RESUMEN
Maladaptive, non-resolving inflammation contributes to chronic inflammatory diseases such as atherosclerosis. Because macrophages remove necrotic cells, defective macrophage programs can promote chronic inflammation with persistent tissue injury. Here, we investigated the mechanisms sustaining vascular macrophages. Intravital imaging revealed a spatiotemporal macrophage niche across vascular beds alongside mural cells (MCs)-pericytes and smooth muscle cells. Single-cell transcriptomics, co-culture, and genetic deletion experiments revealed MC-derived expression of the chemokines CCL2 and MIF, which actively preserved macrophage survival and their homeostatic functions. In atherosclerosis, this positioned macrophages in viable plaque areas, away from the necrotic core, and maintained a homeostatic macrophage phenotype. Disruption of this MC-macrophage unit via MC-specific deletion of these chemokines triggered detrimental macrophage relocalizing, exacerbated plaque necrosis, inflammation, and atheroprogression. In line, CCL2 inhibition at advanced stages of atherosclerosis showed detrimental effects. This work presents a MC-driven safeguard toward maintaining the homeostatic vascular macrophage niche.
Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Humanos , Macrófagos/metabolismo , Aterosclerosis/metabolismo , Placa Aterosclerótica/metabolismo , Quimiocinas/metabolismo , Inflamación/metabolismo , Necrosis/metabolismoRESUMEN
Risk of hepatitis B virus (HBV) reactivation was assessed in B-cell non-Hodgkin lymphoma (NHL) patients with resolved HBV infection (hepatitis B surface antigen negative, hepatitis B core antibody positive) who received obinutuzumab- or rituximab-containing immunochemotherapy in the phase 3 GOYA and GALLIUM studies. HBV DNA monitoring was undertaken monthly to 1 year after the last dose of study drug. In case of HBV reactivation (confirmed, HBV DNA ≥29 IU/mL), immunochemotherapy was withheld and nucleos(t)ide analog treatment (preemptive NAT) started. Immunochemotherapy was restarted if HBV DNA became undetectable or reactivation was not confirmed, and discontinued if HBV DNA exceeded 100 IU/mL on NAT. Prophylactic NAT was allowed by investigator discretion. Among 326 patients with resolved HBV infection, 27 (8.2%) had HBV reactivation, occurring a median of 125 days (interquartile range, 85-331 days) after the first dose. In 232 patients without prophylactic NAT, 25 (10.8%) had HBV reactivation; all received preemptive NAT. Ninety-four patients received prophylactic NAT; 2 (2.1%) had HBV reactivation. No patients developed HBV-related hepatitis. On multivariate Cox analysis, detectable HBV DNA at baseline was strongly associated with an increased risk of reactivation (adjusted hazard ratio [HR], 18.22; 95% confidence interval [CI], 6.04-54.93; P < .0001). Prophylactic NAT was strongly associated with a reduced risk (adjusted HR, 0.09; 95% CI, 0.02-0.41; P = .0018). HBV DNA monitoring-guided preemptive NAT was effective in preventing HBV-related hepatitis during anti-CD20-containing immunochemotherapy in B-cell NHL patients with resolved HBV infection. Antiviral prophylaxis was also effective and may be appropriate for high-risk patients. These trials were registered at www.clinicaltrials.gov as NCT01287741 (GOYA) and NCT01332968 (GALLIUM).
