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1.
J Allergy Clin Immunol ; 151(1): 260-271, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35987350

RESUMO

BACKGROUND: Severe combined immunodeficiency (SCID) comprises rare inherited disorders of immunity that require definitive treatment through hematopoietic cell transplantation (HCT) or gene therapy for survival. Despite successes of allogeneic HCT, many SCID patients experience incomplete immune reconstitution, persistent T-cell lymphopenia, and poor long-term outcomes. OBJECTIVE: We hypothesized that CD4+ T-cell lymphopenia could be associated with a state of T-cell exhaustion in previously transplanted SCID patients. METHODS: We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT. RESULTS: Compared to post-HCT SCID patients with normal CD4+ T-cell counts, those with poor T-cell reconstitution showed lower frequency of naive CD45RA+/CCR7+ T cells, recent thymic emigrants, and TCR excision circles. They also had a restricted TCR repertoire, increased expression of inhibitory receptors (PD-1, 2B4, CD160, BTLA, CTLA-4), and increased activation markers (HLA-DR, perforin) on their total and naive CD8+ T cells, suggesting T-cell exhaustion and aberrant activation, respectively. The exhaustion score of CD8+ T cells was inversely correlated with CD4+ T-cell count, recent thymic emigrants, TCR excision circles, and TCR diversity. Exhaustion scores were higher among recipients of unconditioned HCT, especially when further in time from HCT. Patients with fewer CD4+ T cells showed a transcriptional signature of exhaustion. CONCLUSIONS: Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion as a result of diminished production of T-lineage cells. Elevated expression of inhibitory receptors on their T cells may be a biomarker of poor long-term T-cell reconstitution.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfopenia , Imunodeficiência Combinada Severa , Humanos , Linfócitos T CD8-Positivos , Exaustão das Células T , Receptores de Antígenos de Linfócitos T
2.
J Clin Immunol ; 41(1): 38-50, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33006109

RESUMO

PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION: NCT01186913.


Assuntos
Controle de Infecções , Infecções/epidemiologia , Infecções/etiologia , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/epidemiologia , Idade de Início , Antibioticoprofilaxia , Tomada de Decisão Clínica , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Infecções/diagnóstico , Masculino , Triagem Neonatal , Prognóstico , Vigilância em Saúde Pública , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia , Inquéritos e Questionários , Tempo para o Tratamento
5.
Pediatr Blood Cancer ; 57(3): 506-13, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21744474

RESUMO

BACKGROUND: High-dose chemotherapy with autologous stem cell rescue (HDC/SCR) has produced responses and prolonged survival for some children with recurrent brain tumors, but is associated with considerable morbidity and mortality. A Phase I trial of two cycles of HDC/SCR for recurrent brain tumors in children was performed to determine the maximum tolerated doses for a novel regimen. PROCEDURES: Two cycles of HDC/SCR were given. Cycle 1 included thiotepa and carmustine given on days -5, -4, and -3. Four to six weeks later, patients received cycle 2 which included thiotepa and carboplatin given on days -5, -4, and -3. Autologous peripheral blood stem cells (PBSC) were infused on day 0 of each cycle. RESULTS: Thirty-two patients were treated and 25 patients received both cycles of HDC/SCR. Common toxicities included mucositis, emesis, diarrhea, anorexia, and pancytopenia. Eight of 32 (25%) assessable children died from regimen-related toxicity. Pulmonary failure occurred in seven patients. Seven patients had grade 3-4 neurotoxicity. The 3-year event-free survival (EFS) was 25%. CONCLUSIONS: We determined the maximum tolerated regimen to be thiotepa 600 mg/m(2) and carmustine 300 mg/m(2) followed by thiotepa 600 mg/m(2) and carboplatin 1,200 mg/m(2) . Pulmonary toxicity was considerable. The toxic death rate was similar to other trials of HDC/SCR for children with recurrent brain tumors performed during the same time period. The regimen resulted in prolonged time to progression for a significant number of patients and long-term survival for some patients with recurrent medulloblastoma and rhabdoid tumor.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/mortalidade , Carboplatina , Carmustina , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Dose Máxima Tolerável , Transplante de Células-Tronco de Sangue Periférico/mortalidade , Análise de Sobrevida , Tiotepa , Transplante Autólogo
6.
J Pediatr Hematol Oncol ; 29(2): 125-7, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17279011

RESUMO

A 4-month-old girl diagnosed with familial hemophagocytic lymphohistiocytosis underwent a matched unrelated, umbilical cord blood transplant. Six weeks later she developed severe acute autoimmune hemolytic anemia and thrombocytopenia requiring multiple transfusions. This was refractory to high-dose steroid and intravenous immunoglobulin, but did respond to Rituximab (anti-CD20 monoclonal antibody) 375 mg/m2. Hemolysis recurred after steroid tapering but responded to a second course of Rituximab. This case report highlights the difficulty in managing posttransplant autoimmune hemolytic anemia.


Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Anemia Hemolítica Autoimune/etiologia , Anticorpos Monoclonais/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Fatores Imunológicos/uso terapêutico , Linfo-Histiocitose Hemofagocítica/terapia , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Murinos , Feminino , Sangue Fetal/transplante , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Rituximab , Trombocitopenia/tratamento farmacológico , Trombocitopenia/etiologia
7.
Biol Blood Marrow Transplant ; 13(4): 386-97, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17382246

RESUMO

B cells appear to play a role in chronic graft-versus-host disease (cGVHD) as shown in murine models and the success of anti-CD20 B cell antibody treatment in humans. Recent studies have shown that immunostimulatory microbial CpG-DNA splenic responses were enhanced in murine GVHD. We hypothesized that CpG-induced B cell responses are increased in human cGVHD. Newly diagnosed cGVHD patients enrolled on the COG protocol ASCT0031 were divided into early (3-8 months postblood and marrow transplant [BMT]) and late (> or =9 months post-BMT) onset groups and compared to time-matched control BMT patients. A significantly greater percentage of phosphorothioate (PS)-modified CpG stimulated B cells from cGVHD patients demonstrated an increased expression of CD86 compared to controls (P = .0004). This response had a significant correlation between B cell TLR9 expression (r(2) = 0.65; P = .002) and CD86 upregulation using the entirely TLR9-dependent native phosphodiester CpG (P = .003). The PS-modified CpG response at 2 months after initiation of cGVHD therapy demonstrated a trend toward predicting therapeutic response at 9 months post-BMT (P = .07). These findings suggest that an increased number of B cells, primed for a TLR9 response, may play a role in the pathophysiology of cGVHD.


Assuntos
Linfócitos B/imunologia , Ilhas de CpG/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Receptor Toll-Like 9/sangue , Adolescente , Antígeno B7-2/metabolismo , Biomarcadores/sangue , Células Cultivadas , Criança , Pré-Escolar , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/fisiopatologia , Humanos , Masculino , Análise por Pareamento , Regulação para Cima
8.
Proc Natl Acad Sci U S A ; 102(47): 17119-24, 2005 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-16284252

RESUMO

Telomeres protect chromosome ends from end-to-end fusion and degradation. Loss of telomere function causes cell-cycle arrest or cell death. Autosomal dominant dyskeratosis congenita (AD DC), a rare inherited bone marrow failure syndrome, is caused by mutations in TERC, the RNA component of telomerase. Here, we studied the telomere dynamics over three generations in a 32-member extended family with AD DC due to a TERC gene deletion. Our analysis shows that peripheral blood cells from family members haploinsufficient for TERC have very short telomeres. Telomeres are equally short in all individuals carrying the TERC gene deletion irrespective of their age. Chromosome-specific telomere analysis distinguishing the parental origin of telomeres showed that in gene deletion carriers, paternal and maternal telomeres are similarly short and similar in length to those of the affected parent. In children of affected parents who have normal TERC genes, parental telomeres are again similar in length, but two generations appear to be necessary to fully restore normal telomere length. These results are consistent with a model in which telomerase preferentially acts on the shortest telomeres. When TERC is limiting, this preference leads to the accelerated shortening of longer telomeres. The limited amount of active telomerase in TERC RNA haploinsufficiency may not be able to maintain the minimal length of the increasing number of short telomeres. Thus, the number of cells with excessively short telomeres and the degree of residual telomerase activity may determine the onset of disease in patients with AD DC.


Assuntos
Disceratose Congênita/enzimologia , Disceratose Congênita/genética , Haploidia , RNA/genética , Telomerase/genética , Telômero/enzimologia , Telômero/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Antecipação Genética/genética , Células Cultivadas , Criança , Pré-Escolar , Disceratose Congênita/fisiopatologia , Feminino , Deleção de Genes , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , RNA/fisiologia , Telomerase/fisiologia
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