RESUMEN
The Feline Leukemia Virus Subgroup C Receptor 1a (FLVCR1a) is a transmembrane heme exporter essential for embryonic vascular development. However, the exact role of FLVCR1a during blood vessel development remains largely undefined. Here, we show that FLVCR1a is highly expressed in angiogenic endothelial cells (ECs) compared to quiescent ECs. Consistently, ECs lacking FLVCR1a give rise to structurally and functionally abnormal vascular networks in multiple models of developmental and pathologic angiogenesis. Firstly, zebrafish embryos without FLVCR1a displayed defective intersegmental vessels formation. Furthermore, endothelial-specific Flvcr1a targeting in mice led to a reduced radial expansion of the retinal vasculature associated to decreased EC proliferation. Moreover, Flvcr1a null retinas showed defective vascular organization and loose attachment of pericytes. Finally, adult neo-angiogenesis is severely affected in murine models of tumor angiogenesis. Tumor blood vessels lacking Flvcr1a were disorganized and dysfunctional. Collectively, our results demonstrate the critical role of FLVCR1a as a regulator of developmental and pathological angiogenesis identifying FLVCR1a as a potential therapeutic target in human diseases characterized by aberrant neovascularization.
Asunto(s)
Células Endoteliales , Neoplasias , Adulto , Animales , Humanos , Ratones , Células Endoteliales/fisiología , Neovascularización Patológica/genética , Neovascularización Fisiológica/genética , Pez CebraRESUMEN
Two thulium-based ParaCEST responsive contrast agents, Tm-DOTAm-py and Tm-DOTAm-ßAla-py, have been synthesized and evaluated for imaging copper and zinc. Unusual for responsive MRI contrast agents, both agents display a complete on/off response in the presence of transition metals. Both complexes function as paraCEST agents in the absence of copper and zinc, with the positively charged Tm-DOTAm-py being more sensitive than the neutrally charged Tm-DOTAm-ßAla-py. In each case, the CEST signal arises from amide protons rather than from a water molecule coordinated to Tm3+ ions. Upon binding to Cu+, Cu2+, or Zn2+, the exchange rate of the amide protons increases substantially, resulting in a complete loss of the CEST signal. This efficient mode of action along with the lack of inner-sphere water molecules both in the presence and absence of transition metals was confirmed by 1/T1 NMRD profiles, 17O NMR measurements, and molecular modelling simulations. Neither complex is selective for copper over zinc. Both form either a 1 : 1 TmL : Cu+ or a 2 : 1 TmL : Cu2+ and TmL : Zn2+ complexes with binding affinities comparable to that of other responsive MRI contrast agents and sensitivity comparable to that of other CEST contrast agents.
RESUMEN
There has been substantial progress in clinical outcomes for patients with multiple myeloma (MM). This encouraging trend derives in large part from the increasing number of effective therapeutic options and the ability because of this to achieve higher quality responses to treatment. The approval of both daratumumab and of elotuzumab in combination with lenalidomide and dexamethasone, in late 2015, was a notable achievement in the field, as daratumumab and elotuzumab represent the first monoclonal antibodies available for use in MM. Given their unique mechanisms of action and favorable side effect profiles, daratumumab and elotuzumab have considerable potential as therapeutic partners with agents in other drug classes and in different clinical settings ranging from newly diagnosed to relapsed disease. This review discusses the development of daratumumab and elotuzumab as well as other monoclonal antibodies currently being evaluated for use in MM.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Dexametasona/administración & dosificación , Diseño de Fármacos , Humanos , Lenalidomida , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Talidomida/administración & dosificación , Talidomida/análogos & derivadosRESUMEN
Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies.
