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1.
Bone Marrow Transplant ; 58(8): 924-935, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37160943

RESUMEN

Graft-versus-host disease (GVHD) is the major factor limiting the widespread use of potentially curative allogeneic hematopoietic stem cell transplant (allo-HSCT). Chronic GVHD is characterized by the activation of alloreactive donor immune cells, especially B- and T-cells, leading to tissue damage and pathogenic fibrosis. In this study, we used highly specific next-generation inhibitors of ITK (PCYC-274), BTK (PCYC-804), and ibrutinib-like BTK/ITK inhibitors (PCYC-914 and PCYC-401) in the B10.D2 → BALB/C model of murine sclerodermatous cGVHD. From the third week onward, allogeneic recipients in each group of respective Tec kinase inhibitors were treated three times weekly with inhibitors at doses of 10 and 30 mg/kg or with saline control via oral gavage. Overall, we found that selective BTK inhibition was less effective than combined ITK/BTK or ITK inhibition in lengthening survival and reducing symptoms of cGVHD. ITK inhibition was most efficacious, with PCYC-274 and PCYC-401 demonstrating a nearly 50 percent reduction in GVHD scoring even at the 10 mg/kg dose, while 30 mg/kg of these compounds almost completely ameliorated GVHD symptomology. BTK/ITK and ITK-treated mice showed significant reductions in overall pathology. Significant reductions in dermal thickness and fibrosis were shown for all treatment groups. There was evidence of mixed Th1 and Th2 cytokine profiles in the skin of mice with dermal cGVHD, as both IFN-gamma and IL-4 were upregulated in the allogeneic control group, while kinase inhibition significantly reduced levels of these cytokines. Using an in vitro model of T-cell polarization, Th1 cell production of TNF-alpha and IFN-gamma were partially blocked by ITK. Th2 cell production of IL-4 was almost completely blocked synergistically by ITK and BTK inhibition. BTK-specific inhibition was unable to block either Th1 or Th2 cytokine production. Taken together, these results confirm previous reports that ITK-focused inhibition inhibits Th1 and Th2 cells. Additionally, the compound's effects on T-cell proliferation were tested by CFSE assay. Pure ITK inhibition was most effective at blocking T-cell proliferation, with no proliferation in PCYC-274-treated cells even at 0.1uM. PCYC-401 and PCYC-914 showed some inhibition at lower doses, with complete inhibition evident at 10uM. PCYC-804 was only partially able to block proliferation even at 10uM. In conclusion, we observed substantial benefit for differential inhibition of Tec kinases in GVHD, with ITK being most efficacious and Th1 cells being more resistant to inhibition, matching the previously reported findings of a Th2 to Th1 selective pressure in cells treated with ibrutinib. Our data warrants the further development of ITK and ITK/BTK inhibitors with specific inhibitory ratios to improve the treatment of GVHD and other T-cell mediated diseases.


Asunto(s)
Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Animales , Ratones , Interleucina-4/uso terapéutico , Ratones Endogámicos BALB C , Citocinas , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/patología , Fibrosis
2.
Transplantation ; 104(12): 2507-2515, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32639407

RESUMEN

BACKGROUND: Prolyl hydroxylase inhibitors (PHI) promote stabilization of hypoxia-inducible factor-1 alpha and affect signaling cascades of inflammation and cell death. Their beneficial use in experimental models of ulcerative colitis and lung allograft rejection led us to test the effect of the PHI dimethyl oxalyl glycine (DMOG) in the pathophysiology of graft versus host disease (GVHD). METHODS: Acute GVHD was induced in lethally irradiated BALB/c mice. DMOG was administered intraperitoneally on alternate days for the first 2-weeks posttransplant, and then twice a week till day +50, while controls received vehicle only. Animals were monitored for clinical GVHD and analyzed at day +7 and at day +50. RESULTS: DMOG treatment of allogeneic recipients improved survival by day +50, which was associated with decreased early gut injury and serum tumor necrosis factor-α compared with allogeneic controls. DMOG treatment of allogeneic recipients resulted in increased hypoxia-inducible factor-1 alpha expression and reduced apoptosis in the terminal ileum via Fas-associated protein with death domain protein repression along with decreased T-cell infiltration. Reduced pathology in colon after DMOG treatment associates with intestinal epithelium integrity and reduced damage caused by diminished recruitment of neutrophils. CONCLUSIONS: Taken together, we show protective effects of DMOG on early gut GVHD and improved survival in a model of allogeneic hematopoietic cell transplantation, providing the rationale for further evaluation of PHIs, in the prevention and treatment of acute GVHD.


