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1.
Am J Transplant ; 22(3): 717-730, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34668635

RESUMO

Prevention of allograft rejection often requires lifelong immune suppression, risking broad impairment of host immunity. Nonselective inhibition of host T cell function increases recipient risk of opportunistic infections and secondary malignancies. Here we demonstrate that AJI-100, a dual inhibitor of JAK2 and Aurora kinase A, ameliorates skin graft rejection by human T cells and provides durable allo-inactivation. AJI-100 significantly reduces the frequency of skin-homing CLA+ donor T cells, limiting allograft invasion and tissue destruction by T effectors. AJI-100 also suppresses pathogenic Th1 and Th17 cells in the spleen yet spares beneficial regulatory T cells. We show dual JAK2/Aurora kinase A blockade enhances human type 2 innate lymphoid cell (ILC2) responses, which are capable of tissue repair. ILC2 differentiation mediated by GATA3 requires STAT5 phosphorylation (pSTAT5) but is opposed by STAT3. Further, we demonstrate that Aurora kinase A activation correlates with low pSTAT5 in ILC2s. Importantly, AJI-100 maintains pSTAT5 levels in ILC2s by blocking Aurora kinase A and reduces interference by STAT3. Therefore, combined JAK2/Aurora kinase A inhibition is an innovative strategy to merge immune suppression with tissue repair after transplantation.


Assuntos
Aurora Quinase A , Imunidade Inata , Animais , Aurora Quinase A/metabolismo , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Janus Quinase 2 , Camundongos , Camundongos Endogâmicos C57BL , Células Th17 , Transplante Homólogo
2.
Proc Natl Acad Sci U S A ; 115(7): 1582-1587, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29382747

RESUMO

Janus kinase 2 (JAK2) signal transduction is a critical mediator of the immune response. JAK2 is implicated in the onset of graft-versus-host disease (GVHD), which is a significant cause of transplant-related mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Transfer of JAK2-/- donor T cells to allogeneic recipients leads to attenuated GVHD yet maintains graft-versus-leukemia. Th1 differentiation among JAK2-/- T cells is significantly decreased compared with wild-type controls. Conversely, iTreg and Th2 polarization is significantly increased among JAK2-/- T cells. Pacritinib is a multikinase inhibitor with potent activity against JAK2. Pacritinib significantly reduces GVHD and xenogeneic skin graft rejection in distinct rodent models and maintains donor antitumor immunity. Moreover, pacritinib spares iTregs and polarizes Th2 responses as observed among JAK2-/- T cells. Collectively, these data clearly identify JAK2 as a therapeutic target to control donor alloreactivity and promote iTreg responses after allo-HCT or solid organ transplantation. As such, a phase I/II acute GVHD prevention trial combining pacritinib with standard immune suppression after allo-HCT is actively being investigated (https://clinicaltrials.gov/ct2/show/NCT02891603).


Assuntos
Diferenciação Celular , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/imunologia , Janus Quinase 2/fisiologia , Mielofibrose Primária/imunologia , Linfócitos T/imunologia , Células Th2/imunologia , Animais , Feminino , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Leucemia/genética , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mielofibrose Primária/genética , Mielofibrose Primária/prevenção & controle , Transplante de Pele , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Control ; 21(3): 251-4, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24955711

RESUMO

A 68-year-old woman with a history of follicular lymphoma had pathological findings of grade 3B follicular lymphoma, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) identified in 1 lymph node. The DLBCL appeared to be a transformation of the follicular lymphoma. The nodules were diffusely and strongly positive for CD20, BCL6, and BCL2. CD43 highlighted smaller lymphocytes in a fraction of the nodules. BCL1 staining was variable with a mixture of nodular and mantle zone patterns. The diffuse areas showed weaker positivity for CD10, BCL2, and BCL6. CD3 and CD5 highlighted intermixed T cells. The Ki-67 proliferative index was overall estimated to be 60%. Fluorescent in situ hybridization performed on the lymph node was positive for CCND1/IGH. The patterns of BCL1 and BCL6 staining demonstrated 2 separate populations of neoplastic B lymphocytes.


