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2.
Clin Immunol ; 197: 219-223, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30368009

RESUMO

Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation.

5.
Front Immunol ; 8: 798, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769923

RESUMO

Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.

6.
Pediatr Blood Cancer ; 64(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28557197

RESUMO

BACKGROUND: Fanconi anemia (FA) is a rare genetic disorder characterized by genome instability, bone marrow failure, and cancer predisposition. Previously, small studies have reported heterogeneous immune dysfunction in FA. PROCEDURE: We performed a detailed immunologic assessment in a large FA cohort who have not undergone bone marrow transplantation or developed malignancies. Comprehensive quantitative and functional immunologic assessment of 29 FA individuals was compared to healthy age-matched controls. RESULTS: Compared to non-FA persons of similar ages, FA individuals showed lower absolute total B cells (P < 0.001), lower memory B cells (P < 0.001), and decreased IgM (P < 0.001) but normal IgG. NK cells (P < 0.001) and NK cytotoxicity (P < 0.001) were decreased. CD4+ T cells were decreased (P = 0.022), while CD8+ T cell and absolute T-cell numbers were comparable. Cytotoxic T cells (P < 0.003), and antigen proliferation response to tetanus (P = 0.019) and candida (P = 0.019), were diminished in FA. Phytohemagglutinin responses and plasma cytokines were normal. Within FA subjects, adults and older children (≥10 years) exhibited higher CD8+ T cells than younger children (P = 0.004). Documented atypical infections were infrequent, although oral human papilloma virus (HPV) prevalence was higher (31% positive) in FA. CONCLUSIONS: Overall, these results demonstrate a high rate of significant humoral and cellular immune dysfunction. Continued longitudinal study of immune function is critical to understand evolution with age, bone marrow failure, and cancer development.


Assuntos
Subpopulações de Linfócitos B/imunologia , Anemia de Fanconi/complicações , Síndromes de Imunodeficiência/etiologia , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Imunidade Adaptativa , Adolescente , Adulto , Criança , Pré-Escolar , Citocinas/metabolismo , Anemia de Fanconi/imunologia , Feminino , Seguimentos , Humanos , Síndromes de Imunodeficiência/patologia , Masculino , Prognóstico , Adulto Jovem
7.
Biol Blood Marrow Transplant ; 22(12): 2220-2225, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27664325

RESUMO

We describe a single-center prospective study of alemtuzumab as a second-line agent for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) in pediatric and young adult allogeneic hematopoietic stem cell transplant recipients. Alemtuzumab was administered for grades II to IV aGVHD if patients did not improve within 5 days or worsened within 48 hours after corticosteroids. Interim analyses of alemtuzumab levels and response were performed after every 5 patients enrolled, resulting in 3 dosing cohorts, as follows: (1) .2 mg/kg alemtuzumab subcutaneously on days 1 to 5 (maximum of 31 mg over 5 days) and .2 mg/kg/dose (not exceeding 10 mg/dose) on days 15, 22, and 29; (2) .2 mg/kg alemtuzumab subcutaneously on days 1 to 5 (maximum of 43 mg over 5 days) and .2 mg/kg/dose on day 7, 10, 15, 22, and 29; and (3) .2 mg/kg subcutaneously on days 1 to 5 and .2 mg/kg/dose on day 7, 10, 15, and 22. Alemtuzumab levels were assessed before starting alemtuzumab and at days 1, 3, 6, 10, and 14 and weekly until day 99, where day 1 was the day of first alemtuzumab dose. Fifteen patients (median age, 10 years; range, 1.4 to 27) received alemtuzumab for grades II (6%), III (74%), and IV (20%) SR-aGVHD. The overall response rate was 67%, with complete response (CR) in 40%, partial response (PR) in 27%, and no response in 33%. The median day 6 alemtuzumab level was 2.79 µg/mL (interquartile range, 1.34 to 4.89) in patients with CR compared with .62 µg/mL (interquartile range, .25 to 1.45) in patients with PR + no response (P < .05). Ninety percent (n = 9) of patients with a CR or PR reduced corticosteroid doses within 8 weeks from first alemtuzumab dose. Side effects included fever (26%) and transient thrombocytopenia (53%). Asymptomatic viremias occurred in all patients but invasive viral disease occurred in 2 patients. One patient developed Epstein-Barr virus-post-transplantation lymphoproliferative disorder. Eighty percent (n = 12) of patients were alive at 6 months, of whom 53% (n = 8) were free of GVHD whereas 13% (n = 2) developed chronic GVHD. Alemtuzumab is an effective second-line agent for children and young adults with SR-aGVHD. Higher alemtuzumab levels are associated with CR. A real-time dose adjusted alemtuzumab study is needed to further optimize the dose of alemtuzumab in aGVHD.


Assuntos
Alemtuzumab/administração & dosagem , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Terapia de Salvação/métodos , Doença Aguda , Adolescente , Adulto , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Febre/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Masculino , Estudos Prospectivos , Indução de Remissão , Esteroides/farmacologia , Esteroides/uso terapêutico , Trombocitopenia/etiologia , Transplante Homólogo , Resultado do Tratamento , Viroses/etiologia , Adulto Jovem
8.
Biol Blood Marrow Transplant ; 22(11): 2011-2018, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27543157