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B/virología , Linfoma de Células B/tratamiento farmacológico , Rituximab/efectos adversos , Activación Viral/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/uso terapéutico , ADN Viral/genética , Femenino , Estudios de Seguimiento , Hepatitis B/inducido químicamente , Hepatitis B/tratamiento farmacológico , Virus de la Hepatitis B/genética , Humanos , Inmunoterapia/efectos adversos , Linfoma de Células B/inmunología , Linfoma de Células B/virología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios ProspectivosRESUMEN
BACKGROUND: Patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for autologous stem-cell transplantation have poor outcomes and few treatment options. Tafasitamab (MOR208) is an Fc-enhanced, humanised, anti-CD19 monoclonal antibody that has shown preclinical and single-agent activity in patients with relapsed or refractory B-cell malignancies. Preclinical data suggested that tafasitamab might act synergistically with lenalidomide. We aimed to assess the antitumour activity and safety of tafasitamab plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for autologous stem-cell transplantation. METHODS: In this multicentre, open-label, single-arm, phase 2 study (L-MIND), patients older than 18 years with histologically confirmed diffuse large B-cell lymphoma, who relapsed or had refractory disease after previous treatment with one to three systemic regimens (with at least one anti-CD20 therapy), were not candidates for high-dose chemotherapy and subsequent autologous stem-cell transplantation, had an Eastern Cooperative Oncology Group performance status of 0-2, and had measurable disease at baseline were recruited from 35 academic and community hospitals in ten countries. Patients received coadministered intravenous tafasitamab (12 mg/kg) and oral lenalidomide (25 mg/day) for up to 12 cycles (28 days each), followed by tafasitamab monotherapy (in patients with stable disease or better) until disease progression. The primary endpoint was the proportion of patients with an objective response (centrally assessed), defined as a complete or partial response according to the 2007 International Working Group response criteria for malignant lymphoma. Antitumour activity analyses are based on all patients who received at least one dose of both tafasitamab and lenalidomide; safety analyses are based on all patients who received at least one dose of either study medication. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, NCT02399085. FINDINGS: Between Jan 18, 2016, and Nov 15, 2017, 156 patients were screened: 81 were enrolled and received at least one dose of either study medication, and 80 received at least one dose of both tafasitamab and lenalidomide. Median follow-up was 13·2 months (IQR 7·3-20·4) as of data cutoff on Nov 30, 2018. 48 (60%; 95% CI 48-71) of 80 patients who received tafasitamab plus lenalidomide had an objective response: 34 (43%; 32-54) had a complete response and 14 (18%; 10-28) had a partial response. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (39 [48%] of 81 patients), thrombocytopenia (14 [17%]), and febrile neutropenia (ten [12%]). Serious adverse events occurred in 41 (51%) of 81 patients. The most frequently reported serious adverse events (in two or more patients) were pneumonia (five [6%]), febrile neutropenia (five [6%]), pulmonary embolism (three [4%]), bronchitis (two [2%]), atrial fibrillation (two [2%]), and congestive cardiac failure (two [2%]). INTERPRETATION: Tafasitamab in combination with lenalidomide was well tolerated and resulted in a high proportion of patients with relapsed or refractory diffuse large B-cell lymphoma ineligible for autologous stem-cell transplantation having a complete response, and might represent a new therapeutic option in this setting. FUNDING: MorphoSys.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lenalidomida/administración & dosificación , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Rituximab-based immunochemotherapy has improved outcomes in patients with follicular lymphoma. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody. We compared rituximab-based chemotherapy with obinutuzumab-based chemotherapy in patients with previously untreated advanced-stage follicular lymphoma. METHODS: We randomly assigned patients to undergo induction treatment with obinutuzumab-based chemotherapy or rituximab-based chemotherapy. Patients with a response received maintenance treatment for up to 2 years with the same antibody that they had received in induction. The primary end point was investigator-assessed progression-free survival. RESULTS: A total of 1202 patients with follicular lymphoma underwent randomization (601 patients in each group). After a median follow-up of 34.5 months (range, 0 to 54.5), a planned interim analysis showed that obinutuzumab-based chemotherapy resulted in a significantly lower risk of progression, relapse, or death than rituximab-based chemotherapy (estimated 3-year rate of progression-free survival, 80.0% vs. 73.3%; hazard ratio for progression, relapse, or death, 0.66; 95% confidence interval [CI], 0.51 to 0.85; P=0.001). Similar results were seen with regard to independently reviewed progression-free survival and other time-to-event end points. Response rates were similar in the two groups (88.5% in the obinutuzumab group and 86.9% in the rituximab group). Adverse events of grade 3 to 5 were more frequent in the obinutuzumab group than in the rituximab group (74.6% vs. 67.8%), as were serious adverse events (46.1% vs. 39.9%). The rates of adverse events resulting in death were similar in the two groups (4.0% in the obinutuzumab group and 3.4% in the rituximab group). The most common adverse events were infusion-related events that were considered by the investigators to be largely due to obinutuzumab in 353 of 595 patients (59.3%; 95% CI, 55.3 to 63.2) and to rituximab in 292 of 597 patients (48.9%; 95% CI, 44.9 to 52.9; P<0.001). Nausea and neutropenia were common. A total of 35 patients (5.8%) in the obinutuzumab group and 46 (7.7%) in the rituximab group died. CONCLUSIONS: Obinutuzumab-based immunochemotherapy and maintenance therapy resulted in longer progression-free survival than rituximab-based therapy. High-grade adverse events were more common with obinutuzumab-based chemotherapy. (Funded by F. Hoffmann-La Roche; GALLIUM ClinicalTrials.gov number, NCT01332968 .).