Assuntos
Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/patologia , Idoso , Antígenos CD5/imunologia , Progressão da Doença , Feminino , Humanos , Linfonodos/imunologia , Linfonodos/patologia , Linfoma Folicular/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma de Célula do Manto/imunologia , Linfoma de Célula do Manto/patologia
4.
Life Sci Alliance ; 7(7)2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38649187

RESUMO

All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways, to accumulate heme intermediates, that is, porphyrins. We coined this essential metabolic rewiring "porphyrin overdrive" and determined that it is cancer-essential and cancer-specific. Among the major drivers are genes encoding mid-step enzymes governing the production of heme intermediates. CRISPR/Cas9 editing to engineer leukemia cell lines with impaired heme biosynthetic steps confirmed our whole-genome data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. Although porphyrin overdrive is absent in differentiated cells or somatic stem cells, it is present in patient-derived tumor progenitor cells, demonstrated by single-cell RNAseq, and in early embryogenesis. In conclusion, we identified a dependence of cancer cells on non-homeostatic heme metabolism, and we targeted this cancer metabolic vulnerability with a novel "bait-and-kill" strategy to eradicate malignant cells.


Assuntos
Sistemas CRISPR-Cas , Heme , Porfirinas , Humanos , Heme/metabolismo , Porfirinas/metabolismo , Porfirinas/farmacologia , Linhagem Celular Tumoral , Neoplasias/metabolismo , Neoplasias/genética , Redes e Vias Metabólicas/genética , Diferenciação Celular/genética , Edição de Genes , Animais , Camundongos
6.
Cancer Control ; 19(1): 18-25, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22143059

RESUMO

BACKGROUND: The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous, with some patients experiencing rapid disease progression and others living for decades without requiring treatment. The Rai and Binet clinical staging systems are used to define disease extent and predict survival. The pathology laboratory also provides important prognostic information. METHODS: A review of the literature was performed on the subject of staging in CLL from clinical and pathologic standpoints. This article also reviews currently available diagnostic approaches related to disease prognosis and to timing of treatment and follow-up in patients with CLL. RESULTS: Novel biological and cytogenetic features such as immunoglobulin heavy-chain variable gene segment [IgVH], genomic aberrations including del(17p13), del(11q23), del(13q14), and trisomy 12, serum markers (thymidine kinase and beta-2 microglobulin), and cellular markers (CD38 and ZAP70) have become increasingly important in predicting prognosis at the time of diagnosis. CONCLUSIONS: Current prognostic factors directly or indirectly influence the management of patients with CLL and help to predict treatment-free and overall survival.


Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Linfocítica Crônica de Células B/terapia , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
7.
Clin Cancer Res ; 27(10): 2712-2722, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33753457

RESUMO

PURPOSE: In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation. PATIENTS AND METHODS: The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3+3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC (n = 12). Acute GVHD was scored through day +100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells. RESULTS: In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4+ T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias. CONCLUSIONS: We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/administração & dosagem , Inibidores de Janus Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Tacrolimo/administração & dosagem , Animais , Aurora Quinase A/metabolismo , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Avaliação Pré-Clínica de Medicamentos , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Humanos , Imunofenotipagem , Janus Quinase 2/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Fator de Transcrição STAT3/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Doadores de Tecidos , Transplante Homólogo
8.
J Clin Invest ; 130(9): 4652-4662, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437331

RESUMO

Graft-versus-host disease (GVHD) remains an important cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). For decades, GVHD prophylaxis has included calcineurin inhibitors, despite their incomplete efficacy and impairment of graft-versus-leukemia (GVL). Distinct from pharmacologic immune suppression, we have developed what we believe is a novel, human CD83-targeted chimeric antigen receptor (CAR) T cell for GVHD prevention. CD83 is expressed on allo-activated conventional CD4+ T cells (Tconvs) and proinflammatory dendritic cells (DCs), which are both implicated in GVHD pathogenesis. Human CD83 CAR T cells eradicate pathogenic CD83+ target cells, substantially increase the ratio of regulatory T cells (Tregs) to allo-activated Tconvs, and provide durable prevention of xenogeneic GVHD. CD83 CAR T cells are also capable of treating xenogeneic GVHD. We show that human acute myeloid leukemia (AML) expresses CD83 and that myeloid leukemia cell lines are readily killed by CD83 CAR T cells. Human CD83 CAR T cells are a promising cell-based approach to preventing 2 critical complications of allo-HCT - GVHD and relapse. Thus, the use of human CD83 CAR T cells for GVHD prevention and treatment, as well as for targeting CD83+ AML, warrants clinical investigation.


