RESUMO
ABSTRACT: Acute graft-versus-host disease (GVHD) grading systems that use only clinical symptoms at treatment initiation such as the Minnesota risk identify standard and high-risk categories but lack a low-risk category suitable to minimize immunosuppressive strategies. We developed a new grading system that includes a low-risk stratum based on clinical symptoms alone and determined whether the incorporation of biomarkers would improve the model's prognostic accuracy. We randomly divided 1863 patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) who were treated for GVHD into training and validation cohorts. Patients in the training cohort were divided into 14 groups based on similarity of clinical symptoms and similar nonrelapse mortality (NRM); we used a classification and regression tree (CART) algorithm to create three Manhattan risk groups that produced a significantly higher area under the receiver operating characteristic curve (AUC) for 6-month NRM than the Minnesota risk classification (0.69 vs 0.64, P = .009) in the validation cohort. We integrated serum GVHD biomarker scores with Manhattan risk using patients with available serum samples and again used a CART algorithm to establish 3 MAGIC composite scores that significantly improved prediction of NRM compared to Manhattan risk (AUC, 0.76 vs 0.70, P = .010). Each increase in MAGIC composite score also corresponded to a significant decrease in day 28 treatment response (80% vs 63% vs 30%, P < .001). We conclude that the MAGIC composite score more accurately predicts response to therapy and long-term outcomes than systems based on clinical symptoms alone and may help guide clinical decisions and trial design.
Assuntos
Biomarcadores , Doença Enxerto-Hospedeiro , Humanos , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/terapia , Biomarcadores/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Prognóstico , Doença Aguda , Resultado do Tratamento , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Idoso , Algoritmos , Adolescente , Adulto JovemRESUMO
The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, P = .02). No other grade ≥3 adverse events occurred in >10% of itacitinib-treated patients. There were no significant differences between groups at 1 year for nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Resultado do Tratamento , Acetonitrilas/uso terapêutico , Pirazóis/efeitos adversos , Corticosteroides/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Clinical- and biomarker-based tools may identify a lower-risk acute graft-versus-host disease (GVHD) population amenable to novel, reduced-intensity treatments. Previous data suggest sirolimus may rival standard of care prednisone. We conducted a National Heart, Lung, and Blood Institute/National Cancer Institute-funded Blood and Marrow Transplant Clinical Trials Network multicenter, open-label, randomized phase 2 trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus vs prednisone as initial treatment of patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA1/2) biomarker status. A total of 127 MN-SR patients were randomized (1:1), and 122 were AA1/2 (sirolimus, n = 58; prednisone, n = 64). Others were AA3 (n = 4), or AA status missing (n = 1). The day 28 CR/PR rates were similar for sirolimus 64.8% (90% confidence interval [CI], 54.1%-75.5%) vs 73% (90% CI, 63.8%-82.2%) for prednisone. The day 28 rate of CR/PR with prednisone ≤0.25 mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs 31.7%; P < .001). No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, nonrelapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2 to 3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy. For patients with clinical- and biomarker-based SR acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. In addition, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life. This trial was registered at www.clinicaltrials.gov as #NCT02806947.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Prednisona/uso terapêutico , Sirolimo/uso terapêutico , Doença Aguda , Adolescente , Adulto , Idoso , Antineoplásicos Hormonais , Transplante de Medula Óssea/efeitos adversos , Criança , Pré-Escolar , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/patologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
Cancer research has led to unprecedented advances in treatment in recent decades. Physician-scientists have played a crucial role in these advances given their unique perspective at the intersection between basic research and clinical care, though their representation in cancer research has been in progressive decline. Cancer research programs that feature strong mentorship at the medical student level are associated with increased likelihood of alumni choosing a cancer research career path. In an effort to increase the cancer research medical student training pipeline, senior research faculty from the Tisch Cancer Institute (TCI) at the Icahn School of Medicine at Mount Sinai (ISMMS) developed the TCI Scholars Program, a rigorous mentored research training program funding medical students' summer research. This program is currently in its third year and has garnered significant interest among mentors and students alike from all four TCI Cancer Center Support Grant (CCSG)-funded research programs. Herein, we describe the development, implementation, evaluation, and major outcomes of this program.