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Linfoma Folicular/tratamiento farmacológico , Rituximab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Leucopenia/inducido químicamente , Linfoma Folicular/mortalidad , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Rituximab/efectos adversosRESUMEN
Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naïve patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD- rates between arms, the log of the PFS hazard ratio decreased by -0.188 (95% confidence interval, -0.321 to -0.055; P = .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action.
Asunto(s)
Inmunoterapia , Leucemia Linfocítica Crónica de Células B , Modelos Biológicos , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/terapia , Masculino , Neoplasia Residual , Tasa de SupervivenciaRESUMEN
Diffuse large B-cell lymphoma represents a biologically and clinically heterogeneous diagnostic category with well-defined cell-of-origin subtypes. Using data from the GOYA study (NCT01287741), we characterized the mutational profile of diffuse large B-cell lymphoma and evaluated the prognostic impact of somatic mutations in relation to cell-of-origin. Targeted DNA next-generation sequencing was performed in 499 formalin-fixed paraffin-embedded tissue biopsies from previously untreated patients. Prevalence of genetic alterations/mutations was examined. Multivariate Cox regression was used to evaluate the prognostic effect of individual genomic alterations. Of 465 genes analyzed, 59 were identified with mutations occurring in at least 10 of 499 patients (≥2% prevalence); 334 additional genes had mutations occurring in ≥1 patient. Single nucleotide variants were the most common mutation type. On multivariate analysis, BCL2 alterations were most strongly associated with shorter progression-free survival (multivariate hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2). BCL2 alterations were detected in 102 of 499 patients; 92 had BCL2 translocations, 90% of whom had germinal center B-cell-like diffuse large B-cell lymphoma. BCL2 alterations were also significantly correlated with BCL2 gene and protein expression levels. Validation of published mutational subsets revealed consistent patterns of co-occurrence, but no consistent prognostic differences between subsets. Our data confirm the molecular heterogeneity of diffuse large B-cell lymphoma, with potential treatment targets occurring in distinct cell-of-origin subtypes. clinicaltrials.gov identifier: NCT01287741.
Asunto(s)
Linfoma de Células B Grandes Difuso , Proteínas Proto-Oncogénicas c-myc , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Mutación , Prednisona/uso terapéutico , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Rituximab/uso terapéutico , Vincristina/uso terapéuticoRESUMEN
Macrophage migration inhibitory factor (MIF) is pleiotropic cytokine that has multiple effects in many inflammatory and immune diseases. This study reveals a potential role of MIF in acute kidney injury (AKI) in patients and in kidney ischemic reperfusion injury (IRI) mouse model in MIF wild-type (WT) and MIF knockout (KO) mice. Clinically, plasma and urinary MIF levels were largely elevated at the onset of AKI, declined to normal levels when AKI was resolved and correlated tightly with serum creatinine independent of disease causes. Experimentally, MIF levels in plasma and urine were rapidly elevated after IRI-AKI and associated with the elevation of serum creatinine and the severity of tubular necrosis, which were suppressed in MIF KO mice. It was possible that MIF may mediate AKI via CD74/TLR4-NF-κB signalling as mice lacking MIF were protected from AKI by largely suppressing CD74/TLR-4-NF-κB associated renal inflammation, including the expression of MCP-1, TNF-α, IL-1ß, IL-6, iNOS, CXCL15(IL-8 in human) and infiltration of macrophages, neutrophil, and T cells. In conclusion, our study suggests that MIF may be pathogenic in AKI and levels of plasma and urinary MIF may correlate with the progression and regression of AKI.