RESUMO

Myeloablative conditioning (MAC) regimens are commonly used in transplantation for chronic granulomatous disease (CGD) but are associated with toxicity. Reduced-intensity conditioning (RIC) regimens have lower toxicity but may fail to achieve stable donor chimerism. We report a comparison between 4 patients who received a RIC regimen consisting of alemtuzumab (1 mg/kg), fludarabine (150 mg/m2), and melphalan (140 mg/m2) and 14 patients who received a MAC regimen consisting of busulfan (area under the curve, 1800 to 2000 µMol/min twice daily × 4 days), cyclophosphamide (50 mg/kg/day × 4), and antithymocyte globulin (15 mg/kg twice daily on days -2 and -1, then daily on days +1 and +2). Seventy-five percent (n = 3) of RIC patients developed mixed chimerism and needed either withdrawal of immune suppression (n = 1) or additional stem cell products (n = 2) to achieve stable donor chimerism. Ninety-two percent (n = 13) of patients in the MAC group maintained >95% donor chimerism. Complications included acute graft-versus-host disease (MAC 64%, RIC 0%), chronic graft-versus-host disease (MAC 28%, RIC 0%), sinusoidal obstructive syndrome (MAC 7%, RIC 0%), bacteremia (MAC 42%, RIC 0%), fungemia (MAC 14%, RIC 0%), viral disease (MAC 7%, RIC 25%), and death (MAC 21%, RIC 0%). A RIC regimen has lower toxicity but frequently requires interventions to maintain donor chimerism compared with a MAC regimen in CGD.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/terapia , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Alemtuzumab/administração & dosagem , Soro Antilinfocitário/administração & dosagem , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Quimerismo , Ciclofosfamida/administração & dosagem , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Masculino , Melfalan/administração & dosagem , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Adulto Jovem
9.
Sci Immunol ; 1(6)2016 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-28783691

RESUMO

Recombination-activating genes 1 and 2 (RAG1 and RAG2) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome (n = 5), leaky SCID (n = 3), or CID-G/AI (n = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency.

10.
J Allergy Clin Immunol ; 134(4): 935-943.e15, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25109802

RESUMO

BACKGROUND: Patients with severe combined immunodeficiency disease who have matched sibling donors (MSDs) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. OBJECTIVE: We sought to determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URDs), either from volunteer adults or umbilical cord blood, are comparable with those from MSDs. METHODS: We performed a multicenter survey of severe combined immunodeficiency transplantation centers in North America, Europe, and Australia to compile retrospective data on patients who have undergone unconditioned HCT from either URDs (n = 37) or MSDs (n = 66). RESULTS: Most patients undergoing URD HCT (92%) achieved donor T-cell engraftment compared with 97% for those with MSDs; however, estimated 5-year overall and event-free survival were worse for URD recipients (71% and 60%, respectively) compared with MSD recipients (92% and 89%, respectively; P < .01 for both). URD recipients who received pre-HCT serotherapy had similar 5-year overall survival (100%) to MSD recipients. The incidences of grade II to IV acute and chronic graft-versus-host disease were higher in URD (50% and 39%, respectively) compared with MSD (22% and 5%, respectively) recipients (P < .01 for both). In the surviving patients there was no difference in T-cell reconstitution at the last follow-up between the URD and MSD recipients; however, MSD recipients were more likely to achieve B-cell reconstitution (72% vs 17%, P < .001). CONCLUSION: Unconditioned URD HCT achieves excellent rates of donor T-cell engraftment similar to that seen in MSD recipients, and reconstitution rates are adequate. However, only a minority will have myeloid and B-cell reconstitution, and attention must be paid to graft-versus-host disease prophylaxis. This approach might be safer in children ineligible for intense regimens to spare the potential complications of chemotherapy.


Assuntos
Linfócitos B/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/terapia , Irmãos , Linfócitos T/imunologia , Doadores não Relacionados , Adulto , Austrália , Criança , Quimerismo , Europa (Continente) , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Histocompatibilidade , Teste de Histocompatibilidade , Humanos , Lactente , Recém-Nascido , Masculino , América do Norte , Estudos Retrospectivos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/mortalidade , Análise de Sobrevida , Condicionamento Pré-Transplante , Resultado do Tratamento , Voluntários
11.
Pediatr Transplant ; 18(1): 94-102, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24384050

RESUMO

SR-aGVHD remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Alemtuzumab has been used with success in adult patients but has not been studied in the pediatric setting. To estimate the effectiveness of alemtuzumab for the treatment of SR-aGVHD in pediatric patients, we retrospectively reviewed the charts of 19 patients (median age 4 yr, range 0.5-28 years) with grades II (n = 3), III (n = 10), or IV (n = 6) SR-aGVHD who received alemtuzumab treatment. Patients received a median dose of 0.9 mg/kg alemtuzumab (range 0.3-2 mg/kg) divided over 2-6 days. Eighty-nine percent of patients received additional courses. A complete response, defined as GVHD of grade 0 at four wk following the first alemtuzumab course, was observed in nine patients (47%). A partial response, defined as an improvement in grade after four wk, was observed in five patients (26%). There was no response in five patients (26%). The overall response rate at four wk was 73%. Infectious complications included bacteremia (47%), presumed or documented fungal infections (21%), adenovirus viremia (52%), EBV viremia (36%), and CMV viremia (36%). We conclude that alemtuzumab is effective for SR-aGVHD in pediatric patients with a tolerable spectrum of complications.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Esteroides/uso terapêutico , Infecções por Adenoviridae/tratamento farmacológico , Adolescente , Adulto , Alemtuzumab , Algoritmos , Anti-Infecciosos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Criança , Pré-Escolar , Infecções por Citomegalovirus/tratamento farmacológico , Resistência a Medicamentos , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Humanos , Lactente , Micoses/tratamento farmacológico , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Viroses/tratamento farmacológico , Adulto Jovem
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