Assuntos
Pesquisa Biomédica , Neoplasias , Estudantes de Medicina , Academias e Institutos , Pesquisa Biomédica/educação , Docentes , Humanos , Mentores , Neoplasias/prevenção & controle , Avaliação de Programas e Projetos de SaúdeRESUMO
Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3α) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P = .004) and for Minnesota risk (0.72, P = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies.
Assuntos
Corticosteroides/uso terapêutico , Resistência a Medicamentos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Adolescente , Corticosteroides/farmacologia , Adulto , Idoso , Biomarcadores/sangue , Criança , Pré-Escolar , Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Pessoa de Meia-Idade , Proteínas Associadas a Pancreatite/sangue , Prognóstico , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor [EGF] receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.
Assuntos
Indutores da Angiogênese/sangue , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/terapia , Doença Aguda , Adulto , Idoso , Estudos de Casos e Controles , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus-host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab versus placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day -1 and day +20 after transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-α production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse in vivo and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at clinicaltrials.gov identifier: 01713400).
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Interleucina-12/antagonistas & inibidores , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Células Th1/imunologia , Células Th17/imunologia , Ustekinumab/administração & dosagem , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Ustekinumab/efeitos adversos , Adulto JovemRESUMO
A xenograft model of stem cell rejection was developed by co-transplantating human CD34+ and allogeneic CD3+ T cells into NOD-scid ɣ-chainnull mice. T cells caused graft failure when transplanted at any CD34/CD3 ratio between 1:50 and 1:.1. Kinetics experiments showed that 2 weeks after transplantation CD34+ cells engrafted the marrow and T cells expanded in the spleen. Then, at 4 weeks only memory T cells populated both sites and rejected CD34+ cells. Blockade of T cell costimulation was tested by injecting the mice with abatacept (CTLA4-IgG1) from day -1 to +27 (group A), from day -1 to +13 (group B), or from day +14 to +28 (group C). On day +56 groups B and C had rejected the graft, whereas in group A graft failure was completely prevented, although with lower stem cell engraftment than in controls (P = .03). Retransplantation of group A mice with same CD34+ cells obtained a complete reconstitution of human myeloid and B cell lineages and excluded latent alloreactivity. In this first xenograft model of stem cell rejection we showed that transplantation of HLA mismatched CD34+ cells may be facilitated by treatment with abatacept and late stem cell boost.
Assuntos
Abatacepte/farmacologia , Antígenos CD34 , Complexo CD3 , Rejeição de Enxerto/prevenção & controle , Linfócitos T/transplante , Abatacepte/administração & dosagem , Abatacepte/uso terapêutico , Animais , Rejeição de Enxerto/etiologia , Xenoenxertos , Humanos , Camundongos Endogâmicos NOD , Reoperação , Linfócitos T/imunologia , Fatores de TempoRESUMO
Interleukin (IL)-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces pro-inflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory graft-versus-host disease (GVHD) and mortality. However, whether sST2 has a role as an immune modulator or only as a biomarker during GVHD was unclear. We show increased IL-33 production by nonhematopoietic cells in the gastrointestinal (GI) tract in mice post-conditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and tumor necrosis factor-α production was significantly reduced in il33(-/-) recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2(-/-) vs wild-type (WT) donor T cells had a marked reduction in GVHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2(-/-) T cells, and linked to reduced interferon-γ production by st2(-/-) vs WT T cells during GVHD. Blockade of IL-33/ST2 interactions during allogeneic-hematopoietic cell transplantation by exogenous ST2-Fc infusions had a marked reduction in GVHD lethality, indicating a role of ST2 as a decoy receptor modulating GVHD. Together, these studies point to the IL-33/ST2 axis as a novel and potent target for GVHD therapy.