Asunto(s)
Resistencia a Antineoplásicos , Linfoma Anaplásico de Células Grandes/genética , FN-kappa B/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Factor 1 Asociado a Receptor de TNF/genética , Translocación Genética/genética , Quinasa de Linfoma Anaplásico , Animales , Western Blotting , Citometría de Flujo , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunoprecipitación , Hibridación Fluorescente in Situ , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/mortalidad , Ratones , Ratones Endogámicos NOD , FN-kappa B/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Inhibidores de Proteasoma/farmacología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Factor 1 Asociado a Receptor de TNF/metabolismo , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The NF-kappaB signaling pathways have a critical role in the development and progression of various cancers. In this study, we demonstrated that the small cell lung cancer cell line (SCLC) H69 expressed a unique NF-kappaB profile as compared to other cancer cell lines. The p105/p50, p100/p52, c-Rel, and RelB protein and mRNA transcripts were absent in H69 cells but these cells expressed RelA/p65. The activation of H69 cells by lipopolysaccharide (LPS) resulted in the induction of RelB and p100 expression. The treatment also induced the nuclear translocation of RelB without the processing of p100 to p52. Furthermore, LPS-induced beta1 integrin expression and cellular attachment through an NF-kappaB-dependent mechanism. Blocking RelB expression prevented the increase in the expression of beta1 integrin and the attachment of H69. Taken together, the results suggest that RelB was responsible for the LPS-mediated attachment and may play an important role in the progression of some cancers.
Asunto(s)
Núcleo Celular/metabolismo , Neoplasias Pulmonares/patología , Subunidad p52 de NF-kappa B/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología , Factor de Transcripción ReIB/metabolismo , Transporte Activo de Núcleo Celular , Adhesión Celular , Línea Celular Tumoral , Humanos , Integrina beta1/biosíntesis , Lipopolisacáridos/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células Pequeñas/inmunología , Carcinoma Pulmonar de Células Pequeñas/metabolismoRESUMEN
We evaluated the synergistic activity of AS101 (ammonium trichloro-(dioxoethylene-0-0')-tellurate) with the protein kinase C (PKC) activators, Bryostatin-1 and phorbol-12-myristate-13-acetate (PMA), on human myelocytic leukemia cell differentiation in vitro, and in a mouse model. Use of AS101 with Bryostatin-1 or with a low concentration of PMA resulted in the differentiation of HL-60 cell line to cells with characteristics of macrophages. A similar synergistic effect was found in vivo. Compared with mice treated with AS101 alone or with Bryostatin-1 alone, the infiltration of leukemic cells into the spleen and the peritoneum of mice treated with both compounds, as well as the number of the HL-60 colonies extracted from those organs, were markedly reduced. The antitumor effects were associated with significantly prolonged survival (100% for 125 days) of the treated mice. Finally, the mechanism of action of this antitumor effect was explored, and was found to involve the Ras/extracellular signal-regulated kinase signaling pathway. Combined treatment with AS101 and Bryostatin-1 synergistically increased p21(waf1) expression levels independently of p53. Upregulation of p21(waf1) was necessary for HL-60 cell differentiation, which was found to be both c-raf-1 and mitogen-activated protein kinase dependent. This study may have implications for the development of strategies to induce differentiation in myeloid leukemias, myelodysplasias and possibly in other malignancies.
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Diferenciación Celular/efectos de los fármacos , Etilenos/farmacología , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/patología , Macrólidos/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Brioestatinas , Sinergismo Farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células HL-60/trasplante , Humanos , Trasplante de Neoplasias , Proteínas ras/metabolismoRESUMEN
The regulatory benefit of apoptosis (activation-induced cell death, AICD) in T cells can be influenced by immunosuppressive agents. We examined this for mycophenolate mofetile (MMF, using it's active metabolite, mycophenolate (MPA)) compared with rapamycin (RAPA) and the calcineurin inhibitors (CI) cyclosporin (CYA) and FK506 (FK). Pure T cells from peripheral blood leucocytes (PBL) were stimulated by anti-CD3 plus anti-CD28. Cell division (sequential cohort reduction in carboxyflourescein diacetate succinimidyl ester, CFSE) was used to measure proliferation and determine status of different cell generations without or with added drug at 4 d. Apoptosis was measured by Annexin V staining of activated cells using flow cytometry. We confirmed in this stringent system the inhibition of AICD by CI and showed that RAPA is intermediate and MPA most effective in this potentiation of AICD.
