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1.
Attenuated poxvirus expressing three immunodominant CMV antigens as a vaccine strategy for CMV infection. 总被引:2,自引:0,他引:2
Zhongde Wang Corinna La Rosa Simon F Lacey Rebecca Maas Shahram Mekhoubad William J Britt Don J Diamond 《Journal of clinical virology》2006,35(3):324-331
BACKGROUND: Human cytomegalovirus (CMV) infection is an important risk factor in the post-transplant (Tx) recovery phase for both hematopoietic stem cell Tx (HSCT) and solid organ Tx (SOT) recipients. CMV infection may be prevented or controlled by simultaneously inducing both CMV-specific neutralizing antibody (nAb) and cellular immunity. Soluble (s) UL55 (surface glycoprotein), UL83 (tegument protein) and UL123/e4 (nuclear protein) are immunodominant in eliciting both CMV nAb and cellular immunity. An attenuated poxvirus, modified vaccinia Ankara (MVA) was selected to develop this vaccine strategy in Tx recipients, because of its clinical safety record, large foreign gene capacity, and capability to activate strong humoral and cellular immune responses against recombinant antigens. OBJECTIVES: A subunit vaccine that targets multiple CMV antigens will be used to gain maximal coverage and protective function against CMV infection. rMVA simultaneously expressing sUL55, UL83 and UL123/e4 will be generated, and humoral and cellular immunity it elicits will be characterized, after murine immunization and in vitro to amplify clinical recall responses. STUDY DESIGN: rMVA will be constructed in two steps using UL123/e4-pLW22 followed by sUL55-UL83-pLW51 transfer plasmids. Western blots will be used to characterize expression levels of each antigen. Primary immunity will be evaluated in mouse models, while recall responses to the virally expressed CMV antigens will be assessed in human peripheral blood. RESULTS: We generated CMV-MVA via homologous recombination, and demonstrated high expression levels of sUL55, UL83 and UL123/e4 by Western blot. CMV-MVA immunization potently induced both humoral and cellular immunity to sUL55, UL83 and UL123 after murine immunization, and cellular immunity to UL83 and UL123 by in vitro amplification of T cell recall responses in human PBMC. CONCLUSIONS: rMVA promotes high level expression of three immunodominant CMV antigens, which is reflected in results of immunization studies in which high titers of UL55-specific antibodies and CD4+ T-help are detected, as well as high levels of UL83-specific and moderate levels of UL123-specific CD8+ CTL. 相似文献
2.
《Biology of blood and marrow transplantation》2013,19(7):1013-1020
Varicella-zoster virus (VZV) reactivation is a frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Although previous studies have revealed that cellular immunity is important for suppressing reactivation, the role of humoral immunity against VZV has been poorly evaluated. We analyzed inherited polymorphisms in the immunoglobulin G (IgG) heavy chain constant regions of 50 HSCT recipient-donor pairs to distinguish donor-derived and recipient-derived antibodies. Twelve pairs were informative regarding the origin of IgG, since either the donors (n = 3) or recipients (n = 9) were homozygous null for the IgG1m(f) allotype. In these 9 homozygous-null recipients, allotype-specific IgG against VZV were measured by enzyme-linked immunosorbent assay and compared with measles-IgG. All 9 homozygous-null recipients were monitored for more than 1 year after HSCT, with (n = 4, localized zoster) or without (n = 5) clinical VZV disease. In 3 patients with VZV disease, donor-derived IgG against VZV was elevated between 500 to 700 days after HSCT after the episode of VZV disease. In 1 patient who suffered from VZV disease just before HSCT, donor-derived VZV IgG was elevated within 3 months after HSCT. On the other hand, 2 patients who received reduced-intensity conditioning (RIC) transplantation from an IgG1m(f) null donor maintained recipient-derived IgG against VZV for more than 1 year, whereas it was decreased within 3 months in 1 recipient who received conventional conditioning. In conclusion, the production of anti-VZV IgG by recipient plasma cells persists long after RIC. In patients without symptomatic VZV reactivation, donor-derived anti-VZV IgG did not reach titers comparable to those measured in healthy virus carriers. 相似文献
3.