Assuntos
Transferência Adotiva , Antígenos CD/imunologia , Linfócitos T CD4-Positivos/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Imunoglobulinas/imunologia , Leucemia Mieloide Aguda/terapia , Glicoproteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Aloenxertos , Animais , Linfócitos T CD4-Positivos/transplante , Linhagem Celular Tumoral , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Camundongos , Antígeno CD83
9.
JCI Insight ; 5(9)2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32255769

RESUMO

Immunosuppressive donor Tregs can prevent graft-versus-host disease (GVHD) or solid-organ allograft rejection. We previously demonstrated that inhibiting STAT3 phosphorylation (pSTAT3) augments FOXP3 expression, stabilizing induced Tregs (iTregs). Here we report that human pSTAT3-inhibited iTregs prevent human skin graft rejection and xenogeneic GVHD yet spare donor antileukemia immunity. pSTAT3-inhibited iTregs express increased levels of skin-homing cutaneous lymphocyte-associated antigen, immunosuppressive GARP and PD-1, and IL-9 that supports tolerizing mast cells. Further, pSTAT3-inhibited iTregs significantly reduced alloreactive conventional T cells, Th1, and Th17 cells implicated in GVHD and tissue rejection and impaired infiltration by pathogenic Th2 cells. Mechanistically, pSTAT3 inhibition of iTregs provoked a shift in metabolism from oxidative phosphorylation (OxPhos) to glycolysis and reduced electron transport chain activity. Strikingly, cotreatment with coenzyme Q10 restored OxPhos in pSTAT3-inhibited iTregs and augmented their suppressive potency. These findings support the rationale for clinically testing the safety and efficacy of metabolically tuned, human pSTAT3-inhibited iTregs to control alloreactive T cells.


Assuntos
Rejeição de Enxerto , Doença Enxerto-Hospedeiro , Fator de Transcrição STAT3/fisiologia , Linfócitos T Reguladores , Animais , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Camundongos , Oxirredução , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
11.
Front Immunol ; 9: 2887, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30574153

RESUMO

Acute graft- vs. -host disease (GVHD) is an important cause of morbidity and death after allogeneic hematopoietic cell transplantation (HCT). We identify a new approach to prevent GVHD that impairs monocyte-derived dendritic cell (moDC) alloactivation of T cells, yet preserves graft- vs.-leukemia (GVL). Exceeding endoplasmic reticulum (ER) capacity results in a spliced form of X-box binding protein-1 (XBP-1s). XBP-1s mediates ER stress and inflammatory responses. We demonstrate that siRNA targeting XBP-1 in moDCs abrogates their stimulation of allogeneic T cells. B-I09, an inositol-requiring enzyme-1α (IRE1α) inhibitor that prevents XBP-1 splicing, reduces human moDC migration, allo-stimulatory potency, and curtails moDC IL-1ß, TGFß, and p40 cytokines, suppressing Th1 and Th17 cell priming. B-I09-treated moDCs reduce responder T cell activation via calcium flux without interfering with regulatory T cell (Treg) function or GVL effects by cytotoxic T lymphocytes (CTL) and NK cells. In a human T cell mediated xenogeneic GVHD model, B-I09 inhibition of XBP-1s reduced target-organ damage and pathogenic Th1 and Th17 cells without impacting donor Tregs or anti-tumor CTL. DC XBP-1s inhibition provides an innovative strategy to prevent GVHD and retain GVL.


Assuntos
Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Terapia de Imunossupressão/métodos , Leucemia/terapia , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/imunologia , Endorribonucleases/antagonistas & inibidores , Endorribonucleases/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Técnicas de Silenciamento de Genes , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/imunologia , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Isoanticorpos/imunologia , Isoanticorpos/metabolismo , Isoantígenos/imunologia , Leucemia/imunologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/metabolismo , Transplante de Pele , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Quimeras de Transplante , Transplante Homólogo/efeitos adversos , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/imunologia , Proteína 1 de Ligação a X-Box/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Leukoc Biol ; 97(4): 807-19, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25663681