Asunto(s)
Apoptosis/efectos de los fármacos , Inmunosupresores/farmacología , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacología , Linfocitos T/fisiología , División Celular/efectos de los fármacos , Células Cultivadas , Ciclosporina/farmacología , Citometría de Flujo , Humanos , Activación de Linfocitos , Sirolimus/farmacología , Linfocitos T/efectos de los fármacos , Tacrolimus/farmacologíaRESUMEN
Natural killer (NK) cells mediate acute rejection of bone marrow, but not solid tissue, allografts in lethally irradiated mice. Precisely how and why this rejection occurs is still unclear. In allogeneic bone marrow transplantation (BMT), a spectrum of results is possible; one result can be marrow graft failure due to host rejection of the graft by NK and T cells and, at the opposite spectrum, the occurrence of graft-versus-host disease (GVHD). Donor NK cells, however, appear capable of improving donor engraftment without giving rise to GVHD and thus may be of use as an immunotherapy following BMT. As NK-cell inhibitory receptors play a role in bone marrow cell rejection, these same inhibitory receptors may also affect NK responses towards tumor cells. It has been demonstrated that blocking the interaction of inhibitory receptors with MHC determinants on tumor cells can result in greater antitumor effects. Thus, NK cells are capable of mediating both positive and negative effects during BMT depending on whether they are of host versus donor origin and their state of activation. Understanding their role in BMT provides insights as to their physiological roles and points the way to potential clinical uses.
Asunto(s)
Antígenos Ly , Trasplante de Médula Ósea/inmunología , Células Asesinas Naturales/inmunología , Animales , Refuerzo Inmunológico de Injertos , Rechazo de Injerto/inmunología , Humanos , Inmunoterapia , Células Asesinas Naturales/clasificación , Células Asesinas Naturales/trasplante , Lectinas Tipo C , Glicoproteínas de Membrana/metabolismo , Ratones , Modelos Biológicos , Receptores Inmunológicos/metabolismo , Receptores KIR , Receptores Similares a Lectina de Células NK , Trasplante HomólogoRESUMEN
We conducted a phase II randomized trial of recombinant granculocyte-macrophage colony-stimulating factor (GM-CSF) administered before topotecan chemotherapy to determine whether it could prevent myelosuppression and to determine the antitumor activity of this topoisomerase I inhibitor in 53 patients with metastatic malignant melanoma and renal cell cancer. All patients received GM-CSF after topotecan at a dose of 250 microg/m(2) daily for at least 8 days. Patients randomly assigned to receive GM-CSF priming were treated with GM-CSF at 250 microg/m(2) twice daily for 5 days before treatment. Twenty-five patients were randomly assigned to receive GM-CSF priming and 28 to receive topotecan without priming. The primary analysis was restricted to the protective effects seen during the first cycle of therapy. Grade 4 neutropenia occurred in 8 of 23 patients (35%) and grade 3 neutropenia in 5 of 23 patients (22%) randomized to GM-CSF priming, whereas 18 of 26 (69%) and 5 of 26 (19%) patients experienced grade 4 or 3 neutropenia, respectively, without GM-CSF priming (P =.0074). The mean duration of neutropenia was reduced by GM-CSF priming: grade 3 neutropenia from 5.2 +/- 0.7 to 2.8 +/- 0.7 days (P =.0232) and grade 4 neutropenia from 2.7 +/- 0.6 to 1.1 +/- 0.4 days (P = 0.0332). The protective effects of GM-CSF extended to the second cycle of treatment. The incidence of febrile neutropenia was also reduced. Chemotherapy-induced anemia and thrombocytopenia were similar in both groups. One partial response was seen in a patient with melanoma, and one patient with renal cell cancer had complete regression of pulmonary metastases and was rendered disease-free by nephrectomy. (Blood. 2001;97:1942-1946)
Asunto(s)