Asunto(s)
Aminoácidos Dicarboxílicos/farmacología , Colon/efectos de los fármacos , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Íleon/efectos de los fármacos , Enfermedades Intestinales/prevención & control , Prolil Hidroxilasas/metabolismo , Inhibidores de Prolil-Hidroxilasa/farmacología , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Colon/enzimología , Colon/inmunología , Colon/patología , Enfermedad Injerto contra Huésped/enzimología , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Íleon/enzimología , Íleon/inmunología , Íleon/patología , Enfermedades Intestinales/enzimología , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/patología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Factores de Tiempo , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento , Irradiación Corporal Total
4.
Transplantation ; 104(3): 500-510, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31634333

RESUMEN

BACKGROUND: Gastrointestinal acute graft-versus-host disease (GVHD) occurring after allogeneic hematopoietic cell transplant is an allo-reactive T cell and inflammatory cytokine driven organ injury with epithelial apoptosis as 1 of its hallmark findings and is associated with significant mortality. Tumor necrosis factor (TNF)-alpha-induced protein 8 (TNFAIP8 or TIPE) acts as a negative mediator of apoptosis via inhibition of caspase-3 activation, promotes cell proliferation and Tipe deficiency is associated with increased inflammation. METHODS: To evaluate the role of TIPE in acute GVHD, naive C57BL/6 and Tipe C57BL/6 mice were conditioned with 1000 cGy single dose total body irradiation, followed by transplantation of 10 million bone marrow cells and 20 million splenocytes from either syngeneic C57BL/6 or allogeneic BALB/c donors. RESULTS: Allo TIPE-deficient mice developed exacerbated gut GVHD compared with allo controls and had significantly decreased survival (6 wk overall survival: 85% versus 37%; P < 0.05), higher clinical GVHD scores, more profound weight loss, increased serum proinflammatory cytokines (interleukin-17A, TNF, interleukin-6, and interferon-γ). T-cell infiltration into the ileum was increased; epithelial proliferation was decreased along with significantly higher levels of chemokines KC and monokine induced by gamma interferon. Using bone marrow chimeric experiments, TIPE was found to have a role in both hematopoietic and nonhematopoietic cells. CONCLUSIONS: Absence of TIPE results in excessive inflammation and tissue injury after allo-HCT, supporting that TIPE confers immune homeostasis and has tissue-protective function during the development of gut GVHD and may be a potential future target to prevent or treat this complication after allogeneic HCT.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/deficiencia , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedades del Íleon/inmunología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Trasplante de Médula Ósea , Modelos Animales de Enfermedad , Femenino , Enfermedad Injerto contra Huésped/patología , Humanos , Enfermedades del Íleon/patología , Íleon/inmunología , Íleon/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Quimera por Trasplante/inmunología , Trasplante Homólogo/efectos adversos
5.
Front Immunol ; 10: 2470, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31681336