Protection against pathogens is mediated by both humoral responses (neutralizing antibodies) and cellular immunity, both CD4+ and CD8+ cells. In the case of influenza viruses, circulating strains contain both variable and conserved T and B cell epitopes that are challenged after vaccination and/or infection. During infection, the role of T cells is to prevent viral dissemination in the organism by killing the infected cells and helping B cell antibody production to neutralize the virus. The threat of influenza virus increases the preparedness of protective immunity to pandemic and seasonal infection by vaccination. Several questions remain that need to be further addressed for the future development of innovative and rapidly efficient vaccines strategies. Firstly, what are the correlates of long-term protection (antibodies and/or T cells) against variant strains of influenza? How does the individual factors (age, natural immunity, vaccination and/or infection history) influence the generation and maintenance of memory cells? What are the factors allowing the maintenance of immune memory (regular contact with the pathogen or re-vaccination)? Secondly, what is the nature and quality (function / phenotype / location) of memory B and T cells? Finally, is it necessary to induce and maintain immunological memory against conserved proteins and/or to re-vaccinate against viral variants? What would be the consequences of repeated vaccination? These questions remain a subject of debate that will be further discussed. Since immunological memory is the cornerstone of vaccination, it is essential that we have a better understanding of its generation and maintenance over time as well as its contribution to recall responses during pandemics or after vaccination. 相似文献
4.
Infectious complications are a serious cause of morbidity and mortality following hematopoietic stem cell transplantation
(HSCT), and the lung is a particular target organ post-transplant. Our laboratory has used a murine bone marrow transplant
model to study alterations in immunity that occur as a result of transplantation. Our studies focus on immune responses that
occur following immune cell reconstitution in the absence of immunosuppressive drug therapy or graft-versus-host disease.
We have found that impaired clearance of both bacterial and viral pulmonary infections is related to specific alterations
in immune cell function and cytokine production. Our data offer insight into mechanisms that contribute to opportunistic infections
in HSCT recipients. 相似文献
5.
Olkinuora H von Willebrand E Kantele JM Vainio O Talvensaari K Saarinen-Pihkala U Siitonen S Vettenranta K 《Scandinavian journal of immunology》2011,73(6):586-593
Viral infections and graft‐versus‐host disease (GVHD) render an impact on both the clinical and immunological recovery following allogeneic hematopoietic stem cell transplantation (HSCT). We studied the recuperation of the immune defence after transplant in the paediatric setting and assessed the impact of early (<100 days post‐HSCT) viral [cytomegalovirus (CMV), Ebstein‐Barr virus (EBV) and adenovirus] reactivations/infections and GVHD. Fifty‐one paediatric recipients of HSCT were enrolled. T cell recovery was evaluated on lymphocyte subpopulations using flow cytometry and functionally by measuring T cell excision circles (TRECs) and through the analysis of T lymphocyte responses to mitogens. B cell recovery was studied by flow cytometry and functionally by ELISPOT. Acute and mild chronic GVHD allowed for a brisk recovery of both cellular and humoral immunity while moderate to severe chronic graft‐versus‐host disease (cGVHD) associated with a significant, tampering effect on the immunological recovery after transplant. In the former group, the early viral reactivations/infections seemingly linked with a delayed recovery of T lymphocytes and low TRECs values. Moderate to severe cGVHD appears to associate with an impaired immunological recovery after HSCT. Early viral infections linked with prolonged T cell immunodeficiency and thymic dysfunction may be indicative of the presence of subclinical GVHD. 相似文献
6.
Dendritic cells in genetic immunization. 总被引:1,自引:0,他引:1
Both humoral and cellular immune responses are inducible by inoculation of naked plasmid DNA encoding a polypeptide antigen. This new vaccination protocol, known as genetic immunization, has been used to initiate protective immunity against a variety of infectious pathogens and tumors in experimental animals. Dendritic cells (DC) are thought to play at least three distinct roles in genetic immunization: (1) MHC class II-restricted presentation of antigens secreted by neighboring, transfected cells, (2) MHC class I-restricted "cross" presentation of antigens released by neighboring, transfected cells, and (3) direct presentation of antigens by transfected DC themselves. Several new technologies have been developed recently in an attempt to improve the overall efficacy of genetic vaccination, as well as to regulate the type and class of resulting immune responses. These technologies include modification of plasmid DNA, co-delivery of genes encoding immunoregulatory molecules, and DC targeting. We will overview some of these new technologies in genetic immunization. 相似文献
7.