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Interleucinas/metabolismo , Receptores de Superfície Celular/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Doença Aguda , Animais , Análise por Conglomerados , Modelos Animais de Doenças , Expressão Gênica , Perfilação da Expressão Gênica , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Interferon gama/biossíntese , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/genética , Mucosa Intestinal/metabolismo , Intestinos/patologia , Intestinos/efeitos da radiação , Isoantígenos/imunologia , Camundongos , Camundongos Knockout , Receptores de Superfície Celular/genética , Índice de Gravidade de Doença , Doadores de Tecidos , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
The coinhibitory receptor programmed death-1 (PD-1) maintains immune homeostasis by negatively regulating T cell function and survival. Blockade of PD-1 increases the severity of graft-versus-host disease (GVHD), but the interplay between PD-1 inhibition and T cell metabolism is not well studied. We found that both murine and human alloreactive T cells concomitantly upregulated PD-1 expression and increased levels of reactive oxygen species (ROS) following allogeneic bone marrow transplantation. This PD-1(Hi)ROS(Hi) phenotype was specific to alloreactive T cells and was not observed in syngeneic T cells during homeostatic proliferation. Blockade of PD-1 signaling decreased both mitochondrial H2O2 and total cellular ROS levels, and PD-1-driven increases in ROS were dependent upon the oxidation of fatty acids, because treatment with etomoxir nullified changes in ROS levels following PD-1 blockade. Downstream of PD-1, elevated ROS levels impaired T cell survival in a process reversed by antioxidants. Furthermore, PD-1-driven changes in ROS were fundamental to establishing a cell's susceptibility to subsequent metabolic inhibition, because blockade of PD-1 decreased the efficacy of later F1F0-ATP synthase modulation. These data indicate that PD-1 facilitates apoptosis in alloreactive T cells by increasing ROS in a process dependent upon the oxidation of fat. In addition, blockade of PD-1 undermines the potential for subsequent metabolic inhibition, an important consideration given the increasing use of anti-PD-1 therapies in the clinic.
Assuntos
Sobrevivência Celular , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos/imunologia , Apoptose/genética , Apoptose/imunologia , Transplante de Medula Óssea/efeitos adversos , Sobrevivência Celular/genética , Ácidos Graxos/metabolismo , Feminino , Expressão Gênica , Doença Enxerto-Hospedeiro/etiologia , Xenoenxertos , Humanos , Camundongos , Camundongos Transgênicos , Oxirredução , Fenótipo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doença Aguda , Aloenxertos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: No plasma biomarkers are associated with the response of acute graft-versus-host disease (GVHD) to therapy after allogeneic hematopoietic stem-cell transplantation. METHODS: We compared 12 biomarkers in plasma obtained a median of 16 days after therapy initiation from 10 patients with a complete response by day 28 after therapy initiation and in plasma obtained from 10 patients with progressive GVHD during therapy. The lead biomarker, suppression of tumorigenicity 2 (ST2), was measured at the beginning of treatment for GVHD in plasma from 381 patients and during the first month after transplantation in three independent sets totaling 673 patients to determine the association of this biomarker with treatment-resistant GVHD and 6-month mortality after treatment or transplantation. RESULTS: Of the 12 markers, ST2 had the most significant association with resistance to GVHD therapy and subsequent death without relapse. As compared with patients with low ST2 values at therapy initiation, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within 6 months after therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GVHD grade (11% vs. 31% among patients with grade I or II GVHD and 14% vs. 67% among patients with grade III or IV GVHD, P<0.001 for both comparisons). Plasma ST2 values at day 14 after transplantation were associated with 6-month mortality without relapse, regardless of the intensity of the conditioning regimen. CONCLUSIONS: ST2 levels measured at the initiation of therapy for GVHD and during the first month after transplantation improved risk stratification for treatment-resistant GVHD and death without relapse after transplantation. (Funded by the National Institutes of Health.)