Asunto(s)
Lesión Renal Aguda/sangre , Oxidorreductasas Intramoleculares/sangre , Riñón/patología , Factores Inhibidores de la Migración de Macrófagos/sangre , Daño por Reperfusión/sangre , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/orina , Adulto , Anciano , Animales , Antígenos de Diferenciación de Linfocitos B/metabolismo , Quimiocina CCL2/metabolismo , Creatinina/sangre , Citocinas/sangre , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/orina , Riñón/inmunología , Riñón/metabolismo , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/orina , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , FN-kappa B/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/orina , Receptor Toll-Like 4/metabolismoRESUMEN
AIMS: Rituximab is standard care in a number of lymphoma subtypes, including follicular lymphoma (FL), although many patients are resistant to rituximab, or develop resistance with repeated treatment, and a high proportion relapse. Obinutuzumab is a novel anti-CD20 monoclonal antibody with improved efficacy over rituximab. It is approved for previously untreated chronic lymphocytic leukaemia (CLL), and for use with bendamustine in patients with rituximab-relapsed/refractory FL. METHODS: Using a previously described population pharmacokinetic (PK) model of obinutuzumab in patients with non-Hodgkin lymphoma and CLL, we conducted an exposure-response analysis using data from 6 clinical trials in patients with CD20+ B-cell malignancies (CLL11, GADOLIN, GATHER, GAUDI, GAUGUIN and GAUSS) to describe the PK properties of obinutuzumab, identify covariates influencing exposure, and explore how exposure affects safety, efficacy and pharmacodynamics. RESULTS: A 2-compartment model with linear and time-dependent clearance described obinutuzumab PK. Disease type and subtype, body weight, baseline tumour size, and sex had the largest effects on PK. Obinutuzumab exposure was not associated with occurrence or severity of adverse events, but higher exposure appeared to be associated with greater efficacy, particularly longer progression-free survival. However, in multivariate Cox regression analysis, progression-free survival benefit in the obinutuzumab plus bendamustine arm was independent of exposure. CONCLUSION: The updated population PK model reported here accurately describes the PK of obinutuzumab patients with non-Hodgkin lymphoma and CLL. The selected obinutuzumab dosing regimen offers clinical benefit in a majority of rituximab-refractory FL patients treated with bendamustine, irrespective of variability in exposure, whilst minimising adverse events.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos Inmunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Linfoma Folicular/tratamiento farmacológico , Modelos Biológicos , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorhidrato de Bendamustina/farmacología , Clorhidrato de Bendamustina/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Linfoma Folicular/mortalidad , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Rituximab/farmacología , Rituximab/uso terapéuticoRESUMEN
AIMS: Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (CmeanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial. METHODS: Individual exposures (CmeanIND ) were obtained from a previously established population pharmacokinetic model updated with GALLIUM data. Multivariate Cox proportional hazard models and univariate Kaplan-Meier plots investigated relationships of PFS with exposure and other potential prognostic factors. RESULTS: Overall, G exposure was lower in high body-weight patients and in males, and slightly lower in patients with high baseline tumour burden. Analysis of clinical outcomes showed that variability in G exposure did not impact PFS in G-bendamustine-treated patients; PFS was inferior in males and patients with FCGR2a/2b T232 T low-affinity receptor variant, and superior in patients with FCGR2a/2b I232T variant. In G-CHOP/CVP arms, PFS improved with increasing CmeanIND (hazard ratio = 1.74 and 0.394 at 5th and 95th percentile compared to median CmeanIND ) and was inferior in patients with high baseline tumour size and B symptoms. CONCLUSIONS: It remains unclear whether for G-CHOP/CVP patients lower G exposure is a consequence of adverse disease biology and/or resistance to chemotherapy backbone (higher clearance in nonresponder patients, as demonstrated for rituximab) rather than being the cause of poorer clinical outcome. A study with >1 dose level of G could help resolve this uncertainty.