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1.
J Immunol ; 202(10): 2945-2956, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988115

RESUMO

Imprime PGG (Imprime) is an i.v. administered, yeast ß-1,3/1,6 glucan in clinical development with checkpoint inhibitors. Imprime-mediated innate immune activation requires immune complex formation with naturally occurring IgG anti-ß glucan Abs (ABA). We administered Imprime to healthy human volunteers to assess the necessity of ABA for Imprime-mediated immunopharmacodynamic (IPD) changes. Imprime (4 mg/kg) was administered i.v. in single and multiple infusions. Subsets of subjects were premedicated with antihistamine and corticosteroid. Peripheral blood was measured before, during and after Imprime administration for IPD changes (e.g., ABA, circulating immune complexes, complement activation, complete blood counts, cytokine/chemokine, and gene expression changes). IPD changes were analyzed based on pretreatment serum ABA levels: low-ABA (<20 µg/ml), mid-ABA (≥20-50 µg/ml), and high-ABA (≥50 µg/ml). At the end of infusion, free serum ABA levels decreased, circulating immune complex levels increased, and complement activation was observed. At ∼1-4 h after end of infusion, increased expression of cytokines/chemokines, a 1.5-4-fold increase in neutrophil and monocyte counts and a broad activation of innate immune genes were observed. Low-ABA subjects typically showed minimal IPD changes except when ABA levels rose above 20 µg/ml after repeated Imprime dosing. Mild-to-moderate infusion-related reactions occurred in subjects with ABA ≥20 µg/ml. Premedications alleviated some of the infusion-related reactions, but also inhibited cytokine responses. In conclusion, ABA levels, being critical for Imprime-mediated immune activation may provide a plausible, mechanism-based biomarker to identify patients most likely to respond to Imprime-based anticancer immunotherapy.


Assuntos
Adjuvantes Imunológicos , Polissacarídeos Fúngicos , Imunoterapia , Neoplasias , Saccharomyces cerevisiae/química , beta-Glucanas , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacocinética , Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Quimiocinas/sangue , Quimiocinas/imunologia , Feminino , Polissacarídeos Fúngicos/administração & dosagem , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/farmacocinética , Humanos , Masculino , Neoplasias/sangue , Neoplasias/imunologia , Neoplasias/terapia , beta-Glucanas/administração & dosagem , beta-Glucanas/química , beta-Glucanas/farmacocinética
2.
PLoS One ; 11(11): e0165909, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27812183

RESUMO

Imprime PGG (Imprime), an intravenously-administered, soluble ß-glucan, has shown compelling efficacy in multiple phase 2 clinical trials with tumor targeting or anti-angiogenic antibodies. Mechanistically, Imprime acts as pathogen-associated molecular pattern (PAMP) directly activating innate immune effector cells, triggering a coordinated anti-cancer immune response. Herein, using whole blood from healthy human subjects, we show that Imprime-induced anti-cancer functionality is dependent on immune complex formation with naturally-occurring, anti-ß glucan antibodies (ABA). The formation of Imprime-ABA complexes activates complement, primarily via the classical complement pathway, and is opsonized by iC3b. Immune complex binding depends upon Complement Receptor 3 and Fcg Receptor IIa, eliciting phenotypic activation of, and enhanced chemokine production by, neutrophils and monocytes, enabling these effector cells to kill antibody-opsonized tumor cells via the generation of reactive oxygen species and antibody-dependent cellular phagocytosis. Importantly, these innate immune cell changes were not evident in subjects with low ABA levels but could be rescued with exogenous ABA supplementation. Together, these data indicate that pre-existing ABA are essential for Imprime-mediated anti-cancer immune activation and suggest that pre-treatment ABA levels may provide a plausible patient selection biomarker to delineate patients most likely to benefit from Imprime-based therapy.


