Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Más filtros

Banco de datos
Tipo de estudio
Tipo del documento
Asunto de la revista
País de afiliación
Intervalo de año de publicación
1.
Haematologica ; 99(12): 1854-9, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25150256

RESUMEN

Minor histocompatibility antigens are highly immunogeneic polymorphic peptides playing crucial roles in the clinical outcome of HLA-identical allogeneic stem cell transplantation. Although the introduction of genome-wide association-based strategies significantly has accelerated the identification of minor histocompatibility antigens over the past years, more efficient, rapid and robust identification techniques are required for a better understanding of the immunobiology of minor histocompatibility antigens and for their optimal clinical application in the treatment of hematologic malignancies. To develop a strategy that can overcome the drawbacks of all earlier strategies, we now integrated our previously developed genetic correlation analysis methodology with the comprehensive genomic databases from the 1000 Genomes Project. We show that the data set of the 1000 Genomes Project is suitable to identify all of the previously known minor histocompatibility antigens. Moreover, we demonstrate the power of this novel approach by the identification of the new HLA-DP4 restricted minor histocompatibility antigen UTDP4-1, which despite extensive efforts could not be identified using any of the previously developed biochemical, molecular biological or genetic strategies. The 1000 Genomes Project-based identification of minor histocompatibility antigens thus represents a very convenient and robust method for the identification of new targets for cancer therapy after allogeneic stem cell transplantation.


Asunto(s)
Variación Genética/genética , Genoma Humano , Estudio de Asociación del Genoma Completo , Neoplasias Hematológicas/genética , Análisis por Micromatrices , Antígenos de Histocompatibilidad Menor/clasificación , Antígenos de Histocompatibilidad Menor/genética , Frecuencia de los Genes , Haplotipos/genética , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Humanos , Polimorfismo de Nucleótido Simple/genética , Trasplante Homólogo
2.
Clin Cancer Res ; 13(13): 4009-15, 2007 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-17606735

RESUMEN

PURPOSE: Donor T cells directed to hematopoietic minor histocompatibility antigens (mHag) are appealing tools for adoptive immunotherapy of hematological malignancies after allogeneic stem cell transplantation (allo-SCT). Toward the development of a convenient strategy for ex vivo generation of human leukocyte antigen (HLA) class II--restricted mHag-specific T cells, we evaluated the feasibility of rebuilding mHag-specific T cell functions in donor-derived recall antigen-specific T cells via T cell receptor (TCR) transfer. EXPERIMENTAL DESIGN: TCR alpha- and beta-chains of an HLA-DPB1*0401--restricted T-cell clone recognizing a multiple myeloma-associated mHag were retrovirally transferred into a tetanus toxoid (TT)--specific clone derived from the original stem cell donor. TCR double-transduced cells were compared with the parent mHag- and TT-specific clones for antigen specificity, cytokine secretion, and cytotoxic activity and were analyzed for their in vitro expansion capacity in a TT- or mHag-specific fashion. RESULTS: mHag-TCR--transduced TT-specific cells displayed both TT and mHag specificity. Similar to the parent cells, they secreted Th-1 cytokines and exerted significant cytotoxic activity against TT-pulsed or mHag(+) target cells, including multiple myeloma cells. A 4-week expansion of TCR-transduced cells via the TT-specific TCR had no negative influence on the mHag-specific cytotoxic activity and resulted in 10- to 100-fold better cell yields as compared with mHag-specific expansion. CONCLUSIONS: HLA class II--restricted, mHag-specific effector functions can be successfully reconstructed in donor-derived TT-specific T cells via TCR transfer. Effective expansion of these T cells via TT-specific TCRs illustrate the suitability of this strategy for ex vivo expansion and possibly for in vivo TT-specific reboosting of HLA class II--restricted immunotherapeutic T cells.


