RESUMO
INTRODUCTION: IgA nephropathy (IgAN) can cause end-stage kidney disease (ESKD). This study assesses the impact of induction and maintenance immunosuppression on IgAN recurrence, graft survival, and mortality in living and deceased donor kidney transplants (LDKT and DDKT). METHODS: Retrospective analysis of the UNOS database in adults with ESKD secondary to IgAN who received kidney transplants between January 2000 and June 30, 2022. Patients with thymoglobulin (ATG), alemtuzumab, or basiliximab/daclizumab induction with calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) with or without prednisone maintenance were analyzed. Multivariate logistic regression was performed to identify factors correlated with IgA recurrence. Multivariable Cox regression analyses were performed for clinically suspected risk factors. Kaplan Meir Analysis was utilized for overall graft survival. RESULTS: Compared to ATG with steroid maintenance, alemtuzumab with steroid increased the odds of IgAN recurrence in DDKTs (OR 1.90, p < .010, 95% CI [1.169-3.101]). Alemtuzumab with and without steroid increased the odds of recurrence by 52% (p = .036) and 56% (p = .005), respectively, in LDKTs. ATG without steroids was associated with less risk of IgAN recurrence (HR .665, p = .044, 95% CI [.447-.989]), graft failure (HR .758, p = .002, 95% CI [.633-.907]), and death (HR .619, p < .001, 95% CI [.490-.783]) in DDKTs. Recurrence was strongly associated with risks of graft failure in DDKTs and LDKTs and death in LDKTs. CONCLUSION: In patients with IgAN requiring a kidney transplant, Alemtuzumab induction correlates with increased IgAN recurrence. Relapse significantly affects graft survival and mortality. ATG without steroids is associated with the least graft loss and mortality.
Assuntos
Glomerulonefrite por IGA , Falência Renal Crônica , Transplante de Rim , Adulto , Humanos , Imunossupressores/uso terapêutico , Alemtuzumab/uso terapêutico , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/cirurgia , Estudos Retrospectivos , Transplante de Rim/efeitos adversos , Falência Renal Crônica/cirurgia , Falência Renal Crônica/etiologia , Esteroides , Sobrevivência de Enxerto , Rejeição de Enxerto/etiologiaRESUMO
INTRODUCTION: Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical-practice guidelines panel to evaluate the effectiveness and safety of IT in adult HT patients, we conducted this systematic review and network meta-analysis (NMA). METHODS: We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient-important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework. RESULTS: From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily-used IT agents-basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30-day (OR 1.13; 95% CI 1.06-1.20) and 1-year (OR 1.11; 95% CI 1.02-1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5-year cardiac allograft vasculopathy (OR .82; 95% CI .74-.90) compared to no IT, as well as 30-day (OR .85; 95% CI .80-.92), 1-year (OR .87; 95% CI .79-.96), and overall (HR .84; 95% CI .76-.93) mortality compared to basiliximab. CONCLUSION: With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients.
Assuntos
Rejeição de Enxerto , Transplante de Coração , Imunossupressores , Humanos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Metanálise em Rede , Prognóstico , Medicina Baseada em Evidências , Sobrevivência de Enxerto/efeitos dos fármacos , Guias de Prática Clínica como Assunto/normas , Quimioterapia de InduçãoRESUMO
BACKGROUND: Older (≥65) KT recipients differ from their younger counterparts in their immune response to immunosuppression (IS) and may have a different risk of malignancy after receiving induction. METHODS: We identified 66 700 adult KT recipients treated with anti-thymocyte globulin (ATG) (n = 40 443) or interleukin-2 receptor antagonist (IL-2RA) (n = 26 327) induction (1/1/1999-12/31/2014) using USRDS/Medicare data. We estimated the risk of first-diagnosed post-KT malignancy associated with induction (ATG vs. IL-2RA) using Cox proportional hazard models. We then tested whether these risks differed between older and younger recipients (Wald test for interaction). Models incorporated inverse probability of treatment weights to adjust for confounders. RESULTS: The 3-year cumulative incidences of any diagnosed malignancy were 11.5%. ATG was associated with a higher malignancy risk (HR = 1.12, 95%CI:1.06-1.18). This association differed (pinteraction = 0.04) between younger (HR = 1.12, 95%CI:1.06-1.18) and older recipients (HR = 1.03, 95%CI:0.96-1.09). ATG was also associated with higher risk of skin (HR = 1.18, 95%CI:1.08-1.29), lung (HR = 1.24, 95%CI:1.05-1.47), and ovary malignancies (HR = 1.94, 95%CI:1.08-3.48). However, only the association of ATG with post-KT skin malignancy differed (pinteraction = 0.01) between younger (HR = 1.18; 95%CI:1.08-1.29) and older (HR = 1.01; 95%CI:0.93-1.09) recipients. CONCLUSIONS: Compared with IL-2RA induction, ATG was associated with elevated post-KT malignancy risk but only among younger recipients. Transplant centers may need to tailor induction IS for younger recipients to mitigate malignancy risk.