Antineoplásicos/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Neutropenia/prevención & control , Neoplasias Cutáneas/tratamiento farmacológico , Topotecan/efectos adversos , Anemia/inducido químicamente , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/sangre , Diabetes Mellitus Tipo 1/complicaciones , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Humanos , Hipotensión/inducido químicamente , Neoplasias Renales/sangre , Melanoma/sangre , Neutropenia/inducido químicamente , Premedicación , Estudios Prospectivos , Inducción de Remisión , Índice de Severidad de la Enfermedad , Neoplasias Cutáneas/sangre , Accidente Cerebrovascular/etiología , Trombocitopenia/inducido químicamente , Topotecan/uso terapéutico , Resultado del TratamientoRESUMEN
The polo-like kinase (Plk) has been shown to be associated with the anaphase-promoting complex at the transition from metaphase to anaphase and to regulate ubiquitination, the process that targets proteins for degradation by proteasomes. In this study, we have identified proteasomal proteins interacting with Plk by mass spectrometry and found that Plk and 20S proteasome subunits could be reversibly immunoprecipitated from both human CA46 cells and HEK 293 cells transfected with HA-Plk. Furthermore, both coprecipitated Plk and baculovirus-expressed Plk were able to phosphorylate proteasome subunits, and metabolic labeling studies indicate that Plk is partially responsible for the phosphorylation of 20S proteasome subunits C9 and C8 in vivo. In addition, phosphorylation of proteasomes by Plk enhanced proteolytic activity toward an artificial substrate Suc-L-L-V-Y-AMC in vitro and in vivo. Finally, we were also able to detect Plk associated with 26S proteasomes under certain conditions. Together our results suggest that Plk is an important mitotic regulator of proteasome activity.
Asunto(s)
Cisteína Endopeptidasas/metabolismo , Proteínas de Drosophila , Complejos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Anafase , Animales , Baculoviridae/metabolismo , Línea Celular , Electroforesis en Gel Bidimensional , Electroforesis en Gel de Poliacrilamida , Humanos , Inmunoglobulina G/metabolismo , Insectos , Espectrometría de Masas , Metafase , Mitosis , Ácido Ocadaico/farmacología , Fosforilación , Pruebas de Precipitina , Complejo de la Endopetidasa Proteasomal , Proteínas Recombinantes/metabolismo , Transfección , Células Tumorales CultivadasRESUMEN
Administration of donor T cells expressing the herpes simplex-thymidine kinase (HS-tk) with a hematopoietic stem cell (HSC) transplantation could allow, if graft-versus-host disease (GVHD) was to occur, a selective in vivo depletion of these T cells by the use of ganciclovir (GCV). The study evaluates the feasibility of such an approach. Escalating numbers of donor HS-tk-expressing CD3(+) gene-modified cells (GMCs) are infused with a T-cell-depleted bone marrow transplantation (BMT). Twelve patients with hematological malignancies received 2 x 10(5) (n = 5), 6 x 10(5) (n = 5), or 20 x 10(5) (n = 2) donor CD3(+) GMCs/kg with a BMT from a human leukocyte antigen (HLA)-identical sibling. No acute toxicity was associated with GMC administration. An early increase of circulating GMCs followed by a progressive decrease and long-lasting circulation of GMCs was documented. GCV treatment resulted in significant rapid decrease in circulating GMCs. Three patients developed acute GVHD, with a grade of at least II, while one patient developed chronic GVHD. Treatment with GCV alone was associated with a complete remission (CR) in 2 patients with acute GVHD, while the addition of glucocorticoids was necessary to achieve a CR in the last case. Long-lasting CR occurred with GCV treatment in the patient with chronic GVHD. Unfortunately, Epstein-Barr virus-lymphoproliferative disease occurred in 3 patients. Overall, the administration of low numbers of HS-tk-expressing T cells early following an HLA-identical BMT is associated with no acute toxicity, persistent circulation of the GMCs, and GCV-sensitive GVHD. Such findings open the way to the infusion of higher numbers of gene-modified donor T cells to enhance post-BMT immune competence while preserving GCV-sensitive alloreactivity.