Asunto(s)
Antígenos de Histocompatibilidad Clase II/genética , Inmunoterapia Adoptiva/métodos , Antígenos de Histocompatibilidad Menor/química , Linfocitos T/inmunología , Traslado Adoptivo , Línea Celular Tumoral , Separación Celular , Trasplante de Células , Clonación Molecular , Citometría de Flujo , Humanos , Inmunofenotipificación , Mieloma Múltiple/metabolismo , Retroviridae/genética , Linfocitos T/química , Factores de Tiempo
3.
Clin Cancer Res ; 16(22): 5481-8, 2010 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-21062930

RESUMEN

PURPOSE: The essential role of CD4(+) T cells as helpers of anticancer immunity is indisputable. Little is known, however, about their capacity to serve as effector cells in cancer treatment. Therefore, we explored the efficacy of immunotherapy with sole CD4(+) cytotoxic human T cells directed at a hematopoietic-restricted minor histocompatibility antigen (mHag). EXPERIMENTAL DESIGN: In macrophage-depleted Rag2(-/-)γc(-/-) mice, which were also devoid of T, B, and natural killer cells, mHag-specific native T cells or tetanus toxoid (TT)-specific T cells transduced with the mHag-specific T-cell receptor (TCR) were injected to treat full-blown mHag(+) human multiple myeloma tumors. RESULTS: mHag-specific antitumor responses were achieved after injection of native or mHag-TCR-transduced T cells. Although the therapy completely eradicated the primary tumors in the bone marrow, it failed to control extramedullary relapses, even after repeated T-cell injections. Detailed analyses ruled out mHag or MHC downregulation as mechanisms of extramedullary tumor escape. Impaired T-cell survival in vivo or defective homing to the tumor site were also ruled out as mechanisms behind extramedullary relapses, because injections of TT-loaded antigen presenting cells could facilitate homing of long-term surviving T cells to s.c. tumor sites. Moreover, intratumoral treatment of extramedullary tumors with 3AB11 was also ineffective. CONCLUSIONS: Taken together, these results for the first time show the feasibility of immunotherapy of primary bone marrow tumors with sole CD4(+) human T cells directed to a tumor-associated mHag. Extramedullary relapses, probably due to microenvironment-dependent inhibitory mechanisms, remain a challenging issue towards effective cellular immunotherapy of hematologic malignancies.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Antígenos de Histocompatibilidad Menor/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T/uso terapéutico , Animales , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/inmunología , Humanos , Inmunoterapia , Ratones , Antígenos de Histocompatibilidad Menor/administración & dosificación , Antígenos de Histocompatibilidad Menor/inmunología , Mieloma Múltiple/inmunología , Receptores de Antígenos de Linfocitos T/administración & dosificación , Receptores de Antígenos de Linfocitos T/inmunología
4.
Clin Cancer Res ; 15(23): 7137-43, 2009 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-19934307

RESUMEN

PURPOSE: Identification of minor histocompatibility antigens (mHag) with classic methods often requires sophisticated technologies, determination, and patience. We here describe and validate a nonlaborious and convenient genetic approach, based on genome-wide correlations of mHag zygosities with HapMap single-nucleotide polymorphism genotypes, to identify clinical relevant mHags within a reasonable time frame. EXPERIMENTAL DESIGN: Using this approach, we sought for the mHag recognized by a HLA-DRB1*1501-restricted T-cell clone, isolated from a multiple myeloma patient during a strong graft-versus-tumor effect associated with acute graft-versus-host disease grade 3. RESULTS: In a period of 3 months, we determined the mHag phenotype of 54 HapMap individuals, deduced the zygosity of 20 individuals, defined the mHag locus by zygosity-genotype correlation analyses, tested the putative mHag peptides from this locus, and finally showed that the mHag is encoded by the arginine (R) allele of a nonsynonymous single-nucleotide polymorphism in the SLC19A1 gene. CONCLUSIONS: We conclude that this powerful and convenient strategy offers a broadly accessible platform toward rapid identification of mHags associated with graft-versus-tumor effect and graft-versus-host disease.