Intramuscular injection of bacterially derived plasmid DNA results in the development of both humoral and cellular immune responses against plasmid-encoded antigens. Immunostimulatory CpG sequences within bacterial DNA are thought to enhance this process by stimulating the secretion of proinflammatory cytokines such as interferon gamma (IFNgamma) by cells of the innate immune system. Although IFNgamma induction by CpG elements within plasmid DNA has been documented in vitro and more recently in vivo, and coimmunization with plasmids expressing IFNgamma has been shown to enhance DNA-immunization-induced immune responses, it is unclear if IFNgamma is necessary for successful DNA immunization. To address this issue, we compared humoral and cellular immune responses in wild-type and IFNgamma-deficient mice vaccinated with a plasmid (pCMVNP) expressing the nucleoprotein gene from the arenavirus lymphocytic choriomeningitis virus (LCMV). IFNgamma-positive (BALB/c) and IFNgamma-negative (GKO) mice responded to DNA vaccination by the development of antigen-specific CD8(+) T cells, which were detectable directly ex vivo by intracellular cytokine staining and comprised 0.7-2.5% of all CD8(+) T cells in the vaccine. DNA vaccines also induced virus-specific cytotoxic T lymphocytes (CTL), even in the absence of IFNgamma. DNA vaccination of both mouse strains also was associated with a significant reduction in viral titers after LCMV challenge, indicating that, at least in the presence of other immune effector mechanisms, IFNgamma is not required for induction of protective anti-viral immunity by DNA immunization. No quantitative differences were observed in antiviral IgG levels among GKO and BALB/c vaccinees, although GKO mice did exhibit a significant reduction of the IgG2a:IgG1 ratio, in agreement with the previously documented requirement for IFNgamma in isotype switching to IgG2a. Immunized BALB/c mice produced similar levels of both IgG1 and IgG2a, indicating a mixed Th1/Th2 response to intramuscular immunization with pCMVNP. These results show that IFNgamma induction by bacterially derived plasmid DNA does not contribute to the magnitude of the antibody response and is not required for the induction or short-term maintenance of DNA-induced CTL. However, IFNgamma is necessary for the development of IgG2a antibodies that may be crucial for protection against some pathogens. 相似文献
8.
A study of the efficacy of typhoid vaccine in inducing humoral and cell-mediated immune responses in human volunteers. 总被引:2,自引:1,他引:2
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T R Nath A N Malaviya R Kumar K Balakrishnan B P Singh 《Clinical and experimental immunology》1977,30(1):38-43
The nature of protective immunity against typhoid fever in man is not at present well understood. Work on animal models and earlier studies from this laboratory indicate an important protective role for cellular immunity. The present work attempts to study the efficacy of the conventional typhoid vaccine in inducing specific cellular and humoral immune responses. The study on fifty-eight new army recruits and thirty-one civilian volunteers showed adequate humoral responses after vaccination. However, vaccination failed to induce a significant cellular immune response. In addition, a transient suppression of cellular immunity was observed in the immediate post-vaccination period in ten subjects who possessed natural cellular immunity before vaccination. These findings indicate the need for improving the typhoid vaccine so that it will induce cellular immunity as well as a humoral response. It also points to the necessity for obtaining detailed knowledge of the post-vaccination anergy as it could be important in timing public health programmes. 相似文献
9.
Adenoviral vector has been extensively studied as a vaccine platform because of its ability to induce potent cellular and humoral immunity. One main advantage of adenoviral vectors is their natural tropism for mucosal surfaces, which makes them ideal for the purpose of mucosal vaccination against pathogens that preferentially initiate infection at the mucosal site. The current understanding of mucosal immunity suggests that mucosal vaccination is far superior to parenteral vaccination in protecting mucosal surfaces. Mucosal vaccination is particularly relevant to those infections for which parenteral immunization strategies have failed to confer protection. This review examines the use of adenoviral vector at mucosal sites for infectious disease against which the current vaccination strategies have been unsuccessful in eliciting protection. Data from animal models have suggested that adenoviral vectors are effective in protecting against infections caused by HIV, herpes simplex virus and Mycobacterium tuberculosis. We believe that these encouraging results will lead to further evaluation in clinical trials in the near future. 相似文献
10.
