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1.
Blood ; 138(1): 34-43, 2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-33657225

RESUMEN

Decreased cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is associated with late CMV reactivation and increased mortality. Whether letermovir prophylaxis-associated reduction in viral exposure influences CMV-specific immune reconstitution is unknown. In a prospective cohort of allogeneic HCT recipients who received letermovir, we compared polyfunctional CMV-specific T-cell responses to those of controls who received PCR-guided preemptive therapy before the introduction of letermovir. Thirteen-color flow cytometry was used to assess T-cell responses at 3 months after HCT following stimulation with CMV immediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) antigens. Polyfunctionality was characterized by combinatorial polyfunctionality analysis of antigen-specific T-cell subsets. Use of letermovir and reduction of viral exposure were assessed for their association with CMV-specific T-cell immunity. Polyfunctional T-cell responses to IE-1 and pp65 were decreased in letermovir recipients and remained diminished after adjustment for donor CMV serostatus, absolute lymphocyte count, and steroid use. Among letermovir recipients, greater peak CMV DNAemia and increased viral shedding were associated with stronger CD8+ responses to pp65, whereas the CMV shedding rate was associated with greater CD4+ responses to IE-1. In summary, our study provided initial evidence that letermovir may delay CMV-specific cellular reconstitution, possibly related to decreased CMV antigen exposure. Evaluating T-cell polyfunctionality may identify patients at risk for late CMV infection after HCT.


Asunto(s)
Acetatos/farmacología , Citomegalovirus/inmunología , Trasplante de Células Madre Hematopoyéticas , Quinazolinas/farmacología , Linfocitos T/inmunología , Adulto , Anciano , Citomegalovirus/efectos de los fármacos , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Supervivencia sin Enfermedad , Femenino , Humanos , Modelos Lineales , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fenotipo , Linfocitos T/efectos de los fármacos , Activación Viral/efectos de los fármacos , Adulto Joven
2.
J Infect Dis ; 221(9): 1470-1479, 2020 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-31734696

RESUMEN

BACKGROUND: The influence of humoral immunity on the prevention of primary cytomegalovirus (CMV) infection after hematopoietic cell transplantation (HCT) is poorly understood. METHODS: To determine whether neutralizing antibodies (nAbs) against CMV pentameric complex (PC)-mediated epithelial cell entry decrease CMV infection after HCT, samples were analyzed from a randomized controlled trial of CMV intravenous immunoglobulin (IVIG) prophylaxis. Weekly serum from 61 CMV donor-positive/recipient-negative (D+/R-) HCT patients (33 control, 28 CMV IVIG) was tested using a PC-entry nAb assay and quantitative CMV polymerase chain reaction (PCR). RESULTS: There was a trend toward higher weekly PC-entry nAb titers (P = .07) and decreased CMV infection by PCR at viral load cutoffs of ≥1000 and ≥10 000 IU/mL in the CMV IVIG arm. High nAb titers were not significantly protective against CMV infection later after HCT in both study arms. Among CMV-infected patients, each log2 increase in nAb titer was associated with an average 0.2 log10 decrease in concurrent CMV viral load after infection (P = .001; adjusted for study arm). CONCLUSIONS: This study provides initial support that CMV IVIG prophylaxis moderately enhances PC-entry nAB activity in D+/R- HCT recipients.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Antivirales/administración & dosificación , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunidad Humoral , Adolescente , Adulto , Anticuerpos Antivirales/inmunología , Niño , Preescolar , Citomegalovirus , Infecciones por Citomegalovirus/tratamiento farmacológico , Células Epiteliales/efectos de los fármacos , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Persona de Mediana Edad , Donantes de Tejidos , Receptores de Trasplantes , Carga Viral/efectos de los fármacos , Adulto Joven
3.
J Infect Dis ; 220(5): 752-760, 2019 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-31112280

RESUMEN

The differential impact of preemptive therapy (PET) and antiviral prophylaxis (AP) on development of cytomegalovirus (CMV)-specific neutralizing antibody (nAb) and T-cell responses have not previously been directly compared in high-risk donor-seropositive/recipient-seronegative (D+R-) organ transplant recipients. We prospectively assessed T-cell and nAb responses 3 months after transplantation in cohorts of high-risk D+R- liver transplant recipients who received either PET (n = 15) or AP (n = 25) and a control group of CMV-seropositive transplant recipients (R+) (AP; n = 24). CMV phosphoprotein 65 (pp65)- and immediate early protein 1-specific multifunctional T-cell responses were determined by means of intracellular cytokine staining and nAbs against BADrUL131-Y4 CMV in adult retinal pigment epithelial cell line-19 human epithelial cells; nAbs were detected in 8 of 12 (67%) in the PET group, none of 17 in the AP group, and 20 of 22 (91%) in the R+ group. Multifunctional CD8 and CD4 T-cell responses to pp65 were generally similar between PET and R+ groups, and lower for the AP group; multifunctional CD4 responses were similar across all groups. Among D+R- liver transplant recipients, PET was associated with the development of greater nAb and multifunctional CD8 T-cell responses compared with AP, providing a potential mechanism to explain the relative protection against late-onset disease with PET. Future studies are needed to define specific immune parameters predictive of late-onset CMV disease with AP.


Asunto(s)
Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Inmunidad , Trasplante de Hígado , Receptores de Trasplantes , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos/inmunología , Línea Celular , Citocinas/metabolismo , Citomegalovirus/efectos de los fármacos , Infecciones por Citomegalovirus/prevención & control , Esquema de Medicación , Células Epiteliales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Factores de Riesgo , Donantes de Tejidos , Inmunología del Trasplante
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