RESUMO

Th17 cells contribute to severe GVHD in murine bone marrow transplantation. Targeted deletion of the RORγt transcription factor or blockade of the JAK2-STAT3 axis suppresses IL-17 production and alloreactivity by Th17 cells. Here, we show that pSTAT3 Y705 is increased significantly in CD4(+) T cells among human recipients of allogeneic HCT before the onset of Grade II-IV acute GVHD. Examination of target-organ tissues at the time of GVHD diagnosis indicates that the amount of RORγt + Th17 cells is significantly higher in severe GVHD. Greater accumulation of tissue-resident Th17 cells also correlates with the use of MTX- compared with Rapa-based GVHD prophylaxis, as well as a poor therapeutic response to glucocorticoids. RORγt is optimally suppressed by concurrent neutralization of TORC1 with Rapa and inhibition of STAT3 activation with S3I-201, supporting that mTOR- and STAT3-dependent pathways converge upon RORγt gene expression. Rapa-resistant T cell proliferation can be totally inhibited by STAT3 blockade during initial allosensitization. We conclude that STAT3 signaling and resultant Th17 tissue accumulation are closely associated with acute GVHD onset, severity, and treatment outcome. Future studies are needed to validate the association of STAT3 activity in acute GVHD. Novel GVHD prevention strategies that incorporate dual STAT3 and mTOR inhibition merit investigation.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Doença Enxerto-Hospedeiro/imunologia , Processamento de Proteína Pós-Traducional , Fator de Transcrição STAT3/metabolismo , Células Th17/imunologia , Doença Aguda , Adulto , Idoso , Aloenxertos , Ácidos Aminossalicílicos/farmacologia , Benzenossulfonatos/farmacologia , Transplante de Medula Óssea , Células Dendríticas/imunologia , Feminino , Glucocorticoides/uso terapêutico , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/terapia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Imunossupressores/uso terapêutico , Teste de Cultura Mista de Linfócitos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/biossíntese , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/sangue , Transplante de Células-Tronco de Sangue Periférico , Fosforilação , Estudos Prospectivos , Receptores de Interleucina-6/sangue , Fator de Transcrição STAT3/antagonistas & inibidores , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/fisiologia
14.
Leuk Res ; 37(12): 1656-61, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24220584

RESUMO

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell malignancies that represent a diagnostic challenge for pathologists. Accurate classification and prognostic scoring are essential to treating MDS. To understand factors that affect MDS management, a case-based survey was distributed to hematopathologists (n=53) and general pathologists (n=72) to identify perceived barriers, attitudes, and practices in MDS diagnosis. Results demonstrated confidence and practice gaps. Only 33% of general pathologists are confident in diagnosing MDS. Neither general pathologists nor hematopathologists are comfortable using the International Prognostic Scoring System to characterize risk. Thirty percent of general pathologists and 22% of hematopathologists would not include bone marrow aspirate and cytogenetics in initial testing of a neutropenic patient. Most practitioners tested appropriately for disease classification and prognosis; discrepancies were identified in testing to differentiate MDS from acute myeloid leukemia and testing in post treatment specimens. These results have implications in the management of MDS.


Assuntos
Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/patologia , Patologia Clínica , Prática Profissional/normas , Atitude do Pessoal de Saúde , Competência Clínica/estatística & dados numéricos , Coleta de Dados , Fidelidade a Diretrizes/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Percepção , Prognóstico , Literatura de Revisão como Assunto , Recursos Humanos
15.
Int J Clin Exp Pathol ; 6(2): 155-67, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23330001

RESUMO

Mature B-cell lymphomas with both BCL2 and MYC translocations are known as "double hit" lymphomas. These lymphomas are aggressive and show high proliferation rate due to the growth advantages provided by MYC and BCL2 translocation and overexpression. Mantle cell lymphoma (MCL) is a neoplasm of mature B-lymphocytes with characteristic t(11;14) and subsequent Cyclin D1 overexpression. Secondary cytogenetic changes are frequent in MCL, but MYC translocation has only been rarely reported. In this study, we report four cases of MCL with MYC translocation or MYC gene amplification detected by conventional cytogenetics, fluorescence in situ hybridization and whole genome single nucleotide polymorphism (SNP) array, and determined the clinicopathologic features. Our study provides further evidence supporting the concept of "double hit" MCL with co-involvement of MYC gene rearrangement and/or amplification and CCND1 gene rearrangement.


Assuntos
Amplificação de Genes/genética , Rearranjo Gênico do Linfócito B/genética , Linfoma de Célula do Manto/genética , Proteínas Proto-Oncogênicas c-myc/genética , Idoso , Idoso de 80 Anos ou mais , Ciclina D1/genética , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade
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