Assuntos
Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Receptores de Superfície Celular/sangue , Medição de Risco/métodos , Biomarcadores/sangue , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Transplante HomólogoRESUMO
There are no validated biomarkers for chronic GVHD (cGVHD). We used a protein microarray and subsequent sequential enzyme-linked immunosorbent assay to compare 17 patients with treatment-refractory de novo-onset cGVHD and 18 time-matched control patients without acute or chronic GVHD to identify 5 candidate proteins that distinguished cGVHD from no cGVHD: CXCL9, IL2Rα, elafin, CD13, and BAFF. We then assessed the discriminatory value of each protein individually and in composite panels in a validation cohort (n = 109). CXCL9 was found to have the highest discriminatory value with an area under the receiver operating characteristic curve of 0.83 (95% confidence interval, 0.74-0.91). CXCL9 plasma concentrations above the median were associated with a higher frequency of cGVHD even after adjustment for other factors related to developing cGVHD including age, diagnosis, donor source, and degree of HLA matching (71% vs 20%; P < .001). A separate validation cohort from a different transplant center (n = 211) confirmed that CXCL9 plasma concentrations above the median were associated with more frequent newly diagnosed cGVHD after adjusting for the aforementioned factors (84% vs 60%; P = .001). Our results confirm that CXCL9 is elevated in patients with newly diagnosed cGVHD.
Assuntos
Quimiocina CXCL9/sangue , Doença Enxerto-Hospedeiro/sangue , Adulto , Doença Crônica , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , Terapia de Imunossupressão , Pessoa de Meia-IdadeRESUMO
For several decades, it has been known that T-cell activation in vitro leads to increased glycolytic metabolism that fuels proliferation and effector function. Recently, this simple model has been complicated by the observation that different T-cell subsets differentially regulate fundamental metabolic pathways under the control of distinct molecular regulators. Although the majority of these data have been generated in vitro, several recent studies have documented the metabolism of T cells activated in vivo. Here, we review the recent data surrounding the differential regulation of metabolism by distinct T-cell subsets in vitro and in vivo and discuss how differential metabolic regulation might facilitate T-cell function vis-à-vis proliferation, survival, and energy production. We further discuss the important therapeutic implications of differential metabolism across T-cell subsets and review recent successes in exploiting lymphocyte metabolism to treat immune-mediated diseases.
Assuntos
Imunomodulação , Ativação Linfocitária , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Metabolismo Energético , Glicólise , Humanos , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Espécies Reativas de Oxigênio/metabolismoRESUMO
To develop a novel acute graft-versus-host disease (GVHD) risk score, we examined the GVHD clinical stage and grade of 1723 patients at the onset of treatment with systemic steroids. Using clinical grouping, descriptive statistics and recursive partitioning, we identified poorly responsive, high-risk (HR) acute GVHD by the number of involved organs and severity of GVHD at onset. The overall response (complete response/partial response) rate 28 days after initiation of steroid therapy for acute GVHD was lower in the 269 patients with HR-GVHD than in the 1454 patients with standard risk (SR)-GVHD (44% [95% confidence interval (CI) 38% to 50%] versus 68% [95% CI, 66% to 70%], P < .001). Patients with HR-GVHD were less likely to respond at day 28 (odds ratio [OR], .3; 95% CI, .2 to .4; P < .001) and had higher risks of mortality (relative risk, 2.1; 95% CI, 1.7 to 2.6; P < .001) and transplant-related mortality (relative risk, 2.5; 95% CI, 2.0% to 3.2%, P < .001) than patients with SR-GVHD. This refined definition of acute GVHD risk is a better predictor of response, survival, and transplant-related mortality than other published acute GVHD risk scores. Patients with HR-GVHD are candidates for studies investigating new treatment approaches. Likewise, patients with SR-GVHD are candidates for studies investigating less toxic therapy.
