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1.
Blood ; 137(8): 1090-1103, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32976550

RESUMO

The nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4+ T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3- T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic.


Assuntos
Transplante de Medula Óssea , Ciclopropanos/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Efeito Enxerto vs Leucemia/efeitos dos fármacos , Receptores X de Retinoides/agonistas , Animais , Transplante de Medula Óssea/efeitos adversos , Reposicionamento de Medicamentos , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologia
2.
Blood ; 134(19): 1670-1682, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31533918

RESUMO

Myeloid-derived suppressor cells (MDSCs) can subdue inflammation. In mice with acute graft-versus-host disease (GVHD), donor MDSC infusion enhances survival that is only partial and transient because of MDSC inflammasome activation early posttransfer, resulting in differentiation and loss of suppressor function. Here we demonstrate that conditioning regimen-induced adenosine triphosphate (ATP) release is a primary driver of MDSC dysfunction through ATP receptor (P2x7R) engagement and NLR pyrin family domain 3 (NLRP3) inflammasome activation. P2x7R or NLRP3 knockout (KO) donor MDSCs provided significantly higher survival than wild-type (WT) MDSCs. Although in vivo pharmacologic targeting of NLRP3 or P2x7R promoted recipient survival, indicating in vivo biologic effects, no synergistic survival advantage was seen when combined with MDSCs. Because activated inflammasomes release mature interleukin-1ß (IL-1ß), we expected that IL-1ß KO donor MDSCs would be superior in subverting GVHD, but such MDSCs proved inferior relative to WT. IL-1ß release and IL-1 receptor expression was required for optimal MDSC function, and exogenous IL-1ß added to suppression assays that included MDSCs increased suppressor potency. These data indicate that prolonged systemic NLRP3 inflammasome inhibition and decreased IL-1ß could diminish survival in GVHD. However, loss of inflammasome activation and IL-1ß release restricted to MDSCs rather than systemic inhibition allowed non-MDSC IL-1ß signaling, improving survival. Extracellular ATP catalysis with peritransplant apyrase administered into the peritoneum, the ATP release site, synergized with WT MDSCs, as did regulatory T-cell infusion, which we showed reduced but did not eliminate MDSC inflammasome activation, as assessed with a novel inflammasome reporter strain. These findings will inform future clinical using MDSCs to decrease alloresponses in inflammatory environments.


Assuntos
Trifosfato de Adenosina/metabolismo , Doença Enxerto-Hospedeiro/imunologia , Inflamassomos/imunologia , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/transplante , Animais , Feminino , Camundongos , Camundongos Knockout
3.
J Clin Invest ; 128(10): 4604-4621, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30106752

RESUMO

Regulatory T cells (Tregs) are critical for maintaining immune homeostasis. However, current Treg immunotherapies do not optimally treat inflammatory diseases in patients. Understanding the cellular processes that control Treg function may allow for the augmentation of therapeutic efficacy. In contrast to activated conventional T cells, in which protein kinase C-θ (PKC-θ) localizes to the contact point between T cells and antigen-presenting cells, in human and mouse Tregs, PKC-θ localizes to the opposite end of the cell in the distal pole complex (DPC). Here, using a phosphoproteomic screen, we identified the intermediate filament vimentin as a PKC-θ phospho target and show that vimentin forms a DPC superstructure on which PKC-θ accumulates. Treatment of mouse Tregs with either a clinically relevant PKC-θ inhibitor or vimentin siRNA disrupted vimentin and enhanced Treg metabolic and suppressive activity. Moreover, vimentin-disrupted mouse Tregs were significantly better than controls at suppressing alloreactive T cell priming in graft-versus-host disease (GVHD) and GVHD lethality, using a complete MHC-mismatch mouse model of acute GVHD (C57BL/6 donor into BALB/c host). Interestingly, vimentin disruption augmented the suppressor function of PKC-θ-deficient mouse Tregs. This suggests that enhanced Treg activity after PKC-θ inhibition is secondary to effects on vimentin, not just PKC-θ kinase activity inhibition. Our data demonstrate that vimentin is a key metabolic and functional controller of Treg activity and provide proof of principle that disruption of vimentin is a feasible, translationally relevant method to enhance Treg potency.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Filamentos Intermediários/imunologia , Ativação Linfocitária , Linfócitos T Reguladores/imunologia , Vimentina/imunologia , Animais , Células Apresentadoras de Antígenos/patologia , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Humanos , Filamentos Intermediários/genética , Filamentos Intermediários/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Proteína Quinase C-theta/genética , Proteína Quinase C-theta/imunologia , Linfócitos T Reguladores/patologia , Vimentina/genética
4.
Mol Ther ; 26(6): 1423-1434, 2018 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-29735365

