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1.
Clin Immunol ; 90(2): 173-81, 1999 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10080828

RESUMEN

We determined whether a classical conditioning paradigm may be used to condition immunologic responses in normal human subjects receiving an optimal immunostimulating dose of recombinant human interferon-gamma (rhIFN-gamma). We conducted a placebo-controlled, double-blind study of 31 normal volunteers in order to determine whether an initially immune-neutral stimulus, oral propylene glycol (PG), could eventually elicit an immune response as a consequence of its being paired with a known immunostimulatory dose and schedule of rhIFN-gamma. Subjects were randomly assigned to one of three groups: (A) rhIFN-gamma injections paired with PG; (B) normal saline injections paired with PG; (C) rhIFN-gamma injections alone. During the 4-week study, subjects received progressively fewer injections so that, by the final week of the study, no injections were given and groups A and B received only PG. The principal outcome measures were serum concentrations of quinolinic acid (QUIN) and neopterin, two nonspecific but sensitive markers of immune activation, and expression of Fc receptors (CD64) on peripheral blood mononuclear cells. RhIFN-gamma injections produced significant and predictable alterations in each of the measured immune parameters. No group B subject made an immune response. Mean serum QUIN levels were significantly higher at the end of week three for subjects in the experimental condition (group A) than for subjects receiving rhIFN-gamma alone (group C) despite receiving identical doses of rhIFN-gamma. Similarly, the predicted decay in mean serum neopterin levels from the end of week 1 to the end of week 2 was seen in group C but not in group A. The exposure of group A to PG blunted the decline of CD64 expression in week four. The data suggest that the pairing of an unconditioned stimulus (rhIFN-gamma) and a conditioned stimulus (PG) permits the conditioned stimulus alone to prolong a cytokine-induced response in normal humans.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Condicionamiento Clásico/fisiología , Interferón gamma/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Adolescente , Adulto , Citocinas/biosíntesis , Método Doble Ciego , Femenino , Humanos , Interferón gamma/administración & dosificación , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Neopterin/sangre , Propilenglicol/administración & dosificación , Propilenglicol/farmacología , Ácido Quinolínico/sangre , Receptores de IgG/sangre , Proteínas Recombinantes
2.
Ther Immunol ; 2(1): 7-14, 1995 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-7553072

RESUMEN

We have investigated the ability of the novel muramyl dipeptide, GMDP, to act as an adjuvant for the induction of ovalbumin (OVA)-specific, CD8+ cytotoxic T lymphocyte (CTL) responses. C57Bl/6 mice were twice immunized s.c. with 50 micrograms OVA emulsified with a squalane, L121 pluronic containing Tween-80 vehicle either with (STP-GMDP) or without (STP) GMDP. Splenic precursor CD8+ CTL activity against E.G7-OVA, but not against EL-4 parental targets was detected in STP-GMDP immunized mice after 5 days of in vitro re-stimulation with irradiated E.G7-OVA cells, while mice immunized with OVA in STP alone or OVA alone failed to demonstrate CTL activity. OVA emulsified in a microfluidized STP vehicle formulation without GMDP also elicited the E.G7-OVA precursor CTL. The ability of GMDP to induce a class I-restricted, CD8+ CTL response to a soluble protein antigen may have implications for the development of useful vaccines against viral pathogens or tumours against which CTL responses are desirable.


Asunto(s)
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Adyuvantes Inmunológicos/administración & dosificación , Antígenos/administración & dosificación , Linfocitos T CD8-positivos/inmunología , Citotoxicidad Inmunológica , Acetilmuramil-Alanil-Isoglutamina/administración & dosificación , Animales , Femenino , Inmunización , Técnicas In Vitro , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/inmunología , Solubilidad , Células Tumorales Cultivadas
3.
J Exp Med ; 180(3): 1047-57, 1994 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-8064224