RESUMEN

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is often used to treat acute leukemia or defects of hematopoiesis. Its widespread use is hampered by graft-vs.-host disease (GVHD), which has high morbidity and mortality in both acute and chronic subtypes. Chronic GVHD (cGVHD) occurs most frequently in skin and often is characterized by pathogenic fibrosis. Mast cells (MCs) are known to be involved in the pathogenesis of other fibrotic diseases. In a murine model of cGVHD after allo-HSCT, C57BL/6J recipients of allogeneic LP/J donor cells develop sclerodermatous dermal cGVHD which is significantly decreased in mast cell-deficient B6.Cg-KitW-sh/HNihrJaeBsmGlliJ recipients. The presence of MCs is associated with fibrosis, chemokine production, and recruitment of GVHD effector cells to the skin. Chemokine production by MCs is blocked by drugs used to treat cGVHD. The importance of MCs in skin cGVHD is mirrored by increased MCs in the skin of patients with dermal cGVHD. We show for the first time a role for MCs in skin cGVHD that may be targetable for preventive and therapeutic intervention in this disease.


Asunto(s)
Citocinas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Mastocitos/inmunología , Piel/inmunología , Adulto , Animales , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Femenino , Fibrosis , Perfilación de la Expresión Génica/métodos , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Mastocitos/citología , Mastocitos/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Persona de Mediana Edad , Piel/metabolismo , Piel/patología , Trasplante Homólogo
6.
Hum Mol Genet ; 28(3): 501-514, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30329053

RESUMEN

The extracellular signal-related kinase 1 and 2 (ERK1/2) pathway is a highly conserved signaling cascade with numerous essential functions in development. The scaffold protein Shoc2 amplifies the activity of the ERK1/2 pathway and is an essential modulator of a variety of signaling inputs. Germline mutations in Shoc2 are associated with the human developmental disease known as the Noonan-like syndrome with loose anagen hair. Clinical manifestations of this disease include congenital heart defects, developmental delays, distinctive facial abnormalities, reduced growth and cognitive deficits along with hair anomalies. The many molecular details of pathogenesis of the Noonan-like syndrome and related developmental disorders, cumulatively called RASopathies, remain poorly understood. Mouse knockouts for Shoc2 are embryonic lethal, emphasizing the need for additional animal models to study the role of Shoc2 in embryonic development. Here, we characterize a zebrafish shoc2 mutant, and show that Shoc2 is essential for development, and that its loss is detrimental for the development of the neural crest and for hematopoiesis. The zebrafish model of the Noonan-like syndrome described here provides a novel system for the study of structure-function analyses and for genetic screens in a tractable vertebrate system.


Asunto(s)
Hematopoyesis/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Animales , Modelos Animales de Enfermedad , Mutación de Línea Germinal , Péptidos y Proteínas de Señalización Intracelular/fisiología , Síndrome del Cabello Anágeno Suelto/genética , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/fisiología , Mutación , Cresta Neural/metabolismo , Cresta Neural/fisiología , Síndrome de Noonan/genética , Fenotipo , Pez Cebra/genética , Pez Cebra/fisiología , Proteínas de Pez Cebra/genética
7.
Exp Dermatol ; 21(10): 771-7, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23078399

RESUMEN

The epidermis increases pigmentation and epidermal thickness in response to ultraviolet exposure to protect against UV-associated carcinogenesis; however, the contribution of epidermal thickness has been debated. In a humanized skin mouse model that maintains interfollicular epidermal melanocytes, we found that forskolin, a small molecule that directly activates adenylyl cyclase and promotes cAMP generation, up-regulated epidermal eumelanin accumulation in fair-skinned melanocortin-1-receptor (Mc1r)-defective animals. Forskolin-induced pigmentation was associated with a reproducible expansion of epidermal thickness irrespective of melanization or the presence of epidermal melanocytes. Rather, forskolin-enhanced epidermal thickening was mediated through increased keratinocyte proliferation, indirectly through secreted factor(s) from cutaneous fibroblasts. We identified keratinocyte growth factor (Kgf) as a forskolin-induced fibroblast-derived cytokine that promoted keratinocyte proliferation, as forskolin induced Kgf expression both in the skin and in primary fibroblasts. Lastly, we found that even in the absence of pigmentation, forskolin-induced epidermal thickening significantly diminished the amount of UV-A and UV-B that passed through whole skin and reduced the amount of UV-B-associated epidermal sunburn cells. These findings suggest the possibility of pharmacologic-induced epidermal thickening as a novel UV-protective therapeutic intervention, particularly for individuals with defects in pigmentation and adaptive melanization.