Assuntos
Transplante de Rim , Neoplasias , Adulto , Idoso , Soro Antilinfocitário/efeitos adversos , Feminino , Rejeição de Enxerto , Humanos , Terapia de Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Medicare , Neoplasias/epidemiologia , Neoplasias/etiologia , Estudos Prospectivos , Estados Unidos/epidemiologiaRESUMO
Low T cell counts and acute rejection are associated with increased cardiovascular events (CVEs); T cell-depleting agents decrease both. Thus, we aimed to characterize the risk of CVEs by using an induction agent used in kidney transplant recipients. We conducted a secondary data analysis of patients who received a kidney transplant and used Medicare as their primary insurance from 1999 to 2010. Outcomes of interest were incident CVE, all-cause mortality, CVE-related mortality, and a composite outcome of mortality and CVE. Of 47 258 recipients, 29.3% received IL-2 receptor antagonist (IL-2RA), 33.3% received anti-thymocyte globulin (ATG), 7.3% received alemtuzumab, and 30.0% received no induction. Compared with IL-2RA, there was no difference in the risk of CVE in the ATG (adjusted hazard ratio [aHR] 0.98, 95% confidence interval [CI] 0.92-1.05) and alemtuzumab group (aHR 1.01, 95% CI 0.89-1.16), but slightly higher in the no induction group (aHR 1.06, 95% CI 1.00-1.14). Acute rejection did not modify this association in the latter group but did increase CVE by 46% in the alemtuzumab group. There was no difference in the hazard of all-cause or CVE-related mortality. Only in the ATG group, a 7% lower hazard of the composite outcome of mortality and CVE was noted. Induction agents are not associated with incident CVE, although prospective trials are needed to determine a personalized approach to prevention.
Assuntos
Doenças Cardiovasculares/complicações , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
We provide clinical commentary on this edition's case report of immune-mediated encephalitis related to daclizumab therapy.
Assuntos
Daclizumabe/uso terapêutico , Encefalite/tratamento farmacológico , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Imunoglobulina G/uso terapêuticoRESUMO
This report will detail a case of immune-mediated encephalitis in the context of daclizumab therapy. Daclizumab is a humanised monoclonal antibody which, prior to its recent worldwide withdrawal due to safety concerns, was utilised as a disease-modifying therapy in relapsing-remitting multiple sclerosis. The withdrawal of this therapy was prompted by concerns over 12 cases of serious immune-mediated adverse reactions in the central nervous system. We report an additional case, including clinical data and results of neuroimaging, cerebrospinal fluid (CSF) examination and brain biopsy.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Daclizumabe/efeitos adversos , Encefalite/etiologia , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Daclizumabe/uso terapêutico , Encefalite/diagnóstico , Encefalite/tratamento farmacológico , Humanos , Imunoglobulina G/efeitos adversos , Imunoglobulina G/uso terapêutico , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , MasculinoRESUMO
BACKGROUND: Daclizumab is a monoclonal antibody that binds the high-affinity interleukin-2 receptor and was approved for the treatment of relapsing multiple sclerosis. Due to severe inflammatory brain disorders, the approval was suspended in March 2018. OBJECTIVE AND METHODS: This retrospective cohort study summarizes clinical, laboratory, radiological, and histological findings of seven patients who developed meningo-/encephalitis after daclizumab therapy. RESULTS: Patients presented with encephalitis and/or meningitis and suffered from systemic symptoms such as fever (5/7), exanthema (5/7), or gastrointestinal symptoms (4/7). Secondary autoimmune diseases developed. Blood analysis revealed an increase in eosinophils (5/7). Six patients fulfilled the diagnostic criteria for a drug reaction with eosinophilia and systemic symptoms (DRESS). Magnetic resonance imaging (MRI) showed multiple contrast-enhancing lesions, and enhancement of the ependyma (6/7), meninges (5/7), cranial or spinal nerves (2/7), and a vasculitic pattern (3/7). Histology revealed a pronounced inflammatory infiltrate consisting of lymphocytes, plasma cells and eosinophils, and densely infiltrated vessels. Most patients showed an insufficient therapeutic response and a high disability at last follow-up (median Expanded Disability Status Scale (EDSS) 8). Two patients died. CONCLUSION: Meningoencephalitis and DRESS may occur with daclizumab therapy. This potential lethal side effect is characterized by a dysregulated immune response. Our findings underline the importance of postmarketing drug surveillance.