RESUMO

The clinical success of chimeric antigen receptor (CAR) T cell therapy for CD19+ B cell malignancies can be limited by acute toxicities and immunoglobulin replacement needs due to B cell aplasia from persistent CAR T cells. Life-threatening complications include cytokine release syndrome and neurologic adverse events, the exact etiologies of which are unclear. To elucidate the underlying toxicity mechanisms and test potentially safer CAR T cells, we developed a mouse model in which human CD19 (hCD19)-specific mouse CAR T cells were adoptively transferred into mice whose normal B cells express a hCD19 transgene at hemizygous levels. Compared to homozygous hCD19 transgenic mice that have ∼75% fewer circulating B cells, hemizygous mice had hCD19 frequencies and antigen density more closely simulating human B cells. Hemizygous mice given a lethal dose of hCD19 transgene-expressing lymphoma cells and treated with CAR T cells had undetectable tumor levels. Recipients experienced B cell aplasia and antigen- and dose-dependent acute toxicities mirroring patient complications. Interleukin-6 (IL-6), interferon γ (IFN-γ), and inflammatory pathway transcripts were enriched in affected tissues. As in patients, antibody-mediated neutralization of IL-6 (and IFN-γ) blunted toxicity. Apparent behavioral abnormalities associated with decreased microglial cells point to CAR-T-cell-induced neurotoxicity. This model will prove useful in testing strategies designed to improve hCD19-specific CAR T cell safety.


Assuntos
Antígenos CD19/metabolismo , Linfócitos B/metabolismo , Animais , Feminino , Humanos , Imunoterapia Adotiva , Interferon gama/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Transgênicos
5.
JCI Insight ; 1(15): e86850, 2016 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-27699243

RESUMO

Regulatory T cells (Tregs) play a crucial role in the maintenance of peripheral tolerance. Quantitative and/or qualitative defects in Tregs result in diseases such as autoimmunity, allergy, malignancy, and graft-versus-host disease (GVHD), a serious complication of allogeneic stem cell transplantation (SCT). We recently reported increased expression of autophagy-related genes (Atg) in association with enhanced survival of Tregs after SCT. Autophagy is a self-degradative process for cytosolic components that promotes cell homeostasis and survival. Here, we demonstrate that the disruption of autophagy within FoxP3+ Tregs (B6.Atg7fl/fl-FoxP3cre+ ) resulted in a profound loss of Tregs, particularly within the bone marrow (BM). This resulted in dysregulated effector T cell activation and expansion, and the development of enterocolitis and scleroderma in aged mice. We show that the BM compartment is highly enriched in TIGIT+ Tregs and that this subset is differentially depleted in the absence of autophagy. Moreover, following allogeneic SCT, recipients of grafts from B6.Atg7fl/fl-FoxP3cre+ donors exhibited reduced Treg reconstitution, exacerbated GVHD, and reduced survival compared with recipients of B6.WT-FoxP3cre+ grafts. Collectively, these data indicate that autophagy-dependent Tregs are critical for the maintenance of tolerance after SCT and that the promotion of autophagy represents an attractive immune-restorative therapeutic strategy after allogeneic SCT.


Assuntos
Autofagia , Doença Enxerto-Hospedeiro/imunologia , Linfócitos T Reguladores/imunologia , Animais , Medula Óssea/fisiopatologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Tolerância Imunológica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
6.
Blood ; 128(7): 1013-7, 2016 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-27385791

RESUMO

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present.


Assuntos
Transferência Adotiva , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Receptores CXCR5/metabolismo , Linfócitos T Reguladores/imunologia , Doença Aguda , Animais , Anticorpos Monoclonais/uso terapêutico , Doença Crônica , Progressão da Doença , Interleucina-2/uso terapêutico , Camundongos Endogâmicos C57BL , Resultado do Tratamento
7.
Sci Transl Med ; 7(280): 280rv2, 2015 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-25810312

RESUMO

Although major advances have been made in solid organ and hematopoietic stem cell transplantation in the last 50 years, big challenges remain. This review outlines the current immunological limitations for hematopoietic stem cell and solid organ transplantation and discusses new immune-modulating therapies in preclinical development and in clinical trials that may allow these obstacles to be overcome.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunoterapia , Transplante de Órgãos , Ensaios Clínicos como Assunto , Humanos
8.
Blood ; 125(21): 3335-46, 2015 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-25814530

RESUMO

Members of the B7 family have been shown to be important for regulating immune responses by providing either positive or negative costimulatory signals. The function of B7-H3 has been controversial. We show that B7-H3 is upregulated in graft-versus-host disease (GVHD) target organs, including the colon, liver, and lung. Infusion of allogeneic donor T cells into B7-H3(-/-) vs wild-type (WT) recipients resulted in increased GVHD lethality associated with increased T-cell proliferation, colonic inflammatory cytokines, and destruction of epithelial barriers. Allogeneic B7-H3(-/-) vs WT donor T cells also had increased T-cell proliferation and GVHD lethality associated with increased proliferation and cytokine secretion in the spleen, intraepithelial lymphocyte inflammatory cytokines, and intestinal permeability. Both resting and activated regulatory T cells (Tregs) lack B7-H3 messenger RNA. Consistent with these data, GVHD was augmented in recipients of B7-H3(-/-) Treg-depleted grafts. In two delayed lymphocyte infusion (DLI) models, T cells lacking B7-H3 are capable of providing graft-versus-leukemia (GVL) effects. We conclude that B7-H3 is responsible for providing a negative costimulatory signal. Our studies provide support for developing and testing new therapies directed toward the B7-H3 pathway, including approaches to augment host B7-H3 early after bone marrow transplantation to prevent GVHD and to develop potent antagonistic antibodies later after transplant to facilitate DLI-mediated GVL without GVHD complications.


Assuntos
Antígenos B7/imunologia , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/imunologia , Linfócitos T/imunologia , Aloenxertos , Animais , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Camundongos , Reação em Cadeia da Polimerase
9.
Blood ; 125(3): 570-80, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25352130

RESUMO

The common γ chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-γ, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common γ-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation.


Assuntos
Anticorpos Monoclonais/farmacologia , Transplante de Medula Óssea/efeitos adversos , Citocinas/metabolismo , Doença Enxerto-Hospedeiro/prevenção & controle , Subunidade gama Comum de Receptores de Interleucina/antagonistas & inibidores , Doença Aguda , Animais , Western Blotting , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Células Cultivadas , Doença Crônica , Feminino , Citometria de Fluxo , Imunofluorescência , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Janus Quinase 3/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
10.
Immunity ; 38(6): 1250-60, 2013 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-23746652

RESUMO

The CD8⁺ memory T cell population is heterogeneous, and it is unclear which subset(s) optimally mediate the central goal of the immune system-protection against infection. Here we investigate the protective capacities of CD8⁺ T cell subsets present at the memory stage of the immune response. We show that a population of CD8⁺ T cells bearing markers associated with effector cells (KLRG1(hi), CD27(lo), T-bet(hi), Eomes(lo)) persisted to the memory phase and provided optimal control of Listeria monocytogenes and vaccinia virus, despite weak recall proliferative responses. After antigen-specific boosting, this population formed the predominant secondary memory subset and maintained superior pathogen control. The effector-like memory subset displayed a distinct pattern of tissue distribution and localization within the spleen, and their enhanced capacity to eliminate Listeria involved specialized utilization of cytolysis. Together, these data suggest that long-lived effector CD8⁺ T cells are optimal for protective immunity against certain pathogens.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Infecções por Poxviridae/imunologia , Subpopulações de Linfócitos T/imunologia , Vírus Vaccinia/imunologia , Animais , Linfócitos T CD8-Positivos/microbiologia , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Citotoxicidade Imunológica , Feminino , Imunidade Ativa , Memória Imunológica , Lectinas Tipo C/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores Imunológicos , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos T/microbiologia , Subpopulações de Linfócitos T/virologia , Transativadores/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
11.
J Allergy Clin Immunol ; 126(4): 845-852.e10, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20920773

RESUMO

BACKGROUND: Asthma is the most frequent chronic disease in children, and children are at high risk for adverse health consequences associated with ambient air pollution (AAP) exposure. Regulatory T (Treg) cells are suppressors of immune responses involved in asthma pathogenesis. Treg-cell impairment is associated with increased DNA methylation of Forkhead box transcription factor 3 (Foxp3), a key transcription factor in Treg-cell activity. Because AAP exposure can induce epigenetic changes, we hypothesized that Treg-cell function would be impaired by AAP, allowing amplification of an inflammatory response. OBJECTIVES: To assess whether exposure to AAP led to hypermethylation of the Foxp3 gene, causing impaired Treg-cell suppression and worsened asthma symptom scores. METHODS: Children with and without asthma from Fresno, Calif (high pollution, Fresno Asthma Group [FA], n = 71, and Fresno Non Asthmatic Group, n = 30, respectively), and from Stanford, Calif (low pollution, Stanford Asthma Group, n = 40, and Stanford Non Asthmatic Group, n = 40), were enrolled in a cross-sectional study. Peripheral blood Treg cells were used in functional and epigenetic studies. Asthma outcomes were assessed by Global Initiative in Asthma score. RESULTS: Fresno Asthma Group Treg-cell suppression was impaired and FA Treg-cell chemotaxis were reduced compared with other groups (P ≤ .05). Treg-cell dysfunction was associated with more pronounced decreases in asthma Global Initiative in Asthma score in FA versus the Stanford Asthma Group. Foxp3 was decreased in FA compared with the Fresno Non Asthmatic Group (P ≤ .05). FA also contained significantly higher levels of methylation at the Foxp3 locus (P ≤ .05). CONCLUSION: Increased exposure to AAP is associated with hypermethylation of the Foxp3 locus, impairing Treg-cell function and increasing asthma morbidity. AAP could play a role in mediating epigenetic changes in Treg cells, which may worsen asthma by an immune mechanism.


Assuntos
Asma/fisiopatologia , Fatores de Transcrição Forkhead/metabolismo , Material Particulado/efeitos adversos , Linfócitos T Reguladores/patologia , Adolescente , Asma/imunologia , Criança , Estudos Transversais , Metilação de DNA , Epigênese Genética , Feminino , Volume Expiratório Forçado , Fatores de Transcrição Forkhead/genética , Humanos , Masculino , Índice de Gravidade de Doença , Linfócitos T Reguladores/imunologia
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