Asunto(s)
AMP Cíclico/metabolismo , Pigmentos Biológicos/metabolismo , Piel/lesiones , Piel/metabolismo , Rayos Ultravioleta/efectos adversos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Colforsina/farmacología , Modelos Animales de Enfermedad , Epidermis/efectos de los fármacos , Epidermis/lesiones , Epidermis/metabolismo , Epidermis/patología , Epidermis/efectos de la radiación , Humanos , Queratina-14/genética , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/patología , Queratinocitos/efectos de la radiación , Melanocitos/efectos de los fármacos , Melanocitos/metabolismo , Melanocitos/patología , Melanocitos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Piel/efectos de los fármacos , Piel/patología , Piel/efectos de la radiación , Pigmentación de la Piel/efectos de los fármacos , Pigmentación de la Piel/efectos de la radiación
8.
Can J Urol ; 18(5): 5908-10, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22018154

RESUMEN

We present a case of pelvic aggressive angiomyxoma presenting as urinary retention in a male. A 46-year-old male presented with urinary retention and was found on computed tomography (CT) scan of the pelvis to have a large pelvic tumor. A transrectal ultrasound guided needle biopsy of the tumor and prostate revealed a myxoid tumor; low volume, low grade prostate cancer was also detected. The patient underwent radical prostatectomy and excision of the pelvic tumor which was diagnosed as aggressive angiomyxoma (AAM). The patient was free of recurrence after 1 year of follow up. AAM is a benign myxoid tumor seen very rarely in males. Treatment consists of surgical excision with negative margins. Tumors variably express estrogen and progesterone receptors. Immunohistochemistry should be used to exclude other benign and malignant tumors. Patients should be followed with axial imaging as recurrence is common.


Asunto(s)
Mixoma/complicaciones , Mixoma/diagnóstico por imagen , Pelvis , Neoplasias de los Tejidos Blandos/complicaciones , Neoplasias de los Tejidos Blandos/diagnóstico por imagen , Retención Urinaria/etiología , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Biopsia con Aguja , Humanos , Masculino , Persona de Mediana Edad , Mixoma/cirugía , Prostatectomía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Neoplasias de los Tejidos Blandos/cirugía , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Retención Urinaria/diagnóstico
10.
Exp Clin Transplant ; 9(3): 217-22, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21649574

RESUMEN

Hemophagocytic lymphohistiocytosis is a rare and often fatal disease that may occur in solid organ transplant recipients. Here, we describe 2 patients who developed hemophagocytic lymphohistiocytosis after having a lung transplant and present a review of all cases of hemophagocytic lymphohistiocytosis occurring in solid organ transplant recipients. Diagnosis of hemophagocytic lymphohistiocytosis relies on the association of clinical findings and the presence of hemophagocytosis. Clinical presentation is nonspecific and patients may present with unexplained sepsis or multiple organ failure. Management consists of treating the underlying process; but unfortunately, the prognosis is poor.


