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1.
Int J Mol Sci ; 21(3)2020 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-32013193

RESUMEN

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Citocromo P-450 CYP3A/genética , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/farmacocinética , Tacrolimus/farmacocinética , Adulto , Anciano , Bases de Datos Genéticas , Femenino , Genotipo , Mutación de Línea Germinal , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Tacrolimus/farmacología , Tacrolimus/uso terapéutico , Trasplante Homólogo , Adulto Joven
2.
Biol Blood Marrow Transplant ; 25(6): 1062-1074, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30668984

RESUMEN

Despite recent advances in therapy, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for a range of high-risk hematologic malignancies. However, acute graft-versus-host disease (aGVHD) continues to limit the long-term success of HSCT, and new therapies are still needed. We previously demonstrated that aGVHD depends on the ability of donor conventional T cells (Tcons) to express the lymph node trafficking receptor, CC-Chemokine Receptor 7 (CCR7). Consequently, we examined the ability of cosalane, a recently identified CCR7 small-molecule antagonist, to attenuate aGVHD in mouse HSCT model systems. Here we show that the systemic administration of cosalane to transplant recipients after allogeneic HSCT did not prevent aGVHD. However, we were able to significantly reduce aGVHD by briefly incubating donor Tcons with cosalane ex vivo before transplantation. Cosalane did not result in Tcon toxicity and did not affect their activation or expansion. Instead, cosalane prevented donor Tcon trafficking into host secondary lymphoid tissues very early after transplantation and limited their subsequent accumulation within the liver and colon. Cosalane did not appear to impair the intrinsic ability of donor Tcons to produce inflammatory cytokines. Furthermore, cosalane-treated Tcons retained their graft-versus-leukemia (GVL) potential and rejected a murine P815 inoculum after transplantation. Collectively, our data indicate that a brief application of cosalane to donor Tcons before HSCT significantly reduces aGVHD in relevant preclinical models while generally sparing beneficial GVL effects, and that cosalane might represent a viable new approach for aGVHD prophylaxis.


Asunto(s)
Ácido Aurintricarboxílico/análogos & derivados , Enfermedad Injerto contra Huésped/genética , Efecto Injerto vs Leucemia/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Receptores CCR7/metabolismo , Linfocitos T/metabolismo , Acondicionamiento Pretrasplante/métodos , Enfermedad Aguda , Animales , Ácido Aurintricarboxílico/farmacología , Ácido Aurintricarboxílico/uso terapéutico , Humanos , Ratones , Donantes de Tejidos
3.
Biol Blood Marrow Transplant ; 25(2): 391-397, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30244102

RESUMEN

Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK)-guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015. A weight-based test dose of 0.8 mg/kg was used with PK assessments to predict area under the curve (AUCpred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUCtarget). PK from the test dose was then used to calculate a PK-guided first myeloablative busulfan dose. PK assessments were also done after the first dose to assess if the goal area under the curve (AUC) had been achieved (AUCfirst). A PK-guided first dose resulted in achievement of target AUC with target ranges of ±10% in 50% of patients, ±15% in 75%, and ±20% in 94%. This was an improved rate of target achievement compared with the 33%, 44%, and 63% of patients who achieved the desired AUC for these respective target ranges when using weight-based dosing (P = .12, .004, and <.001, respectively). The PK-guided strategy also decreased the variability of AUC from 3.6-fold in AUCpred from the weight-based test doses (2700.8 to 9631 µM*minute; SD, 1211.6 µM*minute) to 1.8-fold in AUCfirst from the PK-guided first doses (3672.1 to 6609.8 µM*minute; SD, 574.7 µM*minute). This reflects a 2-fold improvement in AUC variability with a PK-guided dosing strategy. This is also improved from the 3-fold variability in AUC reported in other studies. Weight and body surface area were significantly associated with the likelihood of AUCfirst being within the ±10% target range (P = .04 for both associations). There was no significant association between AUCfirst and death, relapse, or a composite of the two. These results demonstrate a significant improvement in target AUC attainment and less interpatient variability with PK-guided dosing using a test dose strategy compared with weight-based dosing.


Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Agonistas Mieloablativos , Acondicionamiento Pretrasplante , Adulto , Busulfano/administración & dosificación , Busulfano/farmacocinética , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/administración & dosificación , Agonistas Mieloablativos/farmacocinética
4.
Am J Transplant ; 19(7): 1941-1954, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30748092

RESUMEN

Acute graft-versus-host disease (aGVHD) remains a barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). Previously, we demonstrated that CC-chemokine receptor 7 (CCR7) is critical for aGVHD pathogenesis but dispensable for beneficial graft-versus-leukemia responses. As a result, we evaluated a fully human anti-CCR7-blocking antibody as a new approach to prevent aGVHD in preclinical models. Here we report that antibody R707 is able to block human CCR7 signaling and function in vitro in response to its 2 natural ligands. The antibody was less active against the murine orthologue, however, and failed to substantially limit aGVHD in a standard murine allogeneic HSCT model. Nevertheless, R707 significantly reduced xenogeneic aGVHD induced by human peripheral blood mononuclear cells (PBMCs). R707 limited CD4+ and in particular CD8+ T cell expansion during the period of antibody administration. These effects were transient, however, and T cell numbers recovered after antibody cessation. R707 did not substantially impair the antitumor potential of the PBMC inoculum as antibody-treated mice retained their capacity to reject a human acute myeloid leukemia cell line. Collectively, these data indicate for the first time that an antibody directed against CCR7 might represent a viable new approach for aGVHD prevention.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Leucocitos Mononucleares/inmunología , Receptores CCR7/inmunología , Linfocitos T/inmunología , Enfermedad Aguda , Animales , Anticuerpos Monoclonales/inmunología , Enfermedad Injerto contra Huésped/genética , Trasplante de Células Madre Hematopoyéticas , Xenoinjertos , Humanos , Ratones , Receptores CCR7/genética , Linfocitos T/trasplante , Donantes de Tejidos , Trasplante Homólogo
5.
Blood ; 130(3): 348-359, 2017 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-28550042

RESUMEN

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that affects the function and development of immune cells. Here, we show that recipient mice receiving AhR-/- T cells have improved survival and decreased acute graft-versus-host disease (aGVHD) in 2 different murine allogeneic bone marrow transplant (BMT) models. We also show that CD4+ T cells lacking AhR demonstrate reduced accumulation in secondary lymphoid tissue because of low levels of proliferation 4 days after BMT. Additionally, we found a significant increase in the quantity of peripherally induced regulatory donor T (pTreg) cells in the colon of recipients transplanted with AhR-/- T cells 14 days after transplant. Blockade of AhR using a clinically available AhR antagonist greatly enhanced the in vitro generation of inducible Treg (iTreg) cells from naïve CD4+ human T cells. We have identified AhR as a novel target on donor T cells that is critical to the pathogenesis of aGVHD.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Trasplante de Médula Ósea , Colon/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Receptores de Hidrocarburo de Aril/inmunología , Linfocitos T Reguladores/inmunología , Enfermedad Aguda , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proliferación Celular , Colon/patología , Regulación de la Expresión Génica , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Humanos , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Purinas/farmacología , Receptores de Hidrocarburo de Aril/deficiencia , Receptores de Hidrocarburo de Aril/genética , Sirolimus/farmacología , Análisis de Supervivencia , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/trasplante , Trasplante Heterólogo
6.
Biol Blood Marrow Transplant ; 24(11): 2184-2189, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29981461