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Linfoma Folicular/tratamiento farmacológico , Modelos Biológicos , Anticuerpos Monoclonales Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Clorhidrato de Bendamustina/administración & dosificación , Peso Corporal , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Resistencia a Antineoplásicos , Femenino , Humanos , Linfoma Folicular/patología , Masculino , Prednisona/administración & dosificación , Supervivencia sin Progresión , Factores Sexuales , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
In CLL, progressive disease (PD) following remission after first line treatment can present with varying phenotypes. We hypothesized that the mode of PD correlates with clinical outcomes. Data from three phase III trials of the German CLL Study Group (GCLLSG) (CLL8, CLL10, CLL11) including a total of 2159 patients receiving first line (immuno)-chemotherapy (FCR, FC, CLB, CLB-R, CLB-Ob) were analyzed. Patients were categorized as "ALC" if PD was due to increasing absolute lymphocyte count, or as "Ly" if due to lymphadenopathy. A group of 241 patients progressed with ALC, and 727 progressed with Ly, including 329 who progressed on both modalities. In fit patients, median TTNT after PD in the Ly group was 12.3 months vs 17.0 months in the ALC group (HR 1.299 [1.036-1.628]; P = .024). Median OS after PD was 45.1 months in the Ly group and 42.4 months in the ALC group (HR=1.023 [0.753-1.389]; P = .885). For unfit patients, median TTNT in the Ly group was 11.7 months vs 21.4 months in the ALC group (HR 1.357 [1.051-1.753]; P = .019). Median OS was 42.8 months in the Ly group and not reached in the ALC group (HR 1.851 [1.280-2.677]; P = .001). Patients in the Ly group more frequently showed impairment of quality of life (QoL). This analysis demonstrates that patients with progressive lymphadenopathy have a significantly shorter TTNT, OS and less favorable QoL. Our findings might help physicians to better estimate the clinical course of a progressing CLL patient.
Asunto(s)
Inmunoterapia , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/terapia , Anciano , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Macrophage migration inhibitory factor (MIF) is elevated in patients with acute kidney injury (AKI) and is suggested as a potential predictor for renal replacement therapy in AKI. In this study, we found that MIF also plays a pathogenic role and is a therapeutic target for AKI. In a cisplatin-induced AKI mouse model, elevated plasma MIF correlated with increased serum creatinine and the severity of renal inflammation and tubular necrosis, whereas deletion of MIF protected the kidney from cisplatin-induced AKI by largely improving renal functional and histological injury, and suppressing renal inflammation including upregulation of cytokines such as interleukin (IL)-1ß, tumor necrosis factor-alpha (TNF-α), IL-6, inducible nitric oxide synthase (iNOS), MCP-1, IL-8, and infiltration of macrophages, neutrophils, and T cells. We next developed a novel therapeutic strategy for AKI by blocking the endogenous MIF with an MIF inhibitor, ribosomal protein S19 (RPS19). Similar to the MIF-knockout mice, treatment with RPS19, but not the mutant RPS19, suppressed cisplatin-induced AKI. Mechanistically, we found that both genetic knockout and pharmacological inhibition of MIF protected against AKI by inactivating the CD74-nuclear factor κB (NF-κB) signaling. In conclusion, MIF is pathogenic in cisplatin-induced AKI. Targeting MIF with an MIF inhibitor RPS19 could be a promising therapeutic potential for AKI.