Asunto(s)
Trasplante de Pulmón/efectos adversos , Linfohistiocitosis Hemofagocítica/etiología , Adulto , Anciano , Examen de la Médula Ósea , Resultado Fatal , Femenino , Humanos , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/terapia , Imagen por Resonancia Magnética , Insuficiencia Multiorgánica/etiología , Resultado del Tratamiento
11.
Clin Pediatr (Phila) ; 48(4): 444-8, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19224868
12.
Am J Clin Pathol ; 128(2): 314-22, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17638668

RESUMEN

We report our experience with flow cytometric (FC) analysis of 29 cases of anaplastic large cell lymphoma (ALCL). Morphologic analysis of processed cytocentrifuged preparations demonstrated neoplastic cells in 28 cases. In 25 of these, an aberrant lymphoid population was detected by FC analysis. The majority showed high orthogonal light scatter, similar to monocytes or granulocytes. Of the antigens CD2, CD3, CD4, CD5, and CD7, 5 cases expressed 1, 8 expressed 2, 6 expressed 3, 3 expressed 4, and 3 expressed all 5. CD4 was expressed most commonly (20/25 [80%]), followed by CD2 (18/25 [72%]), CD3 (10/25 [40%]), and CD5 and CD7 (8/25 [32%] each). CD45 was expressed in 23 of 25 cases and CD13 in 7 of 9. Of 21 cases, 13 were anaplastic lymphoma kinase (ALK)+, all of which were CD4+, vs 5 of 8 ALK - cases (P = .042). Most ALCLs can be detected and characterized by multiparameter FC analysis. However, light scatter gating on typical lymphoid regions may yield false-negative results in a substantial number of cases.


Asunto(s)
Antígenos CD/análisis , Citometría de Flujo/métodos , Linfoma de Células B Grandes Difuso/inmunología , Adolescente , Adulto , Anciano , Quinasa de Linfoma Anaplásico , Niño , Preescolar , Femenino , Humanos , Antígeno Ki-1/análisis , Antígenos Comunes de Leucocito/análisis , Luz , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Proteínas Tirosina Quinasas/análisis , Proteínas Tirosina Quinasas Receptoras , Dispersión de Radiación
13.
Cytometry B Clin Cytom ; 70(3): 142-8, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16572417

RESUMEN

BACKGROUND: The immunophenotypic features of angioimmunoblastic T-cell lymphoma (AILT) have not been well described. METHODS: We retrospectively reviewed our institutional experience with the flow cytometric features of 16 cases of AILT. RESULTS: Multiparameter flow cytometry was able to identify a distinct population of immunophenotypically aberrant T cells in 15 of 16 cases. In 13 lymph node specimens, the neoplastic cells ranged from 1.9 to 87% (median 23%) of cells. The ratio of reactive to neoplastic T cells ranged from 0.01 to 20 (median 1.5); reactive T cells outnumbered neoplastic in 9/13 (69%) cases. The neoplastic populations expressed CD2, CD4, CD5, and CD45RO in all cases, lacked expression of CD8 and CD56 in all cases, and showed negative or dim surface CD3 in most cases. CD10 was expressed by the neoplastic populations in 11 of 14 cases at diagnosis; in 3 of these 11 only a subpopulation of the neoplastic cells was CD10(+). CD10 tended to be absent on neoplastic cells in staging bone marrows. The neoplastic population in all but one of the 15 positive cases possessed multiple immunophenotypic abnormalities and these were generally retained during the follow-up analyses of several cases. CONCLUSIONS: These results indicate the potential utility of flow cytometry in the diagnosis and follow-up of AILT.


Asunto(s)
Citometría de Flujo/métodos , Linfadenopatía Inmunoblástica/patología , Inmunofenotipificación/métodos , Linfoma de Células T/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/análisis , Antígenos CD7/análisis , Médula Ósea/patología , Complejo CD3/análisis , Femenino , Estudios de Seguimiento , Reordenamiento Génico de la Cadena gamma de los Receptores de Antígenos de los Linfocitos T/genética , Humanos , Linfadenopatía Inmunoblástica/genética , Linfadenopatía Inmunoblástica/inmunología , Antígenos Comunes de Leucocito/análisis , Ganglios Linfáticos/patología , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Masculino , Persona de Mediana Edad , Neprilisina/análisis , Receptores de Complemento 3d/análisis , Estudios Retrospectivos , Linfocitos T/química , Linfocitos T/metabolismo , Linfocitos T/patología
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