RESUMEN

Acute graft-versus-host disease (aGVHD) remains a barrier to the success of allogeneic hematopoietic stem cell transplantation. In mice, studies have demonstrated that donor conventional T cells traffic into host secondary lymphoid tissues early after transplant, and that this process is critical for the development of disease. As a result, the measurement of cellular proliferation within lymphoid sites early after transplant might be a useful approach for predicting aGVHD in humans. 18F-3'-deoxy-3'-fluorothymidine (FLT) positron emission tomography (PET) imaging has recently emerged as a functional imaging modality in oncology patients. FLT, a thymidine analog, is incorporated into replicating DNA and is thus an indirect marker of cellular proliferation. Here we report that FLT PET imaging can differentiate mice receiving alloreactive T cells and destined to develop lethal aGVHD from control mice. Mice receiving allogeneic T cells demonstrated a stronger FLT signal within the peripheral lymph nodes compared with control mice at all time points after transplant. In addition, allogeneic T cell recipients transiently demonstrated stronger FLT uptake within the spleen. Importantly, these differences were apparent before the development of clinical disease. In contrast, the FLT signal within the host bowel, an important aGVHD target organ, was more variable after transplant and was not consistently different between aGVHD mice and control mice. Collectively, these findings suggest that the imaging of patient lymphoid sites using existing FLT PET technology might be useful for predicting aGVHD in the clinical setting.


Asunto(s)
Fluorodesoxiglucosa F18/uso terapéutico , Enfermedad Injerto contra Huésped/diagnóstico por imagen , Trasplante de Células Madre Hematopoyéticas/métodos , Tomografía de Emisión de Positrones/métodos , Acondicionamiento Pretrasplante/métodos , Enfermedad Aguda , Animales , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped/patología , Ratones
7.
Am J Transplant ; 18(4): 810-820, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28941323

RESUMEN

Graft-versus-host disease (GVHD) is the major cause of nonrelapse morbidity and mortality after allogeneic stem cell transplantation (allo-SCT). Prevention and treatment of GVHD remain inadequate and commonly lead to end-organ dysfunction and opportunistic infection. The role of interleukin (IL)-17 and IL-22 in GVHD remains uncertain, due to an apparent lack of lineage fidelity and variable and contextually determined protective and pathogenic effects. We demonstrate that donor T cell-derived IL-22 significantly exacerbates cutaneous chronic GVHD and that IL-22 is produced by highly inflammatory donor CD4+ T cells posttransplantation. IL-22 and IL-17A derive from both independent and overlapping lineages, defined as T helper (Th)22 and IL-22+ Th17 cells. Donor Th22 and IL-22+ Th17 cells share a similar IL-6-dependent developmental pathway, and while Th22 cells arise independently of the IL-22+ Th17 lineage, IL-17 signaling to donor Th22 directly promotes their development in allo-SCT. Importantly, while both IL-22 and IL-17 mediate skin GVHD, Th17-induced chronic GVHD can be attenuated by IL-22 inhibition in preclinical systems. In the clinic, high levels of both IL-17A and IL-22 expression are present in the skin of patients with GVHD after allo-SCT. Together, these data demonstrate a key role for donor-derived IL-22 in patients with chronic skin GVHD and confirm parallel but symbiotic developmental pathways of Th22 and Th17 differentiation.


Asunto(s)
Enfermedad Injerto contra Huésped/etiología , Interleucina-17/metabolismo , Interleucinas/metabolismo , Enfermedades de la Piel/etiología , Trasplante de Células Madre/efectos adversos , Donantes de Tejidos , Animales , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Pronóstico , Enfermedades de la Piel/metabolismo , Enfermedades de la Piel/patología , Trasplante Homólogo , Interleucina-22
9.
Biol Blood Marrow Transplant ; 23(4): 569-580, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28161607