RESUMEN

Transforming growth factor beta 1 (TGF-beta 1) and TGF-beta 2 can reversibly inhibit the proliferation of hematopoietic progenitor cells in vivo, leading us to hypothesize that such quiescent progenitors might be more resistant to high doses of cell cycle active chemotherapeutic drugs, thereby allowing dose intensification of such agents. Initial studies showed that whereas administration of TGF-beta 1 or TGF-beta 2 did not prevent death in normal mice treated with high doses of 5-fluorouracil (5-FU), those mice that received TGF-beta 2 did exhibit the beginning of a hematologic recovery by day 11 after administration of 5-FU, and were preferentially rescued by a suboptimal number of transplanted bone marrow cells. Subsequently, it was found that the administration of TGF-beta 2 protected recovering progenitor cells from high concentrations of 5-FU in vitro. This protection coincided with the finding that significantly more progenitors for colony-forming unit-culture (CFU-c) and CFU-granulocyte, erythroid, megakaryocyte, macrophage (GEMM) were removed from S-phase by TGF-beta in mice undergoing hematopoietic recovery than in normal mice. Further studies showed that the administration of TGF-beta protected up to 90% of these mice undergoing hematologic recovery from a rechallenge in vivo with high dose 5-FU, while survival in mice not given TGF-beta was < 40%. Pretreatment of mice with TGF-beta 1 or TGF-beta 2 also protected 70-80% of mice from lethal doses of the noncycle active chemotherapeutic drug, doxorubicin hydrochloride (DXR). These results demonstrate that TGF-beta can protect mice from both the lethal hematopoietic toxicity of 5-FU, as well as the nonhematopoietic toxicity of DXR. This report thus shows that a negative regulator of hematopoiesis can be successfully used systemically to mediate chemoprotection in vivo.


Asunto(s)
Doxorrubicina/toxicidad , Fluorouracilo/toxicidad , Factor de Crecimiento Transformador beta/farmacología , Animales , Médula Ósea/efectos de los fármacos , Trasplante de Médula Ósea , División Celular/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/fisiología , Ratones , Ratones Endogámicos BALB C , Proteínas Recombinantes/farmacología
4.
Cancer Res ; 52(11): 3005-10, 1992 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-1591717

RESUMEN

We have performed a phase IB study of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose (poly-ICLC) in combination with interleukin 2 (IL-2) in 25 patients with a variety of cancers. Patients received weekly or biweekly poly-ICLC by i.m. injection, at doses ranging from 0.01 to 1.0 mg/m2, for 1 month. This was followed by 2 months of outpatient therapy with biweekly i.m. poly-ICLC in combination with IL-2 (3 x 10(6) units/m2) given i.v. by 24-h continuous infusion twice weekly, using a portable infusion pump. No objective tumor responses were observed. Toxicity was moderate at all poly-ICLC doses tested and increased only slightly following the addition of IL-2. No increases in peripheral blood natural killer (NK) activity were observed after treatment with poly-ICLC alone. However, high dose poly-ICLC (greater than or equal to 0.3 mg/m2) in combination with IL-2 resulted in NK activity greater than that seen using the same dose of IL-2 in combination with lower poly-ICLC doses. Increases in the number and percentage of CD56+ cells were evident only after initiation of IL-2 therapy and were unaffected by the poly-ICLC dose. In the majority of patients, these increases were preferentially associated with the subset of CD56+ cells coexpressing CD8, while the CD56+/CD16+ population was elevated to a lesser extent. Moderate increases in serum neopterin levels and 2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells were noted at 72 h following initial treatment with 1.0 mg/m2 poly-ICLC. No induction of alpha or gamma interferon was detected. This study shows that the addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity without increases in the dose and, therefore, the toxicity of IL-2 treatment.


Asunto(s)
Carboximetilcelulosa de Sodio/toxicidad , Interleucina-2/toxicidad , Neoplasias/terapia , Poli I-C/toxicidad , Polilisina/toxicidad , Antígenos CD/análisis , Biopterinas/análogos & derivados , Biopterinas/sangre , Carboximetilcelulosa de Sodio/uso terapéutico , Citotoxicidad Inmunológica , Evaluación de Medicamentos , Femenino , Humanos , Interleucina-2/uso terapéutico , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Neopterin , Poli I-C/uso terapéutico , Polilisina/uso terapéutico
5.
J Clin Oncol ; 7(9): 1295-302, 1989 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-2788716

RESUMEN

Localized lymphomas of diffuse and aggressive histology sometimes undergo early hematogenous dissemination such that local therapies (surgery alone or followed by radiation therapy) are not curative in 100% of cases. We have treated 47 clinical stage I or IE patients with aggressive lymphoma histologies (diffuse large-cell, diffuse mixed, diffuse immunoblastic, follicular large-cell, diffuse small-non-cleaved cell) with four monthly cycles of an eight-drug combination chemotherapy program consisting of cyclophosphamide, etoposide, doxorubicin, nitrogen mustard (mechlorethamine), procarbazine, high-dose methotrexate with leucovorin rescue, and prednisone (Pro-MACE-MOPP) administered systemically followed by 40 Gy involved-field radiation therapy. Forty-five (96%) patients achieved a complete remission and no patient has relapsed with a median follow-up time of 42 months (range, 8 to 90). Both patients failing to achieve a complete remission died of lymphoma, and one patient died free of lymphoma 45 months after diagnosis during coronary artery bypass surgery unrelated to lymphoma or its treatment. Hospital admissions were necessary to manage complications on nine of 188 (5%) cycles of treatment. There were no treatment-related deaths. ProMACE-MOPP plus involved-field radiation therapy is safe and effective treatment for localized aggressive lymphoma.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Terapia Combinada , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Humanos , Leucovorina/administración & dosificación , Linfoma/radioterapia , Masculino , Mecloretamina/administración & dosificación , Metotrexato/administración & dosificación , Persona de Mediana Edad , Prednisona/administración & dosificación , Procarbazina/administración & dosificación , Inducción de Remisión , Vincristina/administración & dosificación
6.
J Immunol ; 138(12): 4502-8, 1987 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-3495593

RESUMEN

The therapeutic efficacy of whole ricin, or recombinant ricin A chain, coupled to a monoclonal antibody that reacts with the idiotype of the surface IgM expressed on guinea pig L2C lymphoblasts, was assessed. In vitro studies were done to characterize the immunotoxins (IT) and to demonstrate their specificity before use in vivo. The concentration of whole ricin IT (M6-Ricin) that inhibited protein synthesis by 50% (IC50) in L2C cells was 1.4 X 10(-9) M, in a 5-hr assay, in the presence of lactose to block non-antibody-directed toxicity. M6-Ricin did not inhibit protein synthesis in two control guinea pig cell lines that did not express the idiotype, nor did a whole ricin IT prepared with an isotype-matched monoclonal antibody of irrelevant specificity inhibit protein synthesis in L2C cells. Two recombinant ricin A chain IT, which differed from one another by a factor of 2 to 3 in the number of A chains conjugated per antibody molecule, were less effective in vitro than M6-Ricin (IC50 of greater than 5 X 10(-8) M). For in vivo experiments, the IT were given by the i.p. route 24 hr after the i.p. inoculation of 1 X 10(5) L2C cells. The highest doses of M6-Ricin and M6-Ricin A chain IT tested, 30 micrograms/kg and 3000 micrograms/kg, respectively, were within fourfold to fivefold of their maximum tolerated doses; no deaths or ill effects due to ricin toxicity were noted. These doses increased the median survival time of L2C-bearing guinea pigs to 31 to 34 days, compared with 15 days for untreated animals. This magnitude of increase in survival indicates that 99.999% (5 logs) of injected tumor cells were eliminated, thus accounting for the 12% long-term survival rate obtained. Median survival times for guinea pigs treated with 30 micrograms/kg of the A chain IT were 18 and 21 days for the two conjugates tested, and the median survival for guinea pigs treated with 3000 micrograms/kg of unconjugated antibody was 18 days. Our data demonstrate that recombinant A chain IT are active in vivo and that the B chain of ricin can potentiate IT activity in vivo. Although the potency differs by 100-fold, the therapeutic index of the intact ricin IT is similar to that of the ricin A chain IT.


Asunto(s)
Idiotipos de Inmunoglobulinas/inmunología , Inmunotoxinas/uso terapéutico , Leucemia Experimental/terapia , Ricina/uso terapéutico , Animales , Especificidad de Anticuerpos , Linfocitos B , Evaluación Preclínica de Medicamentos , Cobayas , Inmunotoxinas/inmunología , Leucemia Experimental/inmunología , Ricina/administración & dosificación
7.
Radiology ; 145(3): 629-34, 1982 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-6292995

RESUMEN

Thirty-nine patients with lymphoma were evaluated prospectively to determine the usefulness of Ethiodol-Oil-Emulsion-13 (EOE-13) in the detection of hepatosplenic lymphoma by computed tomography. The detection rate in the spleen increased from 8% (before EOE-13 infusion) to 92% (after EOE-13 infusion). In ten of 39 patients (25%) in this series, lymphomatous disease was recognized only on the postinfusion computed tomographic scan. The postinfusion EOE-13 study demonstrated additional visceral abnormalities in 38% of the patients. The potential usefulness, limitations, and toxicity of this hepatosplenic-specific imaging agent are discussed.


Asunto(s)
Aceite Etiodizado , Enfermedad de Hodgkin/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Linfoma/diagnóstico por imagen , Neoplasias del Bazo/diagnóstico por imagen , Humanos , Estudios Prospectivos , Tomografía Computarizada por Rayos X
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