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1.
Clin Immunol ; 211: 108330, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31899331

RESUMO

Primary immunodeficiency Disorders (PIDD) are a varied group of heritable disorders characterized by defects in components of the innate and/or adaptive arms of the immune system. Although diagnosing these disorders is often challenging, the skin is a readily accessible and easily assessable organ that may provide clues to a diagnosis of PIDD. Specifically, many immunodeficiencies are associated with characteristic cutaneous eruptions that, based on their morphology, distribution and symptomatology, may suggest a specific underlying diagnosis. This review will discuss an approach to identifying and managing PIDDs that typically present with eczematous dermatitis.

2.
J Clin Immunol ; 39(7): 653-667, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376032

RESUMO

INTRODUCTION: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking. METHODS: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016. RESULTS: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT. CONCLUSIONS: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

3.
Blood ; 132(17): 1737-1749, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30154114

RESUMO

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune/imunologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/terapia , Genótipo , Humanos , Contagem de Linfócitos , Estudos Retrospectivos
5.
J Clin Invest ; 127(5): 1689-1699, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28346229

RESUMO

BACKGROUND: Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADA-deficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study. METHODS: Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/progenitor cells, ADA gene expression, and immune reconstitution. RESULTS: With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant. CONCLUSION: These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile. TRIAL REGISTRATION: ClinicalTrials.gov NCT00794508. FUNDING: Food and Drug Administration Office of Orphan Product Development award, RO1 FD003005; NHLBI awards, PO1 HL73104 and Z01 HG000122; UCLA Clinical and Translational Science Institute awards, UL1RR033176 and UL1TR000124.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia , Regulação Enzimológica da Expressão Gênica , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Transdução Genética , Adenosina Desaminase/biossíntese , Adenosina Desaminase/genética , Adolescente , Agamaglobulinemia/enzimologia , Agamaglobulinemia/genética , Agamaglobulinemia/terapia , Autoenxertos , Criança , Pré-Escolar , Feminino , Vetores Genéticos , Humanos , Lactente , Masculino , Retroviridae , Imunodeficiência Combinada Severa/enzimologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia
7.
Pediatr Blood Cancer ; 62(11): 2047-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26011426

RESUMO

Aplastic anemia in the neonate is rare. We report a case of severe combined immunodeficiency (SCID) presenting with neonatal aplastic anemia. This report highlights the importance of considering SCID early in the evaluation of neonatal aplastic anemia prior to the development of infectious complications.


Assuntos
Anemia Aplástica , Imunodeficiência Combinada Severa , Anemia Aplástica/complicações , Anemia Aplástica/patologia , Anemia Aplástica/terapia , Humanos , Recém-Nascido , Masculino , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia
8.
Biol Blood Marrow Transplant ; 20(12): 1996-2003, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25196857

RESUMO

Hematopoietic cell transplantation is an effective treatment for patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM), particularly in patients with comorbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n = 4) or unrelated (n = 27) grafts after conditioning with treosulfan (total dose, 42 g/m(2)), fludarabine (total dose, 150 mg/m(2)), ± thymoglobulin (6 mg/kg; n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II to IV and III to IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10%, and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grades III to IV acute GVHD (0% versus 33%; P = .005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases and support the need for future disease-specific clinical trials.


Assuntos
Anemia Aplástica/terapia , Antineoplásicos Alquilantes/administração & dosagem , Bussulfano/análogos & derivados , Anemia de Fanconi/terapia , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Doadores não Relacionados , Adolescente , Adulto , Anemia Aplástica/mortalidade , Soro Antilinfocitário/administração & dosagem , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Anemia de Fanconi/mortalidade , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Lactente , Masculino , Metotrexato/administração & dosagem , Agonistas Mieloablativos , Estudos Prospectivos , Tacrolimo/administração & dosagem , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
9.
N Engl J Med ; 371(5): 434-46, 2014 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-25075835

RESUMO

BACKGROUND: The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. METHODS: We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). RESULTS: Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. CONCLUSIONS: Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/terapia , Complexo CD3/sangue , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Imunoglobulina A/sangue , Incidência , Lactente , Contagem de Linfócitos , Masculino , Retratamento , Estudos Retrospectivos , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/mortalidade , Irmãos , Taxa de Sobrevida , Linfócitos T/imunologia , Condicionamento Pré-Transplante , Resultado do Tratamento
11.
J Pediatr Hematol Oncol ; 34(7): 569-72, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22510777