RESUMEN

Idiopathic pneumonia syndrome (IPS) is a noninfectious inflammatory disorder of the lungs that occurs most often after fully myeloablative allogeneic hematopoietic stem cell transplantation (HSCT). IPS can be severe and is associated with high 1-year mortality rates despite existing therapies. The canonical nuclear factor-(NF) κB signaling pathway has previously been linked to several inflammatory disorders of the lung, including asthma and lung allograft rejection. It has never been specifically targeted as a novel IPS treatment approach, however. Here, we report that the IκB kinase 2 (IKK2) antagonist BAY 65-5811 or "compound A," a highly potent and specific inhibitor of the NF-κB pathway, was able to improve median survival times and recipient oxygenation in a well-described mouse model of IPS. Compound A impaired the production of the proinflammatory chemokines CCL2 and CCL5 within the host lung after transplantation. This resulted in significantly lower numbers of donor lung infiltrating CD4+ and CD8+ T cells and reduced pulmonary inflammatory cytokine production after allograft. Compound A's beneficial effects appeared to be specific for limiting pulmonary injury, as the drug was unable to improve outcomes in a B6 into B6D2 haplotype-matched murine HSCT model in which recipient mice succumb to lethal acute graft-versus-host disease of the gastrointestinal tract. Collectively, our data suggest that the targeting of the canonical NF-κB pathway with a small molecule IKK2 antagonist may represent an effective and novel therapy for the specific management of acute lung injury that can occur after allogeneic HSCT.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Quinasa I-kappa B/antagonistas & inhibidores , Lesión Pulmonar/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , FN-kappa B/metabolismo , Neumonía/tratamiento farmacológico , Animales , Lesión Pulmonar/etiología , Ratones , Resultado del Tratamiento
10.
Blood ; 123(10): 1604-14, 2014 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-24415540

RESUMEN

Graft-versus-host disease (GVHD) is a systemic inflammatory response due to the recognition of major histocompatibility complex disparity between donor and recipient after hematopoietic stem cell transplantation (HSCT). T-cell activation is critical to the induction of GVHD, and data from our group and others have shown that regulatory T cells (Tregs) prevent GVHD when given at the time of HSCT. Using multiphoton laser scanning microscopy, we examined the single cell dynamics of donor T cells and dendritic cells (DCs) with or without Tregs postallogeneic transplantation. We found that donor conventional T cells (Tcons) spent very little time screening host DCs. Tcons formed stable contacts with DCs very early after transplantation and only increased velocity in the lymph node at 20 hours after transplant. We also observed that Tregs reduced the interaction time between Tcons and DCs, which was dependent on the generation of interleukin 10 by Tregs. Imaging using inducible Tregs showed similar disruption of Tcon-DC contact. Additionally, we found that donor Tregs induce host DC death and down-regulate surface proteins required for donor T-cell activation. These data indicate that Tregs use multiple mechanisms that affect host DC numbers and function to mitigate acute GVHD.


Asunto(s)
Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígeno B7-2/metabolismo , Comunicación Celular/inmunología , Muerte Celular/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped/metabolismo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Molécula 1 de Adhesión Intercelular/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Transgénicos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Trasplante Homólogo
11.
Biol Blood Marrow Transplant ; 21(12): 2129-2135, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26210442

RESUMEN

Intensive chemotherapy or chemotherapy plus irradiation and allogeneic stem cell transplantation can be curative for patients with hematologic diseases. Reduced-intensity transplants can also achieve cure and result in less treatment-related mortality but higher relapse rates. Thus, optimizing the conditioning regimens used in allogeneic transplantation remains an important goal. We conducted a phase I/II trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a continuous infusion of busulfan over 90 hours in conjunction with fludarabine followed by allogeneic related or unrelated donor transplant. Fifty-four patients with advanced hematologic malignancies were enrolled on this study. The MTD was identified as a 24-hour area under the curve (AUC) of approximately 7095 µM/min, which represents a 43% increase over the standard total daily AUC dose of 4800 µM/min given by intermittent schedules. DLTs at doses over 8000 µM/min were identified by a desquamative skin rash and mucositis. No dose-related increase in hepatic, pulmonary, or other organ toxicities were seen, whereas efficacy appeared to be improved at higher dose levels. Continuous-infusion busulfan with intermittent fludarabine provides an alternative treatment strategy that is generally well tolerated and permits an increase in total busulfan dose with encouraging efficacy. (NCI study no. NCT00448357.).