Assuntos
Complexo Antígeno-Anticorpo/metabolismo , Antineoplásicos/farmacologia , beta-Glucanas/farmacologia , Complexo Antígeno-Anticorpo/imunologia , Antineoplásicos/química , Células HEK293 , Humanos , Imunidade Inata/efeitos dos fármacos , Antígeno de Macrófago 1/metabolismo , Receptores de IgG/metabolismo , beta-Glucanas/química , beta-Glucanas/imunologia
3.
J Med Microbiol ; 63(Pt 12): 1750-1759, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25288643

RESUMO

Vaccination with heat-killed Saccharomyces cerevisiae (HKY) protects against experimental infection by pathogenic fungi of five genera. Here we tested whether purified Saccharomyces cell wall ß-glucan could induce protection against systemic aspergillosis. CD-1 mice were given three weekly vaccine doses subcutaneously prior to intravenous infection with Aspergillus fumigatus. Mice received PBS, 2.5 mg HKY, whole glucan particles (WGP), WGP conjugated to BSA (0.06 to 12 mg per dose), a soluble medium molecular mass (MMW) ß-glucan alone or MMW-BSA (≤24 mg per dose). Survival and c.f.u. were determined, and cytokine induction and anti-ß-glucan antibodies were assessed in vaccinated mice. Neither soluble MMW glucan, nor MMW-BSA was effective. HKY protected in two studies (survival and c.f.u. were reduced in brain and kidney organs, P<0.004). Six or 12 mg WGP or WGP-BSA prolonged survival (P≤0.004) and reduced c.f.u. in each organ (P≤0.015) in both experiments; 0.6 mg WGP or WGP-BSA prolonged survival (P≤0.015) and reduced c.f.u. (P≤0.015) in one experiment. Cytokine profiles in serum and bronchoalveolar lavage from uninfected vaccinated mice showed an innate and adaptive immune profile (i.e. upregulation of colony stimulating factors, interferons, TNF-α, chemokines such as MCP-1, MIP-1α, RANTES and KC, and Th17-activating cytokines such as IL-6, IL-1ß, IL-17). No anti-ß-glucan antibodies were in the sera, suggesting an adaptive T cell-mediated, not a B cell-mediated, protective response. Vaccination with WGP or WGP-BSA proved protective against systemic aspergillosis, equivalent to that of HKY, supporting the potential of particulate ß-glucans, alone or conjugated, as vaccines against aspergillosis.


Assuntos
Antígenos de Fungos/imunologia , Aspergilose/prevenção & controle , Aspergillus fumigatus/imunologia , Vacinas Fúngicas/imunologia , Glucanos/imunologia , Saccharomyces cerevisiae/imunologia , Animais , Antígenos de Fungos/administração & dosagem , Antígenos de Fungos/isolamento & purificação , Aspergilose/imunologia , Líquido da Lavagem Broncoalveolar/química , Contagem de Colônia Microbiana , Citocinas/análise , Modelos Animais de Doenças , Vacinas Fúngicas/administração & dosagem , Vacinas Fúngicas/isolamento & purificação , Glucanos/administração & dosagem , Glucanos/isolamento & purificação , Injeções Subcutâneas , Masculino , Camundongos , Soro/química , Análise de Sobrevida , Linfócitos T/imunologia , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/imunologia , Vacinas Conjugadas/isolamento & purificação
4.
Immunology ; 139(2): 197-204, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23311955

RESUMO

Viruses such as Epstein-Barr virus (EBV) have been linked to mechanisms that support autoantibody production in diseases such as systemic lupus erythematosus. However, the mechanisms by which viruses contribute to autoantibody production remain poorly defined. This stems in part, from the high level of seropositivity for EBV (> 95%) and the exquisite species specificity of EBV. In this study we overcame these problems by using murine gammaherpesvirus 68 (MHV68), a virus genetically and biologically related to EBV. We first showed that MHV68 drives autoantibody production by promoting a loss of B-cell anergy. We next showed that MHV68 infection resulted in the expansion of follicular helper T (Tfh) cells in vivo, and that these Tfh cells supported autoantibody production and a loss of B-cell anergy. Finally, we showed that the expansion of Tfh cells and autoantibody production was dependent on the establishment of viral latency and expression of a functional viral gene called Orf73. Collectively, our studies highlighted an unexpected role for viral latency in the development of autoantibodies following MHV68 infection and suggest that virus-induced expansion of Tfh cells probably plays a key role in the loss of B-cell anergy.