Asunto(s)
Trasplante de Médula Ósea/métodos , Depleción Linfocítica/métodos , Linfocitos T/trasplante , Timidina Quinasa/administración & dosificación , Adulto , Antivirales/administración & dosificación , Antivirales/farmacología , Trasplante de Médula Ósea/inmunología , Complejo CD3 , Técnicas de Cultivo de Célula , Supervivencia sin Enfermedad , Infecciones por Virus de Epstein-Barr/complicaciones , Femenino , Ganciclovir/administración & dosificación , Ganciclovir/farmacología , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/terapia , Herpes Simple/tratamiento farmacológico , Herpes Simple/enzimología , Humanos , Trastornos Linfoproliferativos/virología , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Linfocitos T/efectos de los fármacos , Linfocitos T/virología , Timidina Quinasa/efectos de los fármacos , Timidina Quinasa/genética , Timidina Quinasa/uso terapéutico , Factores de Tiempo , Transfección , Trasplante Homólogo/métodos , Resultado del Tratamiento , Proteínas Virales/efectos de los fármacos , Proteínas Virales/genética , Proteínas Virales/uso terapéuticoRESUMEN
A minority (less than 2%) of all lymphoproliferative disorders are derived from small T cells. These include T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, and mycosis fungoides/Sézary syndrome. With the possible exception of early-stage, skin-localized mycosis fungoides, all are considered incurable, although palliation can be achieved with radiation therapy, chemotherapy, biologic therapy, and combinations of these modalities. Of these disorders, mycosis fungoides is the most common; it follows an indolent, though gradually progressive, course that spans years. The T-cell prolymphocytic leukemias, in contrast, are generally refractory to treatment, with a median survival of typically less than 1 year. Although effective therapy remains elusive in most cases, the development of nucleosides as a class of chemotherapeutic agents and biologics, including interferon, monoclonal antibodies, and vitamin A derivatives, offers new hope for at least more effective palliation of these progressive lymphoproliferative disorders. However, rapid improvement in the treatment of these disorders remains hampered by the rarity of these individual entities. More rapid progress in treatment depends on national and international cooperation to accrue patients for definitive trials of sufficient size to evaluate new treatment options quickly.
Asunto(s)
Leucemia de Células T/terapia , Linfoma de Células T/terapia , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Leucemia de Células T/patología , Linfoma de Células T/patología , Pronóstico , RadioterapiaRESUMEN
Long-term memory formation requires de novo RNA and protein synthesis. To assess gene-expression changes associated with learning and memory processes, we used cDNA microarray to analyze hippocampal gene expression in male Fischer-344 rats following training in a multiunit T-maze. Here, we report the identification of 28 clones (18 known genes and 10 ESTs) for which expression increased after the maze learning. Some of the known genes appear to be involved in Ca2+ signaling, Ras activation, kinase cascades, and extracellular matrix (ECM) function, which may regulate neural transmission, synaptic plasticity, and neurogenesis. The gene-expression profile presented here provides the groundwork for future, more focused research to elucidate the contribution of these genes in learning and memory processes.
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Hipocampo/metabolismo , Aprendizaje por Laberinto , Análisis de Secuencia por Matrices de Oligonucleótidos , Animales , Expresión Génica , Hipocampo/fisiología , Masculino , Memoria , Ratas , Ratas Endogámicas F344 , Reacción en Cadena de la Polimerasa de Transcriptasa InversaAsunto(s)
Autoinmunidad/inmunología , Subgrupos de Linfocitos B/citología , Reordenamiento Génico de Cadena Ligera de Linfocito B , Receptores de Antígenos de Linfocitos B/inmunología , Animales , Autoantígenos/inmunología , Genes de Inmunoglobulinas , Genes RAG-1 , Proteínas de Homeodominio/metabolismo , Tolerancia Inmunológica/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/inmunología , Inmunoglobulina M/genética , Inmunoglobulina M/inmunología , Cadenas kappa de Inmunoglobulina/genética , Cadenas kappa de Inmunoglobulina/inmunología , Ratones , Ratones Noqueados , Ratones Transgénicos , Receptores de Antígenos de Linfocitos B/genética , Receptores Fc/inmunología , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Bazo/citología , Bazo/inmunologíaAsunto(s)
Linfoma/clasificación , Animales , Humanos , Linfoma/patología , Organización Mundial de la SaludAsunto(s)