Rajko Reljic Laura Sibley Jen-Min Huang Ilaria Pepponi Andreas Hoppe Huynh A. Hong Simon M. Cutting 《Infection and immunity》2013,81(11):4071-4080
Needle-free, mucosal immunization is a highly desirable strategy for vaccination against many pathogens, especially those entering through the respiratory mucosa, such as Mycobacterium tuberculosis. Unfortunately, mucosal vaccination against tuberculosis (TB) is impeded by a lack of suitable adjuvants and/or delivery platforms that could induce a protective immune response in humans. Here, we report on a novel biotechnological approach for mucosal vaccination against TB that overcomes some of the current limitations. This is achieved by coating protective TB antigens onto the surface of inert bacterial spores, which are then delivered to the respiratory tract. Our data showed that mice immunized nasally with coated spores developed humoral and cellular immune responses and multifunctional T cells and, most importantly, presented significantly reduced bacterial loads in their lungs and spleens following pathogenic challenge. We conclude that this new vaccine delivery platform merits further development as a mucosal vaccine for TB and possibly also other respiratory pathogens. 相似文献
11.
《Biology of blood and marrow transplantation》2014,20(7):992-999
JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. The mechanism of JCV reactivation and immunity in a transplanted immune system remains unclear. We prospectively studied 30 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) and collected blood and urine samples before HSCT and 3, 6, and 12 to 18 months after HSCT. Before HSCT, JCV DNA was detected in 7 of 30 urine, 5 of 30 peripheral blood mononuclear cells (PBMC) and 6 of 30 plasma samples. Although JC viruria remained stable after HSCT with detection in 5 of 21 samples, viremia was detected in only 1 of 22 plasma and none of 22 PBMC samples 12 to 18 months after HSCT. Prevalence of anti-JCV IgG was 83% before HSCT and decreased to 72% at 12 to 18 months. Anti-JCV IgM was rarely detected. JCV-specific CD4+ and CD8+ T cell responses increased 12 to 18 months after HSCT. Although JC viruria correlated directly with detection of anti-JCV IgG, the cellular immune response to JCV measured by ELISpot was inversely correlated with anti-JCV IgG response. The diagnosis of acute myelogenous leukemia and age group were 2 independent patient factors associated with significantly reduced cellular immune responses to JCV. This prospective study in HSCT patients provides a model of interactions between the host immune response and viral activation in multiple compartments during the recovery of the immune system. 相似文献
12.
Complete remission of VZV reactivation treated with valganciclovir in a patient with total lymphocyte depletion and acute kidney injury after allogeneic bone marrow transplantation
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Natalia Maximova Pizzol Antonio Granzotto Marilena Francesca Rovere Paolo Tamaro 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2015,123(1):77-80
Varicella zoster virus (VZV), a threat for hematopoietic stem cell transplantation (HSCT) recipients, is still one of the most common viral pathogens that affect these patients with a reported incidence ranging between 17% and 50% in the post transplantation period. Valganciclovir (V‐GCV), a valine ester pro‐drug of GCV orally administrable, has recently shown great activity against CMV infections, but there are no reports of its clinical efficacy against VZV. We here report a case history of a patient with positive serologic test for VZV, who underwent allogeneic HSCT and developed an atypical varicella‐like illness. First‐line therapy with foscarnet had to be discontinued due rapid development of renal impairment (creatinine: 2.60 mg/dL, urea: 130.6 mg/dL) and therefore was switched to V‐GCV. The renal impairment and skin lesions of the patient fully recovered after few days of therapy, even though the patient had complete lymphocyte depletion. This is the first case of a patient with chickenpox‐like illness treated successfully with V‐GCV. 相似文献
13.
Marked enhancement of the antigen-specific immune response by combining plasmid DNA-based immunization with a Schiff base-forming drug
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Charo J Sundbäck M Wasserman K Ciupitu AM Mirzai B van der Zee R Kiessling R 《Infection and immunity》2002,70(12):6652-6657
Although plasmid DNA (pDNA)-based immunization has proven efficacy, the level of immune responses that is achieved by this route of vaccination is often lower than that induced by traditional vaccines, especially for primates and humans. We report here a simple and potent method to enhance pDNA-based vaccination by using two different plasmids encoding viral or bacterial antigens. This method is based on coadministration of low concentrations of a recently described immunopotentiating, Schiff base-forming drug called tucaresol which has led to significant augmentation of antigen-specific humoral and cellular immune responses. Our data suggest that enhancement of the immune response with tucaresol might provide a powerful tool for the further development of pDNA-based immunization for humans. 相似文献
14.