Assuntos
Linfócitos B/imunologia , Rhadinovirus/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Proteínas Virais/imunologia , Animais , Autoanticorpos/imunologia , Linfócitos B/virologia , Proliferação de Células , Células Cultivadas , Anergia Clonal/imunologia , Técnicas de Cocultura , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Interações Hospedeiro-Patógeno/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia de Fluorescência , Mutação , Rhadinovirus/genética , Rhadinovirus/fisiologia , Linfócitos T Auxiliares-Indutores/virologia , Proteínas Virais/genética , Proteínas Virais/metabolismo , Latência Viral/genética , Latência Viral/imunologia
5.
J Virol ; 86(23): 12826-37, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22993144

RESUMO

Gammaherpesviruses, such as Epstein-Barr virus (EBV), are ubiquitous cancer-associated pathogens that interact with DNA damage response, a tumor suppressor network. Chronic gammaherpesvirus infection and pathogenesis in a DNA damage response-insufficient host are poorly understood. Ataxia-telangiectasia (A-T) is associated with insufficiency of ataxia-telangiectasia mutated (ATM), a critical DNA damage response kinase. A-T patients display a pattern of anti-EBV antibodies suggestive of poorly controlled EBV replication; however, parameters of chronic EBV infection and pathogenesis in the A-T population remain unclear. Here we demonstrate that chronic gammaherpesvirus infection is poorly controlled in an animal model of A-T. Intriguingly, in spite of a global increase in T cell activation and numbers in wild-type (wt) and ATM-deficient mice in response to mouse gammaherpesvirus 68 (MHV68) infection, the generation of an MHV68-specific immune response was altered in the absence of ATM. Our finding that ATM expression is necessary for an optimal adaptive immune response against gammaherpesvirus unveils an important connection between DNA damage response and immune control of chronic gammaherpesvirus infection, a connection that is likely to impact viral pathogenesis in an ATM-insufficient host.


Assuntos
Ataxia Telangiectasia/imunologia , Proteínas de Ciclo Celular/metabolismo , Dano ao DNA/genética , Proteínas de Ligação a DNA/metabolismo , Gammaherpesvirinae , Infecções por Herpesviridae/imunologia , Ativação Linfocitária/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/deficiência , Linhagem Celular , Proteínas de Ligação a DNA/deficiência , Citometria de Fluxo , Infecções por Herpesviridae/enzimologia , Camundongos , Reação em Cadeia da Polimerase , Proteínas Serina-Treonina Quinases/deficiência , Linfócitos T/imunologia , Proteínas Supressoras de Tumor/deficiência
6.
Eur J Immunol ; 42(10): 2597-607, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22777796

RESUMO

The maintenance of B-cell anergy is essential to prevent the production of autoantibodies and autoimmunity. However, B-cell extrinsic mechanisms that regulate B-cell anergy remain poorly understood. We previously demonstrated that regulatory T (Treg) cells are necessary for the maintenance of B-cell anergy. We now show that in Treg-cell-deficient mice, helper T cells are necessary and sufficient for loss of B-cell tolerance/anergy. In addition, we show that the absence of Treg cells is associated with an increase in the proportion of CD4(+) cells that express GL7 and correlated with an increase in germinal center follicular helper T (GC-T(FH) ) cells. These GC-T(FH) cells, but not those from Treg-cell-sufficient hosts, were sufficient to drive antibody production by anergic B cells. We propose that a function of Treg cells is to prevent the expansion of T(FH) cells, especially GC-T(FH) cells, which support autoantibody production.