Adyuvantes Inmunológicos/fisiología , Hormona del Crecimiento/fisiología , Factores de Crecimiento de Célula Hematopoyética/fisiología , Linfocitos T/efectos de los fármacos , Adyuvantes Inmunológicos/efectos adversos , Animales , Artralgia/inducido químicamente , Hormona del Crecimiento/efectos adversos , Factores de Crecimiento de Célula Hematopoyética/efectos adversos , Humanos , Receptores de Hialuranos/inmunología , Ratones , Proyectos Piloto , Receptores de Interleucina-7/inmunología , Transducción de Señal , Linfocitos T/inmunología , Timo/efectos de los fármacos , Timo/inmunologíaRESUMEN
The purpose of this article was to evaluate the antitumor effects of a combination chemotherapy program based on ProMACE (prednisone, methotrexate, doxorubicin [Adriamycin], cyclophosphamide, etoposide) followed by a B cell-specific immunotoxin in the treatment of patients with advanced-stage indolent histology non-Hodgkin's lymphomas. We performed a prospective phase II clinical trial in a referral-based patient population. After confirmation of diagnosis and staging evaluation, 44 patients (10 small lymphocytic lymphoma, 27 follicular lymphoma, 7 mantle cell lymphoma; 30 without prior therapy, 14 previously treated) received six cycles of ProMACE-CytaBOM (cytarabine, bleomycin, vincristine [Oncovin], mechlorethamine) combination chemotherapy (with etoposide given orally daily for five days) followed by a 7-day continuous infusion of anti-B4-blocked ricin immunotoxin at 30 microg/kg/day given every 14 days for up to six cycles. A complete response was achieved in 25 of 44 patients (57%), 21 from the chemotherapy alone, 3 converted from partial to complete response with the immunotoxin, and 1 patient became a complete responder after a surgical procedure to remove an enlarged spleen that was histologically negative for lymphoma. With a median follow-up of 5 years, 14 of 25 complete responders have relapsed (56%); median remission duration was 2 years, and overall survival was 61%. Forty-two percent of the complete responders have been in continuous remission for more than 4 years. The median number of courses of immunotoxin delivered was two usually because of the development of human anti-ricin antibodies. ProMACE-CytaBOM plus anti-B4-blocked ricin does not produce durable complete remissions in the majority of patients with indolent lymphoma. However, the remissions appear quite durable (> 4 years) in about 40% of the complete responders.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Inmunoconjugados/uso terapéutico , Inmunotoxinas/uso terapéutico , Linfoma/tratamiento farmacológico , Ricina/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/uso terapéutico , Ciclofosfamida/uso terapéutico , Citarabina/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/uso terapéutico , Etopósido/uso terapéutico , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Linfoma/mortalidad , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/mortalidad , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/mortalidad , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Prednisona/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Vincristina/uso terapéuticoRESUMEN
Four variant forms of the V1 (T15-H chain) gene are synthesized in mice. Each V1 variant pairs with a distinct L chain to produce a binding site having specificity for phosphocholine (PC). Transgenic mice expressing variant forms of the V1 gene were analyzed to elucidate the factors driving B cell selection into the peripheral repertoire. In all four lines of H chain transgenic mice analyzed, transgene expression caused complete allelic exclusion of endogenous H chains in the bone marrow (BM), whereas most splenic B cells expressed endogenous H chains. The number of sIgM(+) BM B cells and their sIg receptor number was reduced compared to that of normal transgene-negative controls, suggesting that B cells expressing transgene-encoded H chains were being negatively selected in the BM. Mice expressing autoreactive forms of the V1 transgene with lower affinity for PC (M603H and M167H) exhibit positive selection of PC-specific B cells into the spleen, whereas mice expressing the higher affinity T15H variant exhibited elevated PC-specific B cells in the peritoneal cavity but few V(H)1(+) splenic B cells. These data suggest that the higher affinity T15-id(+) B cells preferentially survive in the peritoneal cavity. When these H chain transgenes were crossed into the mu MT knockout mouse in which surface expression of endogenous H chains is blocked, the percent of splenic V(H)1(+) PC-specific B cells increased up to 5-fold and T15-id(+) B cells were detectable in the spleen of T15H mice. This implies that T15-id(+) PC-specific B cells can be selected into the periphery, but they compete poorly with follicular B cells expressing endogenous Ig.