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Lesión Renal Aguda/terapia , Inflamación/terapia , Oxidorreductasas Intramoleculares/genética , Factores Inhibidores de la Migración de Macrófagos/genética , Proteínas Ribosómicas/administración & dosificación , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Animales , Antígenos de Diferenciación de Linfocitos B/genética , Apoptosis/efectos de los fármacos , Cisplatino/efectos adversos , Terapia Genética , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/patología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Riñón/efectos de los fármacos , Riñón/patología , Factores Inhibidores de la Migración de Macrófagos/antagonistas & inhibidores , Ratones , Ratones Noqueados , FN-kappa B/genética , Necrosis , Proteínas Ribosómicas/genética , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study. METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968. FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, p<0·0001). According to Lugano 2014 criteria, 2·5-year progression-free survival in complete metabolic responders was 87·4% (95% CI 83·7-90·2) and in non-complete metabolic responders was 54·9% (40·5-67·3; HR 0·2, 95% CI 0·1-0·3, p<0·0001). INTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed. FUNDING: F Hoffmann-La Roche.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoterapia/métodos , Linfoma Folicular/diagnóstico por imagen , Linfoma Folicular/terapia , Tomografía de Emisión de Positrones , Rituximab/administración & dosificación , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Inmunoterapia/efectos adversos , Linfoma Folicular/inmunología , Linfoma Folicular/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Rituximab/efectos adversos , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Patients with indolent non-Hodgkin lymphoma who fail to achieve adequate disease control with rituximab-based treatment have few treatment options and a poor prognosis. We aimed to assess a combination of obinutuzumab (GA101), a novel glyco-engineered type II anti-CD20 monoclonal antibody, and bendamustine in this patient population. METHODS: In this open-label, randomised, phase 3 study (GADOLIN), patients aged 18 years or older with histologically documented, CD20-positive indolent non-Hodgkin lymphoma refractory to rituximab were enrolled at 83 hospital and community sites in 14 countries in Europe, Asia, and North and Central America. Patients were randomly assigned (1:1) using a hierarchical dynamic randomisation scheme stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographical region, to receive induction treatment (six 28-day cycles) with obinutuzumab plus bendamustine or bendamustine monotherapy, both given intravenously. Obinutuzumab plus bendamustine dosing was obinutuzumab 1000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2-6) plus bendamustine 90 mg/m(2) per day (days 1 and 2, cycles 1-6), and bendamustine monotherapy dosing was 120 mg/m(2) per day (days 1 and 2, all cycles). Non-progressing patients in the obinutuzumab plus bendamustine group received obinutuzumab maintenance (1000 mg every 2 months) for up to 2 years. The primary endpoint was progression-free survival in all randomised patients, as assessed by an independent review committee. Safety was assessed in all patients who received any amount of obinutuzumab or bendamustine. This study is registered with ClinicalTrials.gov, number NCT01059630, and has stopped recruiting patients. FINDINGS: Between April 15, 2010, and Sept 1, 2014, when the study was stopped after a pre-planned interim analysis, 396 patients were randomly assigned (194 to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy). After a median follow-up time of 21·9 months (IQR 12·1-31·0) in the obinutuzumab plus bendamustine group and 20·3 months (9·5-29·7) in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached [95% CI 22·5 months-not estimable]) than with bendamustine monotherapy (14·9 months [12·8-16·6]; hazard ratio 0·55 [95% CI 0·40-0·74]; p=0·0001). Grade 3-5 adverse events occurred in 132 (68%) of 194 patients in the obinutuzumab plus bendamustine group and in 123 (62%) of 198 patients in the bendamustine monotherapy group. The most frequent grade 3 or worse adverse events were neutropenia (64 [33%] in the obinutuzumab plus bendamustine group vs 52 [26%] in the bendamustine monotherapy group), thrombocytopenia (21 [11%] vs 32 [16%]), anaemia (15 [8%] vs 20 [10%]) and infusion-related reactions (21 [11%] vs 11 [6%]). Serious adverse events occurred in 74 patients (38%) in the obinutuzumab plus bendamustine group and in 65 patients (33%) in the bendamustine monotherapy group, and deaths due to adverse events occurred in 12 patients (6%) and 12 patients (6%), respectively. Three (25%) of 12 adverse event-related deaths in the obinutuzumab plus bendamustine group and five (42%) of 12 in the bendamustine monotherapy group were treatment related. INTERPRETATION: Obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy in rituximab-refractory patients with indolent non-Hodgkin lymphoma, with manageable toxicity, and is a new treatment option for patients who have relapsed after or are no longer responding to rituximab-based therapy. FUNDING: F Hoffmann-La Roche Ltd.