Yoshida T Okuda K Xin KQ Tadokoro K Fukushima J Toda S Hagiwara E Hamajima K Koshino T Saito T 《Clinical and experimental immunology》2001,124(3):445-452
We constructed a recombinant replication defective adenovirus vector containing the env gene (Ad-Bal) derived from macrophage-trophic HIV-1 (HIV-1 Bal). We then immunized mice with this vector using several administration routes and protocols, and examined the immune response. When the Ad-Bal viral vector (over 1 x 10(7) pfu) was injected subcutaneously, both humoral and cell-mediated immunities were induced. However, immune response induced by the Ad-Bal vector alone was weaker than that induced by the recombinant vaccinia viral vector. We then employed the following three immunization protocols: (l) DNA vaccination followed by immunization with the Ad-Bal; (2) vaccination using the Ad-Bal vector followed by DNA vaccination; and (3) DNA vaccination followed by Ad-Bal infection and passive transfer of dendritic cells (DCs) infected with the Ad-Bal. Among the three protocols, the last gave the strongest humoral and cell-mediated immunity. These results suggest that the combination of DNA vaccination, Ad-Bal vector infection and passive transfer of Ad-Bal-infected DCs can induce strong immunity against HIV-1 Bal. 相似文献
15.
《Biology of blood and marrow transplantation》2020,26(3):581-592
Outbreaks of viral infections, such as measles, are regularly observed and pose a serious threat to recipients of allogeneic hematopoietic cell transplantation (HCT). The questions of how long cellular and humoral protective host immunity persists, and whether donor immunity can be transferred has not been clarified. Here we present a retrospective analysis of humoral immunity—serial antibody titers against measles, mumps, and rubella—in 331 patients who underwent allogeneic HCT at our single center between 2002 and 2015. Associations between the loss of protective antibody levels and clinical patient characteristics and transplantation parameters were examined. In general, antibody protection against measles persisted longer, with 72% of patients maintaining sufficient titers at 5 years post-HCT even without revaccination, while at that time only 65% and 50% of patients had protective immunity against rubella and mumps, respectively. The great majority of donors were seropositive for all 3 viruses; however, it appeared that donor humoral immunity could not be transferred and had no impact on post-HCT serostatus. Rather, the most relevant factor for persistent protective antibody titers against measles and rubella was whether patients were born before the introduction of the respective vaccine and thus were immunized by the wild-type disease-inducing virus instead of the vaccine. Moreover, the presence of moderate and severe chronic graft-versus-host disease (GVHD) was associated with more rapid loss of immune protection. In contrast, underlying disease, intensity of the conditioning regimen, use of antithymocyte globulin, age, and graft source had no influence on antibody titers. Overall, our findings suggest that the majority of antibodies against measles, mumps, and rubella originate from residual host cells, whereas donor immune status appears to have no influence on antibody protection post-HCT. 相似文献
16.
A. John Barrett Susan Prockop Catherine M. Bollard 《Biology of blood and marrow transplantation》2018,24(1):13-18
Virus infection remains an appreciable cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although pharmacotherapy and/or antibody therapy may help prevent or treat viral disease, these drugs are expensive, toxic, and often ineffective due to primary or secondary resistance. Further, effective treatments are limited for many infections (eg, adenovirus, BK virus), which are increasingly detected after alternative donor transplants. These deficiencies in conventional therapeutics have increased interest in an immunotherapeutic approach to viral disorders, leading to adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs), which can rapidly reconstitute antiviral immunity post-transplantation without causing graft-versus-host disease. This review will explore how the VST field has improved outcomes for many patients with life-threatening viral infections after HSCT, and how to broaden applicability beyond the “patient-specific” products, as well as extending to other viral diseases even outside the context of HSCT. 相似文献
17.
Ballinger MN McMillan TR Moore BB 《Archivum immunologiae et therapiae experimentalis》2007,55(1):1-12
Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for a number of malignant and inherited disorders.
However, the efficacy of this therapy is limited by a number of serious infectious and noninfectious complications. Pulmonary
infections represent a significant cause of morbidity and mortality post-HSCT and can occur both pre- and post-hematopoietic
reconstitution. Susceptibility to Gram-negative bacterial infections despite full hematopoietic engraftment suggests that
innate immunity remains impaired months to years post-HSCT. This review will describe the process and complications of HSCT
and will summarize what is known about innate immune reconstitution post-HSCT. Data from the literature as well as our own
laboratory will be presented to suggest that an eicosanoid imbalance characterized by over-production of prostaglandins and
under-production of leukotrienes leads to impaired lung phagocyte function post-HSCT. Of therapeutic interest, strategies
which limit production of prostaglandins can improve pulmonary host defense in animal HSCT models, which suggests that this
may also be beneficial for human HSCT recipients. 相似文献
18.