Asunto(s)
Busulfano/uso terapéutico , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Agonistas Mieloablativos/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adulto , Área Bajo la Curva , Busulfano/farmacocinética , Esquema de Medicación , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/farmacocinética , Estudios Prospectivos , Recurrencia , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/farmacocinética , Vidarabina/uso terapéutico
12.
Eur J Immunol ; 44(6): 1662-71, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24752751

RESUMEN

Acute graft-versus-host disease (aGvHD) is a major limitation to the use of allogeneic stem cell transplantation for the treatment of patients with relapsed malignant disease. Previous work using animals lacking secondary lymphoid tissue (SLT) suggested that activation of donor T cells in SLT is critically important for the pathogenesis of aGvHD. However, these studies did not determine if impaired migration into, and more importantly, out of SLT, would ameliorate aGvHD. Here, we show that T cells from mice lacking Coronin 1A (Coro 1A(-/-)), an actin-associated protein shown to be important for thymocyte egress, do not mediate acute GvHD. The attenuation of aGvHD was associated with decreased expression of the critical trafficking proteins C-C chemokines receptor type 7 (CCR7) and sphingosine 1 phosphate receptor on donor T cells. This was mediated in part by impaired activation of the canonical NF-κB pathway in the absence of Coro 1A. As a result of these alterations, donor T cells from Coro 1A(-/-) mice were not able to initially traffic to SLT or exit SLT after BM transplantation. However, this alteration did not abrogate the graft-versus-leukemia response. Our data suggest that blocking T-cell migration into and out of SLT is a valid approach to prevent aGvHD.


Asunto(s)
Trasplante de Médula Ósea , Movimiento Celular/inmunología , Enfermedad Injerto contra Huésped/inmunología , Proteínas de Microfilamentos/inmunología , Linfocitos T/inmunología , Enfermedad Aguda , Aloinjertos , Animales , Movimiento Celular/genética , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/patología , Enfermedad Injerto contra Huésped/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Proteínas de Microfilamentos/aislamiento & purificación , FN-kappa B/genética , FN-kappa B/inmunología , Receptores CCR7/genética , Receptores CCR7/inmunología , Receptores de Lisoesfingolípidos/genética , Receptores de Lisoesfingolípidos/inmunología , Receptores de Esfingosina-1-Fosfato , Linfocitos T/patología
13.
Blood ; 122(5): 825-36, 2013 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-23798714

RESUMEN

The infusion of donor regulatory T cells (Tregs) has been used to prevent acute graft-versus-host disease (GVHD) in mice and has shown promise in phase 1 clinical trials. Previous work suggested that early Treg migration into lymphoid tissue was important for GVHD prevention. However, it is unclear how and where Tregs function longitudinally to affect GVHD. To better understand their mechanism of action, we studied 2 Treg-associated chemokine receptors in murine stem cell transplant models. CC chemokine receptor (CCR) 4 was dispensable for donor Treg function in the transplant setting. Donor Tregs lacking CCR8 (CCR8(-/-)), however, were severely impaired in their ability to prevent lethal GVHD because of increased cell death. By itself, CCR8 stimulation was unable to rescue Tregs from apoptosis. Instead, CCR8 potentiated Treg survival by promoting critical interactions with dendritic cells. In vivo, donor bone marrow-derived CD11c(+) antigen-presenting cells (APCs) were important for promoting donor Treg maintenance after transplant. In contrast, host CD11c(+) APCs appeared to be dispensable for early activation and expansion of donor Tregs. Collectively, our data indicate that a sustained donor Treg presence is critical for their beneficial properties, and that their survival depends on CCR8 and donor but not host CD11c(+) APCs.


Asunto(s)
Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/prevención & control , Receptores CCR8/fisiología , Linfocitos T Reguladores/fisiología , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/fisiología , Antígeno CD11c/metabolismo , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Células Cultivadas , Supervivencia de Injerto/genética , Supervivencia de Injerto/inmunología , Enfermedad Injerto contra Huésped/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Transgénicos , Receptores CCR8/genética , Receptores CCR8/metabolismo , Linfocitos T Reguladores/metabolismo , Donantes de Tejidos
14.
Biol Blood Marrow Transplant ; 20(7): 1064-8, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24704385