Assuntos
Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco , Doença Aguda , Adolescente , Adulto , Idoso , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de SobrevidaRESUMO
Acute graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is an often lethal complication of allogeneic hematopoietic cell transplant. Clinical severity correlates with outcomes, but histopathologic grading is primarily used to confirm the clinical diagnosis. One barrier to using histopathologic grading to predict clinical outcomes is inter-grader variability among transplant centers. Recent experimental models have shown that the loss of Paneth cells, which are located in the small intestine and help regulate the GI microbiome by secreting antimicrobial peptides, correlates with clinical GVHD severity. Because Paneth cells are easy to identify and quantify by light microscopy, we evaluated the mean number of Paneth cells per high-powered field (hpf) in 116 duodenal biopsies obtained at diagnosis of GI GVHD at 2 different centers with their clinical outcomes. Paneth cell counts were reproducible between centers (r(2) = 0.81; P < .0001). Lower numbers of Paneth cells at diagnosis correlated with clinically more severe GI GVHD (P < .0001) and less likelihood of response to GVHD treatment (P < .0001). A threshold of 4 Paneth cells per hpf stratified patients according to nonrelapse mortality (28% vs 56%; P = .004). We conclude that the enumeration of duodenal Paneth cells is a readily available index of disease severity that provides important information regarding GVHD prognosis.
Assuntos
Trato Gastrointestinal/patologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Celulas de Paneth/citologia , Adolescente , Adulto , Idoso , Biópsia , Criança , Duodeno/patologia , Doença Enxerto-Hospedeiro/mortalidade , Antígenos HLA/metabolismo , Humanos , Pessoa de Meia-Idade , Prognóstico , Recidiva , Fatores de Risco , Condicionamento Pré-Transplante , Resultado do Tratamento , Adulto JovemRESUMO
Activated T cells require increased energy to proliferate and mediate effector functions, but the metabolic changes that occur in T cells following stimulation in vivo are poorly understood, particularly in the context of inflammation. We have previously shown that T cells activated during graft-versus-host disease (GVHD) primarily rely on oxidative phosphorylation to synthesize adenosine 5'-triphosphate. Here, we demonstrate that alloreactive effector T cells (Teff) use fatty acids (FAs) as a fuel source to support their in vivo activation. Alloreactive T cells increased FA transport, elevated levels of FA oxidation enzymes, up-regulated transcriptional coactivators to drive oxidative metabolism, and increased their rates of FA oxidation. Importantly, increases in FA transport and up-regulation of FA oxidation machinery occurred specifically in T cells during GVHD and were not seen in Teff following acute activation. Pharmacological blockade of FA oxidation decreased the survival of alloreactive T cells but did not influence the survival of T cells during normal immune reconstitution. These studies suggest that pathways controlling FA metabolism might serve as therapeutic targets to treat GVHD and other T-cell-mediated immune diseases.
Assuntos
Ácidos Graxos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Western Blotting , Transplante de Medula Óssea/métodos , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/imunologia , Carnitina O-Palmitoiltransferase/metabolismo , Inibidores Enzimáticos/farmacologia , Compostos de Epóxi/farmacologia , Ácidos Graxos/metabolismo , Feminino , Citometria de Fluxo , Doença Enxerto-Hospedeiro/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Oxirredução , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Transplante HomólogoRESUMO
BACKGROUND: Acute graft-versus-host disease (GVHD) remains a barrier to more widespread application of allogeneic haemopoietic stem-cell transplantation. Vorinostat is an inhibitor of histone deacetylases and was shown to attenuate GVHD in preclinical models. We aimed to study the safety and activity of vorinostat, in combination with standard immunoprophylaxis, for prevention of GVHD in patients undergoing related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation. METHODS: Between March 31, 2009, and Feb 8, 2013, we did a prospective, single-arm, phase 1/2 study at two centres in the USA. We recruited adults (aged ≥18 years) with high-risk haematological malignant diseases who were candidates for reduced-intensity conditioning haemopoietic stem-cell transplantation and