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Linfoma no Hodgkin/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Clorhidrato de Bendamustina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Rituximab/administración & dosificación , Tasa de SupervivenciaAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorambucilo/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Rituximab/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Comorbilidad , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/epidemiología , Persona de Mediana Edad , Neoplasia Residual/diagnóstico , Neoplasia Residual/epidemiología , Pronóstico , Estudios ProspectivosRESUMEN
Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, ß2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Mutación , Fosfoproteínas/genética , Receptor Notch1/genética , Ribonucleoproteína Nuclear Pequeña U2/genética , Proteína p53 Supresora de Tumor/genética , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antimetabolitos/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Empalme de ARN , Rituximab , Análisis de Supervivencia , Resultado del Tratamiento , Vidarabina/uso terapéuticoRESUMEN
The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity, which contributes to the biological functional activity of MIF. In this study, we investigated the effects of blocking the hydrophobic active site of the tautomerase activity of MIF in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumor growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (Mif (P1G)). Primary tumor growth was significantly attenuated in both Mif-KO and Mif (P1G) mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for the tautomerase enzymatic active site of MIF. From primary and secondary screens, the inhibitor SCD-19 was identified, which significantly attenuated the tautomerase enzymatic activity of MIF in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumor inoculation, was found to significantly reduce primary tumor volume by 90% (p < 0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumor was palpable (at d 7 after tumor inoculation) and, again, treatment was found to significantly reduce tumor volume by 81% (p < 0.001) compared with the control treatment. In this report, we identify a novel inhibitor that blocks the hydrophobic pocket of MIF, which houses its specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in vivo systems.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Isocumarinas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Factores Inhibidores de la Migración de Macrófagos/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Línea Celular , Dinoprostona/metabolismo , Femenino , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/metabolismo , Isocumarinas/farmacología , Lipopolisacáridos , Pulmón/efectos de los fármacos , Pulmón/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Carga Tumoral/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The cell-surface glycoprotein CD44 is expressed in chronic lymphocytic leukemia (CLL), but its functional role in this disease is poorly characterized. We therefore investigated the contribution of CD44 to CLL in a murine disease model, the Eµ-TCL1 transgenic mouse, and in CLL patients. Surface CD44 increased during murine CLL development. CD44 expression in human CLL was induced by stimulation with interleukin 4/soluble CD40 ligand and by stroma cell contact. Engagement of CD44 by its natural ligands, hyaluronic acid or chondroitin sulfate, protected CLL cells from apoptosis, while anti-CD44 small interfering RNAs impaired tumor cell viability. Deletion of CD44 during TCL1-driven murine leukemogenesis reduced the tumor burden in peripheral blood and spleen and led to a prolonged overall survival. The leukemic cells from these CD44 knockout animals revealed lower levels of antiapoptotic MCL1, a higher propensity to apoptosis, and a diminished B-cell receptor kinase response. The inhibitory anti-CD44 antibodies IM7 and A3D8 impaired the viability of CLL cells in suspension cultures, in stroma contact models, and in vivo via MCL1 reduction and by effector caspase activation. Taken together, CD44 expression in CLL is mediated by the tumor microenvironment. As a coreceptor, CD44 promotes leukemogenesis by regulating stimuli of MCL1 expression. Moreover, CD44 can be addressed therapeutically in CLL by specific antibodies.