Asunto(s)
Linfocitos B/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Fosforilcolina/inmunología , Animales , Antígenos CD5/análisis , Femenino , Hemocianinas/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Subsets of murine natural killer (NK) cells exist that express the Ly-49 family of molecules that recognize different major histocompatibility complex (MHC) determinants. Bone marrow transplantation studies were performed to examine the in vivo functions of 2 of these subsets. Subsets of Ly-49A and Ly-49G2 NK share specificity for the same MHC class 1 ligand, D(d), binding of which results in an inhibitory signal to the NK cell but allows them to lyse H2(b) targets in vitro. We therefore examined the ability of these subsets to reject H2(b) bone marrow cell allografts in lethally irradiated mice. Surprisingly, depletion of Ly-49A(+) NK cells in BALB/c or B10.D2 mice (both H2(d)) had no effect on the rejection of H2(b) BMC. However, Ly-49A depletion did partially abrogate the ability of B10.BR (H2(k)) mice to reject H2(b) allografts. Although depletion of either Ly-49A(+) or Ly-49G2(+) NK cells alone had no effect on the ability of B10.D2 mice to reject H2(b) BMC, depletion of both subsets dramatically and synergistically abrogated rejection. Studies with various B10 congenic mice and their F(1) hybrids indicate that this synergy between Ly49A and Ly4G2 depletion occurs in every instance. Thus, Ly-49A(+) NK cells appear to play a role in the rejection H2(b) bone marrow allografts, but, in most strains of mice studied, Ly-49G2(+) NK cells must also be eliminated. The putative roles of these NK cell subsets in clinical transplantation remains to be elucidated. (Blood. 2000;95:3840-3844)
Asunto(s)
Antígenos Ly , Trasplante de Médula Ósea/inmunología , Proteínas Portadoras/inmunología , Rechazo de Injerto/inmunología , Células Asesinas Naturales/inmunología , Depleción Linfocítica , Glicoproteínas de Membrana/inmunología , Proteínas de la Membrana/inmunología , Animales , Cruzamientos Genéticos , Células Asesinas Naturales/clasificación , Lectinas Tipo C , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Subfamilia A de Receptores Similares a Lectina de Células NK , Receptores Inmunológicos/inmunología , Receptores Similares a Lectina de Células NK , Trasplante HomólogoRESUMEN
Phosphocholine (PC) is the immunodominant epitope found on the surface of Streptococcus pneumoniae (SPn). T15-idiotype Abs, whose heavy (H) chain variable region is encoded by the V1 gene, are dominant in the anti-PC response in adult mice and protect mice from lethal pneumococcal infection. The ability of anti-PC Abs using H chains other than the V1 H chain to protect against pneumococcal infection remains controversial. We generated V1(-/-) knockout mice to determine whether protective anti-PC Abs could be produced in the absence of the V1 gene. No anti-PC Abs were produced in V1(-/-) mice immunized with avirulent SPn; however, PC-BSA binding Abs were induced after immunization with PC-keyhole limpet hemocyanin but at significantly lower levels than those in wild-type mice. These Abs provided poor protection against virulent SPn; thus, <25% of V1(-/-) mice survived challenge with 10(4) bacteria as compared with 100% survival of V1(+/+) mice. The anti-PC Abs in V1(-/-) mice were heteroclitic, binding to nitrophenyl-PC better than to PC. None of nine hybridomas produced from V1(-/-) mice provided passive protection. However, the V1(-/-) mice produced normal amounts of Ab to SPn proteins that can partially protect mice against SPn. These data indicate that the V1 gene is critical for the production of anti-PC Abs providing optimum protection against infection with SPn, and the V1(-/-) mice could be useful in unmasking epitopes other than the immunodominant PC epitope on SPn capable of providing cross protection.