had an available 8/8 or 7/8 HLA-matched related donor. All patients received a conditioning regimen of fludarabine (40 mg/m(2) daily for 4 days) and busulfan (3.2 mg/kg daily for 2 days) and GVHD immunoprophylaxis of mycophenolate mofetil (1 g three times a day, days 0-28) and tacrolimus (0.03 mg/kg a day, titrated to a goal level of 8-12 ng/mL, starting day -3 until day 180). Vorinostat (either 100 mg or 200 mg, twice a day) was initiated 10 days before haemopoietic stem-cell transplantation until day 100. The primary endpoint was the cumulative incidence of grade 2-4 acute GVHD by day 100. This trial is registered with ClinicalTrials.gov, number NCT00810602. FINDINGS: 50 patients were assessable for both toxic effects and response; eight additional patients were included in the analysis of toxic effects. All patients engrafted neutrophils and platelets at expected times after haemopoietic stem-cell transplantation. The cumulative incidence of grade 2-4 acute GVHD by day 100 was 22% (95% CI 13-36). The most common non-haematological adverse events included electrolyte disturbances (n=15), hyperglycaemia (11), infections (six), mucositis (four), and increased activity of liver enzymes (three). Non-symptomatic thrombocytopenia after engraftment was the most common haematological grade 3-4 adverse event (nine) but was transient and all cases resolved swiftly. INTERPRETATION: Administration of vorinostat in combination with standard GVHD prophylaxis after related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation is safe and is associated with a lower than expected incidence of severe acute GVHD. Future studies are needed to assess the effect of vorinostat for prevention of GVHD in broader settings of haemopoietic stem-cell transplantation. FUNDING: Merck, Leukemia and Lymphoma Society, National Institutes of Health, St Baldrick's Foundation, Michigan Institute for Clinical and Health Research.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Inibidores de Histona Desacetilases/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Imunossupressores/administração & dosagem , Ácido Micofenólico/análogos & derivados , Tacrolimo/administração & dosagem , Condicionamento Pré-Transplante , Doença Aguda , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Estudos Prospectivos , Transplante Homólogo , VorinostatRESUMO
Outcomes of hematopoietic cell transplantation continue to improve. New techniques have reduced transplant toxicities, and there are new sources of hematopoietic stem cells from related and unrelated donors. In June 2007, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) convened a State of the Science Symposium (SOSS) in Ann Arbor and identified 11 high priority clinical trials for the network to pursue. This article reviews both the status of those trials and the record of achievement of the BMT CTN as it convenes another SOSS in Grapevine, Texas in February 2014.
Assuntos
Transplante de Medula Óssea/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Ensaios Clínicos como Assunto , Feminino , História do Século XXI , Humanos , Masculino , Resultado do TratamentoRESUMO
Engraftment syndrome (ES), characterized by fever, rash, pulmonary edema, weight gain, liver and renal dysfunction, and/or encephalopathy, occurs at the time of neutrophil recovery after hematopoietic cell transplantation (HCT). In this study, we evaluated the incidence, clinical features, risk factors, and outcomes of ES in children and adults undergoing first-time allogeneic HCT. Among 927 patients, 119 (13%) developed ES at a median of 10 days (interquartile range 9 to 12) after HCT. ES patients experienced significantly higher cumulative incidence of grade 2 to 4 acute GVHD at day 100 (75% versus 34%, P < .001) and higher nonrelapse mortality at 2 years (38% versus 19%, P < .001) compared with non-ES patients, resulting in lower overall survival at 2 years (38% versus 54%, P < .001). There was no significant difference in relapse at 2 years (26% versus 31%, P = .772). Suppression of tumorigenicity 2, interleukin 2 receptor alpha, and tumor necrosis factor receptor 1 plasma biomarker levels were significantly elevated in ES patients. Our results illustrate the clinical significance and prognostic impact of ES on allogeneic HCT outcomes. Despite early recognition of the syndrome and prompt institution of corticosteroid therapy, outcomes in ES patients were uniformly poor. This study suggests the need for a prospective approach of collecting clinical features combined with correlative laboratory analyses to better characterize ES.