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Daclizumabe/efeitos adversos , Encefalite/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Adulto , Doenças Autoimunes/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Daclizumabe/uso terapêutico , Encefalite/patologia , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood-brain barrier, CD56(bright) NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α4ß1 integrin very late antigen (VLA)-4. Although no MS-related changes in the migratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4(+) T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4(+) T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MS-association studies, and up-regulation of the receptor's ligand CD155 on CD4(+) T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4(+) T cells and the cytolytic activity of NK cells.
Assuntos
Barreira Hematoencefálica/imunologia , Linfócitos T CD4-Positivos/imunologia , Movimento Celular/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Esclerose Múltipla/imunologia , Receptores de Interleucina-2/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Barreira Hematoencefálica/patologia , Linfócitos T CD4-Positivos/patologia , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Células K562 , Células Matadoras Naturais/patologia , Masculino , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Natalizumab/administração & dosagem , Receptores Virais/imunologiaRESUMO
Charge deconvolution infers the mass from mass over charge (m/z) measurements in electrospray ionization mass spectra. When applied over a wide input m/z or broad target mass range, charge-deconvolution algorithms can produce artifacts, such as false masses at one-half or one-third of the correct mass. Indeed, a maximum entropy term in the objective function of MaxEnt, the most commonly used charge deconvolution algorithm, favors a deconvolved spectrum with many peaks over one with fewer peaks. Here we describe a new "parsimonious" charge deconvolution algorithm that produces fewer artifacts. The algorithm is especially well-suited to high-resolution native mass spectrometry of intact glycoproteins and protein complexes. Deconvolution of native mass spectra poses special challenges due to salt and small molecule adducts, multimers, wide mass ranges, and fewer and lower charge states. We demonstrate the performance of the new deconvolution algorithm on a range of samples. On the heavily glycosylated plasma properdin glycoprotein, the new algorithm could deconvolve monomer and dimer simultaneously and, when focused on the m/z range of the monomer, gave accurate and interpretable masses for glycoforms that had previously been analyzed manually using m/z peaks rather than deconvolved masses. On therapeutic antibodies, the new algorithm facilitated the analysis of extensions, truncations, and Fab glycosylation. The algorithm facilitates the use of native mass spectrometry for the qualitative and quantitative analysis of protein and protein assemblies.
Assuntos
Algoritmos , Anticorpos Monoclonais Humanizados/análise , Cetuximab/análise , Glicoproteínas/análise , Imunoglobulina G/análise , Infliximab/análise , Properdina/análise , Daclizumabe , Entropia , Glicosilação , Humanos , Fragmentos de Peptídeos/análise , Mapeamento de Peptídeos , Proteólise , Soluções , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas por Ionização por Electrospray/métodos , Eletricidade Estática , Tripsina/químicaRESUMO
Calcineurin inhibitors (CNIs, eg, tacrolimus) reduce short-term kidney transplant failure, but chronic nephrotoxicity may contribute to late transplant loss. Elective conversion to inhibitors of the mammalian target of rapamycin (mTOR, eg, sirolimus) pathway might avoid long-term CNI renal damage and improve outcomes. The 3C Study was a pragmatic randomized controlled trial of sequential randomizations between alemtuzumab and basiliximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation. The primary outcome of this analysis was estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy randomization; 197 patients were assigned sirolimus-based and 197 to tacrolimus-based therapy. Allocation to sirolimus had no significant effect on eGFR at 18 months: baseline-adjusted mean (SEM) eGFR was 53.7 (0.9) mL/min/1.73 m2 in the sirolimus group versus 54.6 (0.9) mL/min/1.73 m2 in the tacrolimus group (P = .50). Biopsy-proven acute rejection (29 [14.7%]) vs 6 [3.0%]; P < .001) and serious infections (defined as opportunistic infections or those requiring hospitalization; 95 [48.2%] vs 70 [35.5%]; P = .008) were more common among participants allocated sirolimus. Compared with tacrolimus-based therapy, sirolimus-based maintenance therapy did not improve transplant function at 18 months after conversion and was associated with significant hazards of rejection and infection. ClinicalTrials.gov identifier NCT01120028 and ISRCTN88894088.