RESUMEN

Autologous stem cell transplantation remains a mainstay of therapy for diseases such as multiple myeloma and relapsed lymphoma. The use of plerixafor has been shown to augment the ability to collect adequate stem cells, but the optimal use of this agent when used with chemotherapy is not yet clear. We utilized an algorithm-based approach with the addition of plerixafor to 54 patients undergoing chemomobilization with reduced-dose etoposide who had a less than optimal preapheresis CD34(+) cell count. We used a CD34(+) precount of 20 cells/µL as a threshold to initiate stem cell apheresis. Ninety-four percent of patients were successfully collected and proceeded to transplantation. Fourteen of 51 (28%) patients who successfully collected required plerixafor to augment stem cell yield. Of the patients who successfully collected, 94% (89% of the entire population) were able to collect in 2 or fewer days. Compared with previous data from our institution, the rate of patients collecting > 4 × 10(6) CD34(+) cells/kg in a single collection was increased from 39% to 69%. The safety profile of this approach was acceptable. The use of this algorithm-based method to determine when and whether to add plerixafor to chemomobilization was shown to be a successful and cost-effective approach to stem cell collection.


Asunto(s)
Movilización de Célula Madre Hematopoyética/métodos , Compuestos Heterocíclicos/administración & dosificación , Adulto , Anciano , Algoritmos , Bencilaminas , Eliminación de Componentes Sanguíneos/métodos , Ciclamas , Etopósido/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trasplante Autólogo , Adulto Joven
15.
Blood ; 120(12): 2529-36, 2012 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-22896003

RESUMEN

Recent data reveal an important role for B cells in the pathogenesis of chronic GVHD (cGVHD). Patients with cGVHD have delayed B-cell reconstitution and elevated BAFF to B-cell ratios compared to patients without cGVHD. The mechanisms promoting and sustaining B-cell activation in this disease, however, remain unknown. As BAFF increases murine B-cell metabolism and survival and maintains autoreactive B-cell clones, we performed ex vivo analyses of peripheral B cells from 51 patients who either had or did not have active cGVHD and were greater than 1 year from the time of allogeneic hematopoietic stem cell transplantation. We found that B cells from patients with active cGVHD were in a heightened metabolic state and were resistant to apoptosis. Exogenous BAFF treatment amplified cell size and survival in B cells from these patients. We found significantly increased signaling through ERK and AKT that associated with decreased levels of proapoptotic Bim, suggesting a mechanistic link between elevated BAFF levels and aberrant B-cell survival. Thus, we identify a role for BAFF in the pathogenesis of cGVHD and define B-cell activation and survival pathways suitable for novel therapeutic development in cGVHD.


Asunto(s)
Apoptosis , Factor Activador de Células B/metabolismo , Linfocitos B/inmunología , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Transducción de Señal , Adulto , Anciano , Factor Activador de Células B/inmunología , Linfocitos B/metabolismo , Linfocitos B/patología , Tamaño de la Célula , Células Cultivadas , Enfermedad Crónica , Femenino , Citometría de Flujo , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/patología , Enfermedad Injerto contra Huésped/terapia , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Humanos , Immunoblotting , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Trasplante Homólogo , Adulto Joven
16.
J Immunol ; 189(4): 1765-72, 2012 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-22778391

RESUMEN

Graft-versus-host disease (GVHD) remains the most significant complication after allogeneic stem cell transplantation. Previously, acute GVHD had been considered to be mediated predominantly by Th1-polarized T cells. Recently, investigators have identified a second proinflammatory lineage of T cells termed Th17 that is critically dependent on the transcription factor retinoic acid-related orphan receptor (ROR)γt. In this study, we have evaluated the role of Th17 cells in murine acute GVHD by infusing donor T cells lacking RORC and as a consequence the isoform RORγt. Recipients given donor CD4(+) and CD8(+) T cells lacking RORC had significantly attenuated acute GVHD and markedly decreased tissue pathology in the colon, liver, and lung. Using a clinically relevant haploidentical murine transplantation model, we showed that RORC(-/-) CD4(+) T cells alone diminished the severity and lethality of acute GVHD. This was not found when CD4(+) T cells from RORC(-/-) mice were given to completely mismatched BALB/c mice, and it was correlated with absolute differences in the generation of TNF in the colon after transplant. Thus, CD4(+) T cell expression of RORC is important in the pathogenesis of acute GVHD.


Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Células Th17/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Enfermedad Injerto contra Huésped/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Reacción en Cadena en Tiempo Real de la Polimerasa
17.
Lancet Haematol ; 11(5): e358-e367, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38555923

RESUMEN

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30+ lymphoma at high risk of relapse. METHODS: This phase 1 dose-escalation study was performed at two sites in the USA. Patients aged 3 years and older, with classical Hodgkin lymphoma or non-Hodgkin lymphoma with CD30+ disease documented by immunohistochemistry, and a Karnofsky performance score of more than 60% planned for autologous HSCT were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T cells (2 × 107 CAR T cells per m2, 1 × 108 CAR T cells per m2, or 2 × 108 CAR T cells per m2) as consolidation after trilineage haematopoietic engraftment (defined as absolute neutrophil count ≥500 cells per µL for 3 days, platelet count ≥25 × 109 platelets per L without transfusion for 5 days, and haemoglobin ≥8 g/dL without transfusion for 5 days) following carmustine, etoposide, cytarabine, and melphalan (BEAM) and HSCT. The primary endpoint was the determination of the maximum tolerated dose, which was based on the rate of dose-limiting toxicity in patients who received CAR T-cell infusion. This study is registered with ClinicalTrials.gov (NCT02663297) and enrolment is complete. FINDINGS: Between June 7, 2016, and Nov 30, 2020, 21 patients were enrolled and 18 patients (11 with Hodgkin lymphoma, six with T-cell lymphoma, one with grey zone lymphoma) were infused with anti-CD30 CAR T cells at a median of 22 days (range 16-44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2 × 108 CAR T cells per m2, was determined to be the maximum tolerated dose. One patient had grade 1 cytokine release syndrome. The most common grade 3-4 adverse events were lymphopenia (two [11%] of 18) and leukopenia (two [11%] of 18). There were no treatment-related deaths. Two patients developed secondary malignancies approximately 2 years and 2·5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48·2 months (IQR 27·5-60·7) post-infusion, the median progression-free survival for all treated patients (n=18) was 32·3 months (95% CI 4·6 months to not estimable) and the median progression-free survival for treated patients with Hodgkin lymphoma (n=11) has not been reached. The median overall survival for all treated patients has not been reached. INTERPRETATION: Anti-CD30 CAR T-cell infusion as consolidation after BEAM and autologous HSCT is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma at high risk of relapse, highlighting the need for larger studies to confirm these findings. FUNDING: National Heart Lung and Blood Institute, University Cancer Research Fund at the Lineberger Comprehensive Cancer Center.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Inmunoterapia Adoptiva , Antígeno Ki-1 , Trasplante Autólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Anciano , Adolescente , Enfermedad de Hodgkin/terapia , Enfermedad de Hodgkin/inmunología , Adulto Joven , Niño , Receptores Quiméricos de Antígenos/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melfalán/uso terapéutico , Melfalán/administración & dosificación , Linfoma no Hodgkin/terapia , Linfoma no Hodgkin/inmunología , Carmustina/uso terapéutico , Carmustina/administración & dosificación , Etopósido/uso terapéutico , Etopósido/administración & dosificación , Preescolar , Citarabina/uso terapéutico , Citarabina/administración & dosificación
18.
Blood ; 117(12): 3268-76, 2011 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-21245483

RESUMEN

GVHD is a syndrome that results from minor and major histocompatibility complex incompatibilities between the donor and recipient. More than 50 years after its initial description, the pathophysiology of GVHD remains poorly understood. Nonetheless, donor T cells have been shown to be critical to the pathophysiology of acute and chronic GVHD, yet precisely how they function remains unclear. The effector mechanisms by which donor T cells mediate tissue inflammation is even less well understood. Identification of several new lineages of CD4(+) T cells made in the past decade and their roles in the pathophysiology of T cell-mediated diseases has shed new light on these effector mechanisms. In this review, we summarize the recent descriptions of these T-cell lineages and the current data supporting their role in acute and to a lesser extent chronic GVHD. Investigations into the activity of these new T-cell lineages may provide more rationale approaches to the treatment or prevention of GVHD.