RESUMO

A 16-year-old man with splenomegaly presented with ascites and bilateral leg eschars. Although he had intermittently elevated absolute monocyte counts, a diagnosis of juvenile myelomonocytic leukemia (JMML) was discounted because of his age and lack of persistent leukocytosis. Detailed examination demonstrated features consistent with Noonan syndrome (NS), including typical facies, growth retardation, a cardiac defect, and a history of a coagulopathy. He underwent a splenectomy where the surgeons encountered a rind of tissue composed of monocytes encasing the abdominal organs. After splenectomy, his leukocytes rose to over 100×10(9)/L with a monocytosis, suggesting JMML. On the basis of the clinical suspicion of NS, mutation analysis revealed a KRAS mutation, which is known to be common to both NS and JMML. Clinicians should have high index of suspicion for JMML in patients with Noonan features, regardless of a patient's age.


Assuntos
Leucemia Mielomonocítica Juvenil/etiologia , Síndrome de Noonan/complicações , Adolescente , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Masculino , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genética
12.
Pediatr Infect Dis J ; 31(1): 95-7, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21817949

RESUMO

This retrospective review of patients with severe combined immunodeficiency and Pneumocystis jiroveci pneumonia (PCP) evaluated the relationship between duration of therapy to treat PCP and overall survival. We found that 80% of patients receiving only 21 days of antibiotics survived to 12 months beyond hematopoietic cell transplant, whereas only 25% of patients who required longer treatment for PCP survived to stem cell engraftment.


Assuntos
Anti-Infecciosos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Pneumocystis carinii/efeitos dos fármacos , Pneumonia por Pneumocystis/tratamento farmacológico , Imunodeficiência Combinada Severa/mortalidade , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Feminino , Humanos , Lactente , Masculino , Pneumonia por Pneumocystis/microbiologia , Pneumonia por Pneumocystis/mortalidade , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/terapia , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
13.
J Allergy Clin Immunol ; 126(5): 1000-5, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20643476

RESUMO

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is characterized by severe systemic autoimmunity caused by mutations in the forkhead box protein 3 (FOXP3) gene. Hematopoietic cell transplantation is currently the only viable option for long-term survival, but patients are frequently very ill and may not tolerate traditional myeloablative conditioning regimens. OBJECTIVE: Here we present the outcome of hematopoietic cell transplantation using a low-intensity, nonmyeloablative conditioning regimen in 2 patients with IPEX syndrome and significant pretransplant risk factors. METHODS: Two high-risk patients with IPEX syndrome received HLA-matched related bone marrow or unrelated peripheral blood stem cell grafts following conditioning with 90 mg/m(2) fludarabine and 4 Gy total body irradiation. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. Immune reconstitution and immune function was evaluated by measurement of donor chimerism, regulatory T-cell numbers, absolute lymphocyte subsets, and T-cell proliferation assays. RESULTS: Both patients experienced minimal conditioning toxicity and successfully engrafted after hematopoietic cell transplantation. With a follow-up of 4 and 1 years, respectively, patients 1 and 2 have full immune function and normal FOXP3 protein expression. CONCLUSION: A low-intensity, nonmyeloablative conditioning regimen can establish stable engraftment and correct the life-threatening immune deficiency and enteropathy of IPEX syndrome despite the presence of comorbidities that preclude conventional hematopoietic cell transplantation.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes de Imunodeficiência/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Separação Celular , Criança , Ciclosporina/uso terapêutico , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/fisiopatologia , Imunossupressores/uso terapêutico , Lactente , Masculino , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Agonistas Mieloablativos/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndrome , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Irradiação Corporal Total
14.
Ther Clin Risk Manag ; 6: 1-10, 2010 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-20169031