Assuntos
Alemtuzumab/farmacologia , Inibidores de Calcineurina/efeitos adversos , Imunossupressores/efeitos adversos , Nefropatias/induzido quimicamente , Transplante Homólogo/efeitos adversos , Adulto , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
Since 2004, five drugs with new mechanisms of action have been approved by the US Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis (MS). The expanded armamentarium of treatment options offers new opportunities for improved disease control and increased tolerability of medications, and also presents new safety concerns and monitoring requirements with which physicians must familiarize themselves. We review each of the newly approved agents-natalizumab, fingolimod, teriflunomide, dimethyl fumarate, and alemtuzumab-with regard to their mechanism of action, clinical trial data, safety and tolerability concerns, and monitoring requirements. We also review available data for promising agents that are currently in late-phase clinical trials, including daclizumab, ocrelizumab, and ofatumumab.
Assuntos
Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Alemtuzumab , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD20/efeitos dos fármacos , Crotonatos/uso terapêutico , Daclizumabe , Fumarato de Dimetilo/uso terapêutico , Cloridrato de Fingolimode/uso terapêutico , Humanos , Hidroxibutiratos , Imunoglobulina G/uso terapêutico , Fatores Imunológicos/efeitos adversos , Imunossupressores/uso terapêutico , Natalizumab/uso terapêutico , Nitrilas , Recidiva , Toluidinas/uso terapêuticoRESUMO
BACKGROUND: Demonstration of clinical benefits on disability progression measures is an important attribute of effective multiple sclerosis (MS) treatments. OBJECTIVE: Examine efficacy of daclizumab beta versus intramuscular (IM) interferon beta-1a on measures of disability progression in patient subgroups from DECIDE. METHODS: Twenty-four-week confirmed disability progression (CDP), 24-week sustained worsening on a modified Multiple Sclerosis Functional Composite (MSFCS) where 3-Second Paced Auditory Serial Addition Test was replaced by Symbol Digit Modalities Test, and proportion of patients with clinically meaningful worsening in 29-Item Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS) score from baseline to week 96 were examined in the overall population and subgroups defined by baseline demographic/disease characteristics. RESULTS: Daclizumab beta significantly reduced risk of 24-week CDP (hazard ratio (HR), 0.73; 95% confidence interval (95% CI), 0.55-0.98), risk of 24-week sustained MSFCS progression (HR, 0.80; 95% CI, 0.67-0.95), and odds of clinically meaningful worsening in MSIS-29 PHYS (odds ratio, 0.76; 95% CI, 0.60-0.95) versus IM interferon beta-1a. Point estimates showed trends favoring daclizumab beta over IM interferon beta-1a across several patient subgroups for all three outcome measures. CONCLUSION: Daclizumab beta showed consistent benefit versus IM interferon beta-1a across measures assessing patient disability/function and across a range of clinical baseline characteristics in patients with relapsing-remitting MS.