Assuntos
Linfócitos B/imunologia , Anergia Clonal , Centro Germinativo/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Formação de Anticorpos , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Autoanticorpos/imunologia , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Proliferação de Células , Células Cultivadas , Tolerância Imunológica , Ativação Linfocitária , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
7.
J Immunol ; 188(11): 5223-6, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22544930

RESUMO

The absence of regulatory T cells (Tregs) results in significant immune dysregulation that includes autoimmunity. The mechanism(s) by which Tregs suppress autoimmunity remains unclear. We have shown that B cell anergy, a major mechanism of B cell tolerance, is broken in the absence of Tregs. In this study, we identify a unique subpopulation of CD4(+) Th cells that are highly supportive of Ab production and promote loss of B cell anergy. Notably, this novel T cell subset was shown to express the germinal center Ag GL7 and message for the B cell survival factor BAFF, yet failed to express markers of the follicular Th cell lineage. We propose that the absence of Tregs results in the expansion of a unique nonfollicular Th subset of helper CD4(+) T cells that plays a pathogenic role in autoantibody production.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Anergia Clonal/imunologia , Deleção Clonal/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Animais , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Células Cultivadas , Anergia Clonal/genética , Deleção Clonal/genética , Técnicas de Cocultura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
8.
J Immunol ; 185(4): 2147-56, 2010 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-20639490

RESUMO

The importance of regulatory T cells in immune tolerance is illustrated by the human immune dysregulatory disorder IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), caused by a lack of regulatory T cells due to decreased or absent expression of Foxp3. Although the majority of work on regulatory T cells has focused on their ability to suppress T cell responses, the development of significant autoantibody titers in patients with IPEX suggests that regulatory T cells also contribute to the suppression of autoreactive B cells. Using a murine model, deficient in the expression of Foxp3, we show that B cell development is significantly altered in the absence of regulatory T cells. Furthermore, we identify a loss of B cell anergy as a likely mechanism to explain the production of autoantibodies that occurs in the absence of regulatory T cells. Our results suggest that regulatory T cells, by either direct or indirect mechanisms, modulate B cell development and anergy.


Assuntos
Linfócitos B/imunologia , Anergia Clonal/imunologia , Fatores de Transcrição Forkhead/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose/imunologia , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Linfócitos B/metabolismo , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/imunologia , Sobrevivência Celular/imunologia , Células Cultivadas , Citometria de Fluxo , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/genética , Humanos , Immunoblotting , Antígenos Comuns de Leucócito/efeitos dos fármacos , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Baço/citologia , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/metabolismo
9.
Virology ; 405(1): 50-61, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20557919

RESUMO

Many herpesvirus-encoded protein kinases facilitate viral lytic replication. Importantly, the role of viral kinases in herpesvirus latency is less clear. Mouse gammaherpesvirus-68 (MHV68)-encoded protein kinase orf36 facilitates lytic replication in part through activation of the host DNA damage response (DDR). Here we show that MHV68 latency was attenuated in the absence of orf36 expression. Unexpectedly, our study uncovered enzymatic activity-independent role of orf36 in the establishment of MHV68 latency following intraperitoneal route of infection. H2AX, an important DDR protein, facilitates MHV68 lytic replication and may be directly phosphorylated by orf36 during lytic infection. In this study, H2AX deficiency, whether systemic or limited to infected cells, attenuated the establishment of MHV68 latency in vivo. Thus, our work reveals viral kinase-dependent regulation of gammaherpesvirus latency and illuminates a novel link between H2AX, a component of a tumor suppressor DDR network, and in vivo latency of a cancer-associated gammaherpesvirus.


Assuntos
Infecções por Herpesviridae/virologia , Herpesviridae/enzimologia , Histonas/metabolismo , Proteínas Quinases/metabolismo , Latência Viral/fisiologia , Animais , Linfócitos B/virologia , Regulação Enzimológica da Expressão Gênica , Regulação Viral da Expressão Gênica/fisiologia , Histonas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Proteínas Quinases/genética , Baço/citologia , Proteínas Virais/genética , Proteínas Virais/metabolismo
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