RESUMO

Antibody deficiency is the most frequently encountered primary immunodeficiency disease (PIDD) and patients who lack the ability to make functional immunoglobulin require life-long replacement therapy to prevent serious bacterial infections. Human serum immunoglobulin manufactured from pools of donated plasma can be administered intramuscularly, intravenously or subcutaneously. With the advent of well-tolerated preparations of intravenous immunoglobulin (IVIg) in the 1980s, the suboptimal painful intramuscular route of administration is no longer used. However, some patients continued to experience unacceptable adverse reactions to the intravenous preparations, and for others, vascular access remained problematic. Subcutaneously administered immunoglobulin (SCIg) provided an alternative delivery method to patients experiencing difficulties with IVIg. By 2006, immunoglobulin preparations designed exclusively for subcutaneous administration became available. They are therapeutically equivalent to intravenous preparations and offer patients the additional flexibility for the self-administration of their product at home. SCIg as replacement therapy for patients with primary antibody deficiencies is a safe and efficacious method to prevent serious bacterial infections, while maximizing patient satisfaction and improving quality of life.

15.
J Perinatol ; 23(5): 428-30, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12847542

RESUMO

Autoimmune neutropenia of infancy is a primary, usually self-limiting, antineutrophil autoimmune phenomenon seen in infancy and early childhood. These infants are at a higher risk of infection, and early detection, particularly with the availability of newer therapeutic options such as hematopoietic growth factors, can allow close follow-up and, if needed, treatment. We report two infants with autoimmune neutropenia who presented with a persistent perianal abscess, which has not been documented previously in this population.


Assuntos
Abscesso/diagnóstico , Doenças do Ânus/diagnóstico , Doenças Autoimunes/diagnóstico , Neutropenia/diagnóstico , Abscesso/imunologia , Combinação Amoxicilina e Clavulanato de Potássio/administração & dosagem , Doenças do Ânus/imunologia , Autoanticorpos/análise , Autoanticorpos/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doença Crônica , Diagnóstico Diferencial , Quimioterapia Combinada , Seguimentos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Lactente , Recém-Nascido , Masculino , Neutropenia/tratamento farmacológico , Neutropenia/imunologia , Proteínas Recombinantes , Recidiva , Medição de Risco
16.
Nature ; 419(6905): 395-9, 2002 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-12353035

RESUMO

Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, apoptosis counters the proliferation of lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity. The CD95 (Fas, Apo-1) receptor triggers lymphocyte apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex. Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly and autoimmunity. Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective lymphocyte apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphocytes, B lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive lymphocytes.


Assuntos
Caspases/genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Ativação Linfocitária , Linfócitos/imunologia , Linfócitos/patologia , Mutação/genética , Apoptose , Linfócitos B/imunologia , Linfócitos B/patologia , Antígenos CD28/imunologia , Complexo CD3/imunologia , Cálcio/metabolismo , Caspase 8 , Caspase 9 , Divisão Celular , Citocinas/análise , Feminino , Homozigoto , Humanos , Síndromes de Imunodeficiência/enzimologia , Síndromes de Imunodeficiência/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Linhagem , Fenótipo , Linfócitos T/imunologia , Linfócitos T/patologia
17.
Transplantation ; 73(6): 907-10, 2002 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-11923690

RESUMO

Humoral or antibody-mediated rejection in cardiac transplant recipients is mediated by donor-specific cytotoxic antibodies and is histologically defined by linear deposits of immunoglobulin and complement in the myocardial capillaries. Antibody-mediated rejection often is accompanied by hemodynamic compromise and is associated with reduced long-term graft survival. Standard immunosuppression, designed to target T cell immune function, is largely ineffective against this B cell-driven process. Current treatment options for humoral rejection are limited by a lack of specific anti-B cell therapies. We present the case of a 50-year-old woman with hemodynamically significant humoral rejection resistant to steroids, cyclophos-phamide, and plasmapheresis who responded to the addition of anti-CD20 monoclonal antibody therapy (rituximab). One year posttransplant, the patient is rejection-free, with normal left ventricular systolic function and coronary arteries.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfócitos B/imunologia , Rejeição de Enxerto/tratamento farmacológico , Transplante de Coração/imunologia , Doença Aguda , Anticorpos Monoclonais Murinos , Formação de Anticorpos , Antígenos CD20/imunologia , Cardiomiopatias/cirurgia , Resistência a Medicamentos , Feminino , Antígenos HLA/imunologia , Transplante de Coração/patologia , Hemodinâmica , Humanos , Pessoa de Meia-Idade , Rituximab , Fatores de Tempo , Resultado do Tratamento
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