Assuntos
Daclizumabe/farmacologia , Imunossupressores/farmacologia , Interferon beta-1a/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Progressão da Doença , Feminino , Humanos , Imunoglobulina G/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS), with cognitive processing speed being the most frequently affected domain. OBJECTIVE: Examine the effects of daclizumab beta versus intramuscular (IM) interferon (IFN) beta-1a on cognitive processing speed as assessed by Symbol Digit Modalities Test (SDMT). METHODS: In DECIDE, patients with relapsing-remitting multiple sclerosis (RRMS) (age: 18-55 years; Expanded Disability Status Scale (EDSS) score 0-5.0) were randomized to daclizumab beta ( n = 919) or IM IFN beta-1a ( n = 922) for 96-144 weeks. SDMT was administered at baseline and at 24-week intervals. RESULTS: At week 96, significantly greater mean improvement from baseline in SDMT was observed with daclizumab beta versus IM IFN beta-1a ( p = 0.0274). Significantly more patients treated with daclizumab beta showed clinically meaningful improvement in SDMT (increase from baseline of ⩾3 points ( p = 0.0153) or ⩾4 points ( p = 0.0366)), and significantly fewer patients showed clinically meaningful worsening (decrease from baseline of ⩾3 points ( p = 0.0103)). Odds representing risk of worsening versus stability or improvement on SDMT were significantly smaller for daclizumab beta ( p = 0.0088 (3-point threshold); p = 0.0267 (4-point threshold)). In patients completing 144 weeks of treatment, the effects of daclizumab beta were generally sustained. CONCLUSION: These results provide evidence for a benefit of daclizumab beta versus IM IFN beta-1a on cognitive processing speed in RRMS. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01064401 (Efficacy and Safety of BIIB019 (Daclizumab High Yield Process) Versus Interferon ß 1a in Participants With Relapsing-Remitting Multiple Sclerosis (DECIDE)): https://clinicaltrials.gov/ct2/show/NCT01064401 .
Assuntos
Cognição/efeitos dos fármacos , Daclizumabe/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Adulto , Feminino , Humanos , Interferon beta-1a/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/psicologia , Adulto JovemRESUMO
Despite significant advances in the treatment of Hodgkin's lymphoma (HL), a significant proportion of patients will not respond or will subsequently relapse. We identified CD25, the IL-2 receptor alpha subunit, as a favorable target for systemic radioimmunotherapy of HL. The scientific basis for the clinical trial was that, although most normal cells with exception of Treg cells do not express CD25, it is expressed by a minority of Reed-Sternberg cells and by most polyclonal T cells rosetting around Reed-Sternberg cells. Forty-six patients with refractory and relapsed HL were evaluated with up to seven i.v. infusions of the radiolabeled anti-CD25 antibody (90)Y-daclizumab. (90)Y provides strong ß emissions that kill tumor cells at a distance by a crossfire effect. In 46 evaluable HL patients treated with (90)Y-daclizumab there were 14 complete responses and nine partial responses; 14 patients had stable disease, and nine progressed. Responses were observed both in patients whose Reed-Sternberg cells expressed CD25 and in those whose neoplastic cells were CD25(-) provided that associated rosetting T cells expressed CD25. As assessed using phosphorylated H2AX (γ-H2AX) as a bioindicator of the effects of radiation exposure, predominantly nonmalignant cells in the tumor microenvironment manifested DNA damage, as reflected by increased expression of γ-H2AX. Toxicities were transient bone-marrow suppression and myelodysplastic syndrome in six patients who had not been evaluated with bone-marrow karyotype analyses before therapy. In conclusion, repeated (90)Y-daclizumab infusions directed predominantly toward nonmalignant T cells rosetting around Reed-Sternberg cells provided meaningful therapy for select HL patients.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/imunologia , Radioisótopos de Ítrio/química , Adulto , Idoso , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/imunologia , Daclizumabe , Feminino , Doença de Hodgkin/imunologia , Humanos , Imunoglobulina G/química , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Fosforilação , Recidiva , Adulto JovemRESUMO