Asunto(s)
Linfocitos T CD4-Positivos/fisiología , Citocinas/metabolismo , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/metabolismo , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linaje de la Célula/inmunología , Humanos , Modelos Biológicos , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/fisiología , Inmunología del Trasplante/fisiología
19.
Blood ; 115(23): 4914-22, 2010 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-20185583

RESUMEN

CC-chemokine receptor 7 (CCR7) is expressed on the surface of naive T cells, and plays a critical role in their movement into secondary lymphoid tissue. Here, we show that murine T cells lacking CCR7 (CCR7(-/-)) generate attenuated graft-versus-host disease (GVHD) responses compared with wild-type (WT) cells, with the difference varying inversely with the degree of major histocompatibility complex (MHC) disparity between the donor and recipient. CCR7(-/-) T cells exhibited an impaired ability to traffic to recipient lymph nodes, with an increased capacity to home to the spleen. CCR7(-/-) T cells, however, demonstrated a reduced ability to undergo in vivo expansion in the spleen due to impaired interactions with splenic antigen-presenting cells. On a cellular level, CCR7(-/-) T cells were functionally competent, demonstrating a normal in vitro proliferative capacity and a preserved ability to produce inflammatory cytokines. Importantly, CCR7(-/-) T cells were capable of generating robust graft-versus-leukemia (GVL) responses in vivo, as well as complete donor T-cell reconstitution. CCR7(-/-) regulatory T cells were able to protect against lethal GVHD when administered before WT conventional T cells. Our data suggest that CCR7 inhibition in the early posttransplantation period may represent a feasible new therapeutic approach for acute GVHD attenuation without compromising GVL responses.


Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia/inmunología , Receptores CCR7/inmunología , Linfocitos T/inmunología , Animales , Proliferación Celular , Citocinas/inmunología , Enfermedad Injerto contra Huésped/genética , Efecto Injerto vs Leucemia/genética , Humanos , Mediadores de Inflamación/inmunología , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptores CCR7/genética , Bazo/inmunología , Linfocitos T/trasplante
20.
Blood ; 113(6): 1365-74, 2009 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-18957685

RESUMEN

The morbidity and mortality associated with graft-host-disease (GVHD) is a significant obstacle to the greater use of allogeneic stem cell transplantation. Donor T cells that predominantly differentiate into TH1/Tc1 T cells and generate pro-inflammatory cytokines such as interferon-gamma (IFN-gamma) mediate GVHD. Although numerous studies have described a pathogenic role for IFN-gamma, multiple reports have demonstrated that the lack of IFN-gamma paradoxically exacerbated GVHD lethality. This has led to speculation that another subset of T cells may significantly contribute to GVHD mortality. Several groups have demonstrated a new lineage of CD4+ T helper cell development distinct from TH1 or TH2 differentiation. This lineage is characterized by production of interleukin (IL)-17A, IL-17F, IL-22, and IL-21 and has been termed TH17 cells. Here, we demonstrate that a highly purified population of TH17 cells is capable of inducing lethal GVHD, hallmarked by extensive pathologic cutaneous and pulmonary lesions. Upon transfer, these cells migrate to and expand in GVHD target organs and secondary lymphoid tissues. Finally, we demonstrate differential roles for tumor necrosis factor-alpha (TNF-alpha) and IL-17A in the clinical manifestations of GVHD induced by TH17 cells. Our studies demonstrate that cells other than TH1/Tc1 can mediate acute GVHD.


Asunto(s)
Diferenciación Celular , Enfermedad Injerto contra Huésped/etiología , Enfermedades Pulmonares/etiología , Enfermedades de la Piel/etiología , Linfocitos T Colaboradores-Inductores/inmunología , Enfermedad Aguda , Animales , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Citometría de Flujo , Interferón gamma/fisiología , Interleucina-17/inmunología , Leucocitos/citología , Leucocitos/metabolismo , Enfermedades Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Enfermedades de la Piel/patología , Tasa de Supervivencia , Linfocitos T Colaboradores-Inductores/trasplante , Factor de Necrosis Tumoral alfa/sangre
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