Wils EJ Aerts-Kaya FS Rombouts EJ van Mourik I Rijken-Schelen A Visser TP Braakman E Wagemaker G Cornelissen JJ 《Biology of blood and marrow transplantation》2012,18(1):55-65
Deficient thymopoiesis and retarded recovery of naive CD4(+) T cells are important determinants of insufficient immune-competence following hematopoietic stem cell transplantation (HSCT). Although keratinocyte growth factor (KGF) may protect the thymic epithelium, stem cell factor (SCF) is involved in early thymopoiesis. We evaluated whether KGF alone or combined with SCF would affect thymopoiesis and hematologic recovery following myeloablative autologous HSCT into rhesus macaques. Purpose-bred adult rhesus macaques received 10(6) autologous CD34(+)-selected mononuclear bone marrow cells (BMC)/kg after 9 Gy myeloablative conditioning. Animals were treated with phosphate-buffered saline (PBS) (n = 2), KGF alone (n = 2), or KGF combined with SCF (n = 2). KGF-treated animals showed accelerated hematologic recovery, improved thymopoiesis, and enhanced naive T-cell recovery following transplantation. Improved T cell recovery was not associated with protection against cytomegalovirus reactivation nor with improved antibody response to tetanus toxoid vaccination. Animals treated with KGF and SCF experienced severe adverse events that precluded evaluation of thymopoiesis and T cell recovery. Collectively, our data confirm that KGF may enhance thymopoiesis. 相似文献
19.
de Bastos Ascenço Soares R Gomez FJ de Almeida Soares CM Deepe GS 《Infection and immunity》2008,76(9):4214-4221
Paracoccidioides brasiliensis causes a chronic granulomatous mycosis prevalent in Latin America. The successful resolution of infection with this fungus is dependent on the activation of cellular immunity. We previously identified heat shock protein 60 (HSP60) as a target of the humoral response in paracoccidioidomycosis. Herein we expressed the gene encoding HSP60 in Escherichia coli and analyzed the immunological activity of this recombinant antigen. The immunization of BALB/c mice with recombinant protein emulsified in adjuvant stimulated a cellular immune response. Splenocytes from immunized mice proliferated in response to antigen and released interleukin-12 and gamma interferon (IFN-gamma). Vaccination with HSP60 reduced the fungal burden in mice given 10(6) or 10(7) yeasts and protected mice from a lethal challenge. The efficacy of the vaccination was blunted by the neutralization of IFN-gamma. CD4(+) cells were necessary for the efficacy of the vaccination in both the afferent and efferent phases. Thus, we have demonstrated that this immunodominant antigen is a candidate for the development of a vaccine against this fungus. 相似文献
20.
Gaspar HB Cooray S Gilmour KC Parsley KL Adams S Howe SJ Al Ghonaium A Bayford J Brown L Davies EG Kinnon C Thrasher AJ 《Science translational medicine》2011,3(97):97ra79
X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the common cytokine receptor γ chain. These mutations classically lead to complete absence of functional T and natural killer cell lineages as well as to intrinsically compromised B cell function. Although human leukocyte antigen (HLA)-matched hematopoietic stem cell transplantation (HSCT) is highly successful in SCID-X1 patients, HLA-mismatched procedures can be associated with prolonged immunodeficiency, graft-versus-host disease, and increased overall mortality. Here, 10 children were treated with autologous CD34(+) hematopoietic stem and progenitor cells transduced with a conventional gammaretroviral vector. The patients did not receive myelosuppressive conditioning and were monitored for immunological recovery after cell infusion. All patients were alive after a median follow-up of 80 months (range, 54 to 107 months), and a functional polyclonal T cell repertoire was restored in all patients. Humoral immunity only partially recovered but was sufficient in some patients to allow for withdrawal of immunoglobulin replacement; however, three patients developed antibiotic-responsive acute pulmonary infection after discontinuation of antibiotic prophylaxis and/or immunoglobulin replacement. One patient developed acute T cell acute lymphoblastic leukemia because of up-regulated expression of the proto-oncogene LMO-2 from insertional mutagenesis, but maintained a polyclonal T cell repertoire through chemotherapy and entered remission. Therefore, gene therapy for SCID-X1 without myelosuppressive conditioning effectively restored T cell immunity and was associated with high survival rates for up to 9 years. Further studies using vectors designed to limit mutagenesis and strategies to enhance B cell reconstitution are warranted to define the role of this treatment modality alongside conventional HSCT for SCID-X1. 相似文献