Daclizumab, a humanized monoclonal antibody, binds CD25 and blocks formation of the IL-2 receptor on T cells. A study of daclizumab as acute graft-versus-host disease (GVHD) prophylaxis after unrelated bone marrow transplantation was conducted before the importance of CD25+FOXP3+ regulatory T cells (Tregs) was recognized. Tregs can abrogate the onset of GVHD. The relation between Tregs and a graft-versus-malignancy effect is not fully understood. An international, multicenter, double-blind clinical trial randomized 210 adult or pediatric patients to receive 5 weekly doses of daclizumab at 0.3 mg/kg (n = 69) or 1.2 mg/kg (n = 76) or placebo (n = 65) after unrelated marrow transplantation for treatment of hematologic malignancies or severe aplastic anemia. The risk of acute GVHD did not differ among the groups (P = .68). Long-term follow-up of clinical outcomes and correlative analysis of peripheral blood T cell phenotype suggested that the patients treated with daclizumab had an increased risk of chronic GVHD (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.0 to 2.3; P = .08) and a decreased risk of relapse (HR, 0.57; 95% CI, 0.3 to 1.0; P = .05), but similar survival (HR, 0.89; 95% CI, 0.6 to 1.3; P = .53). T cells from a subset of patients (n = 107) were analyzed by flow cytometry. Compared with placebo, treatment with daclizumab decreased the proportion of Tregs among CD4 T cells at days 11-35 and increased the proportion of central memory cells among CD4 T cells at 1 year. Prophylactic administration of daclizumab does not prevent acute GVHD, but may increase the risk of chronic GVHD and decrease the risk of relapse. By delaying Treg reconstitution and promoting immunologic memory, anti-CD25 therapy may augment alloreactivity and antitumor immunity.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoglobulina G/farmacologia , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Daclizumabe , Método Duplo-Cego , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunoglobulina G/uso terapêutico , Lactente , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/citologia , Transplante Homólogo , Adulto JovemRESUMO
Induction therapy with antilymphocyte biological agents is widely used after kidney transplantation, most commonly T lymphocyte-depleting rabbit-derived antithymocyte globulin (rATG) or an IL-2 receptor antagonist (IL2RA). Early randomized trials showed that rATG or IL2RA induction reduces early acute rejection, prompting recommendations by Kidney Disease Improving Global Outcomes that IL2RA induction be used routinely in first-line therapy after kidney transplantation, with lymphocyte-depleting induction reserved for high-risk cases. These studies, however, mainly used outdated maintenance regimens. No large randomized trial has examined the effect of IL2RA or rATG induction versus no induction in patients receiving tacrolimus, mycophenolic acid and steroids. With this triple maintenance therapy, the addition of induction may achieve an absolute risk reduction for acute rejection of only 1-4% in standard-risk patients without improving graft or patient survival. In contrast, rATG induction lowers the relative risk of acute rejection by almost 50% versus IL2RA in patients with high immunological risk. These recent data raise questions about the need for IL2RA in kidney transplantation, as it may no longer be beneficial in standard-risk transplantation and may be inferior to rATG in high-risk situations. Updated evidence-based guidelines are necessary to support clinicians deciding whether and what induction therapy is required for their transplant patients today.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Transplante de Rim/efeitos adversos , Receptores de Interleucina-2/antagonistas & inibidores , Humanos , Indução de Remissão , TransplantadosRESUMO
Immunosuppressive strategies applied in renal transplantation traditionally focus on T cell inhibition. B cells were mainly examined in the context of antibody-mediated rejection, whereas the impact of antibody-independent B cell functions has only recently entered the field of transplantation. Similar to T cells, distinct B cell subsets can enhance or inhibit immune responses. In this study, we prospectively analyzed the evolution of B cell subsets in the peripheral blood of AB0-compatible (n = 27) and AB0-incompatible (n = 10) renal transplant recipients. Activated B cells were transiently decreased and plasmablasts were permanently decreased in patients without signs of rejection throughout the first year. In patients with histologically confirmed renal allograft rejection, activated B cells and plasmablasts were significantly elevated on day 365. Rituximab treatment in AB0-incompatible patients resulted in long-lasting B cell depletion and in a naïve phenotype of repopulating B cells 1 year following transplantation. Acute allograft rejection was correlated with an increase of activated B cells and plasmablasts and with a significant reduction of regulatory B cell subsets. Our study demonstrates the remarkable effects of standard immunosuppression on circulating B cell subsets. Furthermore, the B cell compartment was significantly altered in rejecting patients. A specific targeting of deleterious B cell subsets could be of clinical benefit in renal transplantation.
Assuntos
Sistema ABO de Grupos Sanguíneos/imunologia , Incompatibilidade de Grupos Sanguíneos/imunologia , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto/imunologia , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Transplantados , Adulto , Subpopulações de Linfócitos B/imunologia , Feminino , Seguimentos , Rejeição de Enxerto/sangue , Humanos , Imunossupressores/uso terapêutico , Doadores Vivos , Masculino , Complicações Pós-Operatórias , Prognóstico , Estudos Prospectivos , Fatores de Risco , Transplante HomólogoRESUMO
BACKGROUND: No evidence of disease activity (NEDA) is a composite endpoint being increasingly applied as an outcome measure in clinical trials as well as proposed for individual therapeutic decisions in multiple sclerosis (MS). OBJECTIVE: Assess the proportion of patients with relapsing-remitting MS achieving NEDA in the DECIDE study of daclizumab 150 mg subcutaneous versus intramuscular interferon beta-1a 30 µg for 96-144 weeks. METHODS: NEDA was defined as no relapses, no onset of 12-week confirmed disability progression (CDP), no new/newly enlarging T2 hyperintense lesions (NET2), and no gadolinium-enhancing (Gd+) lesions. Logistic regression models adjusted for baseline covariates compared treatment groups for baseline to week 96, weeks 0-24, and weeks 24-96. RESULTS: From baseline to week 96, more daclizumab versus intramuscular interferon beta-1a patients achieved NEDA (24.6% vs 14.2%; odds ratio (OR; 95% confidence interval): 2.059 (1.592-2.661); p < 0.0001). ORs for clinical NEDA (no relapses, no CDP) and magnetic resonance imaging (MRI) NEDA (no NET2, no Gd+ lesions) were 1.651 (1.357-2.007; p < 0.0001) and 2.051 (1.628-2.582; p < 0.0001), respectively. ORs in favor of daclizumab for weeks 24-96 were consistently higher than for weeks 0-24. CONCLUSION: More daclizumab versus intramuscular interferon beta-1a patients achieved NEDA early in DECIDE, with effects increasing over time.
Assuntos
Adjuvantes Imunológicos/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Imunoglobulina G/farmacologia , Imunossupressores/farmacologia , Interferon beta-1a/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde/métodos , Adjuvantes Imunológicos/administração & dosagem , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Daclizumabe , Feminino , Humanos , Imunoglobulina G/administração & dosagem , Imunossupressores/administração & dosagem , Injeções Intramusculares , Injeções Subcutâneas , Interferon beta-1a/administração & dosagem , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologiaRESUMO
We prospectively studied efficacy and safety outcomes of two 10-mg doses of intravenous basiliximab on day 0 and day 4 for induction therapy in 17 consecutive de novo heart transplant recipients. By the 2-week assessment post-transplant, there were no deaths, graft failures, or acute cellular rejections (ACRs) ISHLT grade ≥ 2R. By the 1-year assessment post-transplant, there were 1 (6%) infectious death, no graft failures, 2 (12%) grade 2R ACRs, 6 (35%) asymptomatic cytomegalovirus (CMV) infections, and 4 (25%) treated infections. Our study was the first to show that low-dose basiliximab induction in heart transplant resulted in favorable efficacy and safety outcomes. Additionally, calcineurin inhibitor (CNI) initiation in a low-risk population could be safely delayed using the strategy of modified low-dose postoperative basiliximab. This strategy also appears to allow subsequent early corticosteroid wean, although with the concomitant maintenance of higher CNI levels and higher dosing of mycophenolate.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Coração/efeitos adversos , Imunossupressores/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Basiliximab , Doenças Cardiovasculares/etiologia , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
An expanding list of immunomodulatory or immunosuppressive monoclonal antibodies (mAbs) and biologic therapeutics is currently entering clinical practice, particularly in the areas of oncology, transplantation and autoimmune disorders. These agents are directed against molecules or cells involved in inflammation and immunity and may therefore be associated with serious and opportunistic infections. The purpose of this review was to critically analyse the literature on invasive fungal infections (IFIs) occurring in association with mAbs and fusion proteins other than tumour necrosis alpha (TNF-α) inhibitors, including therapeutics modulating T-cell-mediated pathologies (muromonab, abatacept, belatacept, ipilimumab, basiliximab, daclizumab), inducing lymphopenia (alemtuzumab), depleting CD20+ B cells (rituximab) and interfering with various targets (anakinra, natalizumab, blodalumab, ixekizumab and others) with a focus on children, and to provide a framework of evaluating the risk for IFIs in this population.