Asunto(s)
Antígenos de Histocompatibilidad Menor/análisis , Mieloma Múltiple/metabolismo , Alelos , Arginina/química , Linfocitos T CD4-Positivos/metabolismo , Genoma , Genotipo , Enfermedad Injerto contra Huésped , Efecto Injerto vs Tumor , Humanos , Proteínas de Transporte de Membrana/genética , Modelos Genéticos , Péptidos/química , Fenotipo , Polimorfismo de Nucleótido Simple , Proteína Portadora de Folato Reducido
5.
J Exp Med ; 205(12): 2863-72, 2008 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-19001137

RESUMEN

Some minor histocompatibility antigens (mHags) are expressed exclusively on patient hematopoietic and malignant cells, and this unique set of antigens enables specific targeting of hematological malignancies after human histocompatability leucocyte antigen (HLA)-matched allogeneic stem cell transplantation (allo-SCT). We report the first hematopoietic mHag presented by HLA class II (HLA-DQA1*05/B1*02) molecules to CD4(+) T cells. This antigen is encoded by a single-nucleotide polymorphism (SNP) in the B cell lineage-specific CD19 gene, which is an important target antigen for immunotherapy of most B cell malignancies. The CD19(L)-encoded antigen was identified using a novel and powerful genetic strategy in which zygosity-genotype correlation scanning was used as the key step for fine mapping the genetic locus defined by pairwise linkage analysis. This strategy was also applicable for genome-wide identification of a wide range of mHags. CD19(L)-specific CD4(+) T cells provided antigen-specific help for maturation of dendritic cells and for expansion of CD8(+) mHag-specific T cells. They also lysed CD19(L)-positive malignant cells, illustrating the potential therapeutic advantages of targeting this novel CD19(L)-derived HLA class II-restricted mHag. The currently available immunotherapy strategies enable the exploitation of these therapeutic effects within and beyond allo-SCT settings.


Asunto(s)
Antígenos CD19/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Genoma Humano , Leucemia de Células B , Sitios Menores de Histocompatibilidad/inmunología , Linfocitos T Citotóxicos/inmunología , Secuencia de Aminoácidos , Antígenos CD19/genética , Secuencia de Bases , Linfocitos T CD4-Positivos/citología , Mapeo Cromosómico , Femenino , Antígenos HLA/genética , Antígenos HLA/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunofenotipificación , Leucemia de Células B/genética , Leucemia de Células B/inmunología , Masculino , Sitios Menores de Histocompatibilidad/genética , Datos de Secuencia Molecular , Linaje , Polimorfismo de Nucleótido Simple , Alineación de Secuencia
6.
Urology ; 62(3): 559-65, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12946777

RESUMEN

OBJECTIVES: The use of recombinant adenoviruses in cancer gene therapy is limited by the widespread expression of the coxsackievirus and adenovirus receptor on normal human cells. Targeting adenoviral vectors to renal cell carcinoma (RCC) cells may improve their potential in cancer gene therapy of patients with metastatic RCC. The G250 protein, also known as the carbonic anhydrase IX protein, is membranously expressed in all cases of clear cell RCC, and clinical studies have demonstrated exceptional tumor targeting with a G250 monoclonal antibody. METHODS: A recombinant bispecific single-chain antibody directed against the RCC-associated G250 protein and the adenovirus fiber knob domain was constructed and used to retarget recombinant adenovirus expressing the green fluorescent protein under control of the cytomegalovirus promoter. G250-specific adenoviral transduction of cells was examined by flow cytometric analysis of green fluorescent protein expression. RESULTS: G250-positive RCC cells displayed enhanced susceptibility for transduction by the green fluorescent protein recombinant adenovirus complexed with the G250-directed bispecific single-chain antibody when compared with native adenovirus. This enhanced transduction was restricted to G250-positive RCC cells and could be abolished completely in the presence of excess G250 protein. CONCLUSIONS: The results of this study demonstrate the feasibility of immunologic retargeting of adenovirus to RCC cells with the highly tumor-specific G250 protein as the target. This strategy may provide the possibility of improving cancer gene therapy for patients with RCC.


Asunto(s)
Carcinoma de Células Renales/terapia , Terapia Genética/métodos , Neoplasias Renales/terapia , Adenoviridae , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias , Antígenos Virales/uso terapéutico , Anhidrasa Carbónica IX , Anhidrasas Carbónicas , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/virología , Humanos , Fragmentos de Inmunoglobulinas/uso terapéutico , Neoplasias Renales/virología , Proteínas de Neoplasias , Proteínas Recombinantes , Transducción Genética , Células Tumorales Cultivadas
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA