded p110α-/-ΔT CD8+ T cells had enhanced levels of LAMP-1 and Granzyme B. By contrast, the expansion of p110α-/-ΔT iTreg cells was diminished. Also, p110α-/-ΔT mice had enhanced anti-keyhole limpet hemocyanin (KLH) IFN-γ, or IL-4 responses and IgG1 and IgG2b anti-KLH antibodies, using CFA or Alum as adjuvant, respectively. When compared to WT mice, p110α-/-ΔT mice inoculated with B16.F10 melanoma showed delayed tumor progression. The percentage of CD8+ T lymphocytes was higher and the percentage of Treg cells lower in the spleen of tumor-bearing p110α-/-ΔT mice. Also, IFN-γ production in tumor antigen-activated spleen cells was enhanced. Thus, PI3K p110α plays a significant role in antigen activation and differentiation of CD4+ and CD8+ T lymphocytes modulating antitumor immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Imunidade Celular , Sistema de Sinalização das MAP Quinases/imunologia , Neoplasias Experimentais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Interferon gama/genética , Interferon gama/imunologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Linfócitos T Reguladores/patologia
18.
Curr Opin Allergy Clin Immunol ; 18(2): 159-166, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29406361

RESUMO

PURPOSE OF THE REVIEW: Since the 1990s with the advances in molecular biology, a number of genetic defects have been described. The International Union of Immunological Sciences has recently updated the classification of genetic defects associated with primary immune deficiencies that now number 354. With the ever-expanding list of new monogenic disorders and a better understanding of the immunobiology and function of these defective genes, new therapies have emerged particularly aimed at the autoimmune and inflammatory conditions that plague these patients. RECENT FINDINGS: Immune deficiencies associated with gain-of-function (GOF) mutations are a potential category for targeted therapies to control the GOF activities of the mutated gene. In addition to the increased susceptibility to infections these patients have autoimmune and inflammatory diseases that are difficult to control with conventional therapies. The dysregulated immune functions of the activated phospholipase-3-kinase δ syndrome, cytotoxic T lymphocyte-associated antigen-4 haploinsufficiency, lipopolysaccharide-responsive beige-like anchor deficiency, the GOF mutations of signal transducer and activator of transcription 1 and 3 immune deficiencies will be reviewed. The targeted therapies for each of these immune deficiencies using small molecule kinase inhibitors and fusion protein biologic modifiers will be described. SUMMARY: In this review, we explore the recent advances in precision medicine treatment of several primary immunodeficiency syndromes in which immune dysregulation is a key feature. Understanding the immunobiology associated with these GOF mutations has led to the use of biologic therapies to better control the associated autoimmune and inflammatory manifestations.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Síndromes de Imunodeficiência/tratamento farmacológico , Medicina de Precisão/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Autoimunidade/genética , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Mutação com Ganho de Função , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia
19.
J Pediatr Hematol Oncol ; 40(5): e319-e322, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29200144

RESUMO

Novel primary immunodeficiency disorders are being identified with next generation sequencing technologies. We describe 1 patient with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency who had recurrent enhancing brain lesions, nodular pulmonary infiltrates, hepatosplenomegaly, immune cytopenias, as well as progressive hypogammaglobulinemia and lymphopenia. We describe a second patient with activated p110δ syndrome (APDS)/p110δ activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) in association with recurrent respiratory tract infections, Epstein-Barr virus infection, lymphadenopathy, elevated serum IgM, and progressive lymphopenia. These presentations highlight the need for astute clinical judgment in the evaluation of patients with potential primary immunodeficiency disorders.


Assuntos
Antígeno CTLA-4 , Classe I de Fosfatidilinositol 3-Quinases , Haploinsuficiência , Síndromes de Imunodeficiência , Adolescente , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia
20.
Front Immunol ; 9: 3079, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30666254

RESUMO

T follicular helper (Tfh) cells are a specialized population of CD4+ T cells that provide help to B cells for the formation and maintenance germinal centers, and the production of high affinity class-switched antibodies, long-lived plasma cells, and memory B cells. As such, Tfh cells are essential for the generation of successful long-term humoral immunity and memory responses to vaccination and infection. Conversely, overproduction of Tfh cells has been associated with the generation of autoantibodies and autoimmunity. Data from gene-targeted mice, pharmacological inhibitors, as well as studies of human and mice expressing activating mutants have revealed that PI3Kδ is a key regulator of Tfh cell differentiation, acting downstream of ICOS to facilitate inactivation of FOXO1, repression of Klf2 and induction of Bcl6. Nonetheless, here we show that after acute LCMV infection, WT and activated-PI3Kδ mice (Pik3cd E1020K/+) show comparable ratios of Tfh:Th1 viral specific CD4+ T cells, despite higher polyclonal Tfh cells in Pik3cd E1020K/+ mice. Thus, the idea that PI3K activity primarily drives Tfh cell differentiation may be an oversimplification and PI3K-mediated pathways are likely to integrate multiple signals to promote distinct effector T cell lineages. The consequences of dysregulated Tfh cell generation will be discussed in the context of the human primary immunodeficiency "Activated PI3K-delta Syndrome" (APDS), also known as "p110 delta-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency" (PASLI). Overall, these data underscore a major role for PI3K signaling in the orchestration of T lymphocyte responses.


Assuntos
Autoimunidade/fisiologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/metabolismo , Linfócitos T Auxiliares-Indutores/fisiologia , Animais , Diferenciação Celular , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Centro Germinativo/imunologia , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucina-2/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Camundongos , Fator 1 de Transcrição de Linfócitos T/metabolismo
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