Asunto(s)
Apoptosis/genética , Transformación Celular Neoplásica/genética , Receptores de Hialuranos/fisiología , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Animales , Células Cultivadas , Progresión de la Enfermedad , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologíaRESUMEN
UNLABELLED: Survival of chronic lymphocytic leukemia (CLL) cells depends on stimuli provided by a suitable microenvironment. The factors and mechanisms providing this growth support for CLL cells are not fully understood. We found that plasma levels of macrophage migration inhibitory factor (MIF), a proinflammatory and immunoregulatory chemokine, were elevated in CLL patients. Therefore, we characterized the functional role of MIF in a CLL mouse model. For this purpose, we crossed Eµ-TCL1 mice with MIF knockout (MIF-/-) mice. The resulting TCL1+/wtMIF/ mice showed a delayed onset of leukemia, reduced splenomegaly and hepatomegaly, and a longer survival than TCL1+/wtMIFwt/wt controls. Immunohistochemical examination of the lymphoid organs showed that the numbers of macrophages were significantly reduced in the spleen and bone marrow of TCL1+/wtMIF/ mice compared with TCL1+/wtMIFwt/wt controls. Mechanistic studies in vitro revealed that the absence of MIF rendered CLL cells more susceptible to apoptosis. Accordingly, incubation with an anti-MIF antibody reduced the survival of CLL cells on a macrophage feeder layer. In addition, the migratory activity of TCL1+/wtMIF/ macrophages was decreased compared with TCL1+/wtMIFwt/wt macrophages. Taken together, our results provide evidence that MIF supports the development of CLL by enhancing the interaction of CLL cells with macrophages. KEY POINTS: Targeted deletion of the gene for macrophage migration inhibitory factor (MIF) delays development of chronic lymphocytic leukemia and prolongs survival in mice. MIF recruits leukemia-associated macrophages to spleen or liver.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Comunicación Celular/inmunología , Oxidorreductasas Intramoleculares/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Factores Inhibidores de la Migración de Macrófagos/inmunología , Macrófagos/inmunología , Animales , Linfocitos T CD8-positivos/patología , Supervivencia Celular , Células Nutrientes , Humanos , Oxidorreductasas Intramoleculares/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Factores Inhibidores de la Migración de Macrófagos/genética , Macrófagos/patología , Ratones , Ratones Noqueados , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patología , Células Tumorales CultivadasRESUMEN
Macrophage migration inhibitory factor (MIF) enhances activation of leukocytes, endothelial cells and fibroblast-like synoviocytes (FLS), thereby contributing to the pathogenesis of rheumatoid arthritis (RA). A MIF promoter polymorphism in RA patients resulted in higher serum MIF concentration and worsens bone erosion; controversially current literature reported an inhibitory role of MIF in osteoclast formation. The controversial suggested that the precise role of MIF and its putative receptor CD74 in osteoclastogenesis and RA bone erosion, mediated by locally formed osteoclasts in response to receptor activator of NF-κB ligand (RANKL), is unclear. We reported that in an in vivo K/BxN serum transfer arthritis, reduced clinical and histological arthritis in MIF(-/-) and CD74(-/-) mice were accompanied by a virtual absence of osteoclasts at the synovium-bone interface and reduced osteoclast-related gene expression. Furthermore, in vitro osteoclast formation and osteoclast-related gene expression were significantly reduced in MIF(-/-) cells via decreasing RANKL-induced phosphorylation of NF-κB-p65 and ERK1/2. This was supported by a similar reduction of osteoclastogenesis observed in CD74(-/-) cells. Furthermore, a MIF blockade reduced RANKL-induced osteoclastogenesis via deregulating RANKL-mediated NF-κB and NFATc1 transcription factor activation. These data indicate that MIF and CD74 facilitate RANKL-induced osteoclastogenesis, and suggest that MIF contributes directly to bone erosion, as well as inflammation, in RA.
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Artritis Reumatoide/fisiopatología , Factores Inhibidores de la Migración de Macrófagos/deficiencia , Factores Inhibidores de la Migración de Macrófagos/fisiología , Osteoclastos/fisiología , Animales , Antígenos de Diferenciación de Linfocitos B/fisiología , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Resorción Ósea , Células Cultivadas , Modelos Animales de Enfermedad , Antígenos de Histocompatibilidad Clase II/fisiología , Factores Inhibidores de la Migración de Macrófagos/farmacología , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Factores de Transcripción NFATC/fisiología , Ligando RANK/metabolismo , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Membrana Sinovial/citologíaRESUMEN
The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G(alphai)- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition.