Search PubMed⌕ Search

Biomedical subjects

J Wijdenes

Publications and source records attributed to J Wijdenes.

At least 127 records · Page 7Linked to original sources
PubMed1993

Treatment of multiple sclerosis with anti-CD4 monoclonal antibody. A preliminary report on B-F5 in 21 patients.

Twenty-one patients with definite active multiple sclerosis (MS) were treated with a monoclonal anti-T CD4/B-F5 (murine IgG1) antibody for 10 days. Side effects were observed in 11 patients during the first infusion. These side effects were accompanied by and probably related to a transient increase in IL6 and TNF alpha serum levels. This problem led to treatment interruption in one patient. Neither clinical improvement nor deterioration was observed in the course of treatment. EDSS improvement (> 1 point) occurred in six patients one month post-treatment. One month after the end of treatment total lymphocytes and CD3+ and CD4+ cells were significantly decreased. Cytokine analysis performed in serum and in CSF before and after treatment showed no induced modifications. Ten patients developed xenogenic antibodies. It is of interest that the patients with relapsing-remitting forms were relapse-free at the 6th month post-therapy.

Adult↗
PubMed1993

Effects of an anti-interleukin-6 (IL-6) murine monoclonal antibody in a patient with acute monoblastic leukemia.

Because IL-6 has been involved in the pathogenesis of acute monoblastic leukemia, we investigated the in vitro anti-proliferative effect and the in vivo anti-tumoral effect of an anti-IL-6 murine monoclonal antibody (mAb) in a patient with M5B type acute leukemia. In the current study, we clearly show the IL-6 dependence of monoblastic cell viability and proliferation in vitro in short-term cultures of malignant cells and the clinical activity of the anti-IL-6 murine mAb. The complete neutralization of IL-6 in vivo was associated with a transient but complete disappearance of malignant monoblastic cells in the peripheral blood, with improvement or even normalization of several other biological parameters of disease activity. No immunization against the anti-IL-6 murine mAb was observed.

Aged↗
PubMed1993

Internalization and degradation of anti-CD4 monoclonal antibodies bound to human peripheral blood lymphocytes.

Treatment of patients with anti-CD4 mAbs induces both functional alterations of CD4+ cells and depletion of circulating CD4+ lymphocytes. Some of these effects depend on the amount of mAb molecules bound per CD4+ cell and on the properties of the Fc part of the mAb (isotype specificity). We have investigated the fate of anti-CD4 monoclonal antibodies (mAbs) after their interaction with CD4 protein on the surface of peripheral blood lymphocytes (PBL). We used seven anti-CD4 mAbs whose epitope specificity, equilibrium constant and kinetics of binding are reported. Lymphocytes were saturated with anti-CD4 mAbs either at +4 degrees C or 37 degrees C then washed and incubated in antibody-free medium. At different time intervals cells were processed for analysis. By indirect immunofluorescence, it was shown that the amount of surface-bound mAb decreased rapidly when cells were incubated at 37 degrees C, but not at 4 degrees C. With 125I-mAbs, we demonstrate that there was a rapid internalization of the molecules followed by the re-expression on the cell surface of a part of initially bound mAbs and by the release of partially degraded antibody in the cell supernatant. In the presence of sodium azide (10 mM) only a slow dissociation of intact antibody occurred, without internalization. The radioactive material eluted in the 100-200 kDa zone from supernatants was only partly adsorbed on protein A and hardly on CD4+ cells, indicating that alterations of the Fc region and loss of antigen binding activity, possibly by formation of CD4-anti-CD4 complexes, had occurred during the process of internalization and release into the extracellular medium. These data may be important to consider for adjusting the dosage of anti-CD4 mAbs to be administered.

Antibodies, Monoclonal↗
PubMed1993

Overall interleukin-6 production exceeds 7 mg/day in multiple myeloma complicated by sepsis.

We previously reported that injection of anti-IL-6 monoclonal antibody (mAb) in a patient with multiple myeloma (MM) induced the circulation of high amounts of IL-6 in the form of IL-6/anti-IL-6 monomeric complexes. This made it possible to estimate overall daily IL-6 production in patients in vivo, which had not been achieved in animals or humans before. In this study, estimations are given for a patient with MM who developed Escherichia coli sepsis during anti-IL-6 mAb. During the first 12 days, the overall IL-6 production was estimated at 1.5 to 2.0 micrograms/day. On day 13, serum IL-6 concentration, in the form of IL-6/anti-IL-6 complexes, increased 1000-fold and was 1.7 x 10(6) pg/ml, in relation with the development of E. coli sepsis. Overall IL-6 production was estimated to be greater than 7 mg/day, i.e. 3500 times higher than before sepsis. Serum IL-6 levels in the form of monomeric immune complexes remained very high for 20 days after sepsis indicating the persistence of very high overall IL-6 production (100 to 3500-fold greater than pre-sepsis production). This study demonstrates a considerable and persistent potential for IL-6 production in this patient during and after sepsis.

Antibodies, Monoclonal↗
PubMed1993

Detection of single cells secreting IFN-gamma, IL-6, and IL-10 in irreversibly rejected human kidney allografts, and their modulation by IL-2 and IL-4.

The frequency of isolated low-density graft-infiltrating cells (GIC) secreting IFN-gamma, IL-6, and IL-10 was studied in 8 cases of irreversible rejection of human renal allografts, using ELISA and SPOT-forming cells (ELISPOT) assays. The GIC were mostly CD8+ T cells, although CD4+ T cells, B cells, and macrophages could also be detected. On the average, in 10(6) cells, 189 secreted IFN-gamma, 747 IL-10, and 17114 IL-6. Culture of GIC in the presence of IL-2 resulted in an increase in the frequency of IFN-gamma-producing cells (IFN-gamma-PC), in a dose-dependent manner, with an optimal 6.5-fold increase at 50 U/ml. In contrast, 25 U/ml IL-4 decreased the frequency of spontaneous and IL-2-induced IFN-gamma-PC by 71.3% and 52.8%, respectively. Furthermore, IL-4 reduced the frequency of IL-6-PC (56.8%). By this new approach to graft rejection, it becomes easier to determine cytokine profiles within an allograft and to study their modulation by different agents. It could be a useful model of study for the development of new treatment.

Adjuvants, Immunologic↗
PubMed1993

CD14 and tolerance to lipopolysaccharide: biochemical and functional analysis.

To evaluate the role of the high-affinity monocyte receptor for lipopolysaccharide (LPS), CD14, in the process of tolerance to LPS, the human monocytic cell line Mono-Mac-6 was cultured in the absence or presence of different amounts of LPS. The kinetics of CD14 modulation in these cells showed an initial 4-day period characterized by increased cell-surface expression, rate of biosynthesis (peaking at 48 hr) and release of its soluble forms (sCD14) which correlated with the amount of LPS in the culture. At this time, tolerance to LPS was already established, as measured by tumour necrosis factor-alpha (TNF-alpha) induction, it was LPS dose dependent and persisted up to 15 days. LPS also reduced the cell proliferation rate in a dose-dependent manner. After 8 days and up to 15 days, the CD14 biosynthesis, cell-surface expression and release of sCD14 inversely correlated with the level of LPS in the culture. The 48-hr LPS-pretreated cells showed a slightly decreased CD14 affinity for LPS, a relative high number of CD14 molecules per cells, and desensitization also to a phorbol 12-myristate 13-acetate (PMA) challenge. An anti-CD14 monoclonal antibody (mAb) protected the cells from tolerization when added at the beginning of culture, as revealed by challenge with LPS and PMA. The data indicate that in this model tolerization to LPS (1) precedes CD14 down-modulation, (2) operates by alteration of the receptor affinity for LPS and by a mechanism which affects a protein kinase C (PKC)-dependent signalling pathway, and (3) that CD14 plays a critical role in the establishment of tolerance to LPS. In addition, analysis of the data suggests the existence of a PKC-independent signalling pathway for LPS tolerization and a CD14-independent mechanism for establishing tolerance.

Antigens, CD↗
PubMed1993

Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody.

Interleukin 6 (IL-6) appears to be a potential mediator of inflammation that may contribute to the pathogenesis of joint inflammation in RA. Anti-IL-6 monoclonal antibodies (Mab) may represent a new tool in RA treatment. Five patients with RA, after previous anti-CD4 therapy (B-F5) without antimouse immunization were included in our open pilot study. The anti-IL-6 Mab (B-E8, IgG1) was given intravenously (10 mg/day) for 10 consecutive days in hospital. No side effects were noted. Clinical and biological (C-reactive protein) improvement appeared during the treatment period. However improvement was transitory (mean: 2 months). Unexpectedly serum IL-6 levels increased in 4 patients with this treatment that seemed to have antiinflammatory effects. Further studies are required to evaluate the real benefit and the mode of action of this Mab.

Antibodies, Monoclonal↗
PubMed1992

[In situ production of interferon gamma and interleukin 6 by infiltrating cells from human kidney allografts in irreversible rejection. Modulation by cytokines].

Using ELISPOT assays, we detected a significant number of cells secreting interferon-gamma and interleukin 6 among 8 irreversibly rejected kidney allografts compared with normal kidneys. Interleukin 2 increases the frequency of interferon-gamma producing cells and interleukin 4 decreases the frequency of both interferon-gamma and interleukin 6 producing cells.

Depression, Chemical↗
PubMed1992

Phase I-II trial of a monoclonal anti-tumor necrosis factor alpha antibody for the treatment of refractory severe acute graft-versus-host disease.

In a multicenter pilot study, 19 patients with severe acute graft-versus-host disease (aGVHD) refractory to conventional therapy and serotherapy with a monoclonal anti-interleukin-2 receptor antibody were treated by in vivo infusion of a monoclonal anti-tumor necrosis factor alpha (TNF alpha) antibody (B-C7). Ten patients were grafted from a genotypically identical sibling, five from an HLA-mismatched family member, and four from an HLA-matched unrelated donor. Before B-C7 treatment, 15 patients had grade IV and four had grade III GVHD. In all cases, patients received cyclosporine/methotrexate as aGVHD prophylaxis. Patients were administered increasing doses of antibody (from 0.1 to 0.4 mg/kg). The antibody was infused in bolus daily for 4 days and then every other day twice (6 doses). No side effects were observed during treatment regardless of the dose level used. Changes in peripheral blood cell counts occurred in 8 of the 19 patients and appeared to be unrelated to B-C7. No truly complete response was observed; eight patients achieved a very good partial response (42.6%) and six a partial response (31.5%). The treatment was ineffective in five patients (26.4%). When present, the response occurred early (less than 3 days). In the 14 responding patients, gut lesions responded best (100%), followed by skin (85%) and liver (35.7%) lesions. In 9 of 11 evaluable patients (81%), GVHD recurred when treatment was discontinued in a median delay of 3 days (range, 2 to 120 days). All except one died from aGVHD. Two patients did not experience GVHD recurrence and are still alive 13 and 18 months post-bone marrow transplantation. This pilot study shows that a monoclonal anti-TNF alpha antibody may be of benefit to some patients with severe refractory aGVHD, but is ineffective to prevent GVHD recurrence in the majority of cases.

Acute Disease↗
PubMed1992

Inhibition of the production of proinflammatory cytokines and immunoglobulins by interleukin-4 in an ex vivo model of rheumatoid synovitis.

OBJECTIVE: To assess the spontaneous production of proinflammatory cytokines and immunoglobulins in rheumatoid arthritis (RA) synovitis and modulation by interleukin-4 (IL-4). METHODS: We developed an ex vivo model of RA synovitis using pieces of RA synovium, and have studied the regulation of the production of IL-1 beta, IL-6, tumor necrosis factor alpha (TNF alpha), IgM, and IgG. RESULTS: Spontaneous production of proinflammatory cytokines in vitro was active, with prolonged cytokine gene transcription and translation. IL-6 was produced at higher levels than either IL-1 beta or TNF alpha, and explants produced more IgG than IgM. In contrast, IL-4 and interferon-gamma were undetectable. When pieces of synovium were incubated in the presence of IL-4, reduction of spontaneous proinflammatory cytokine and Ig production was observed. CONCLUSION: These results extend the observations of the antiinflammatory properties of IL-4 to an ex vivo situation, and provide the rationale for the clinical use of IL-4 in RA.

Adult↗
PubMed1992

High amounts of circulating interleukin (IL)-6 in the form of monomeric immune complexes during anti-IL-6 therapy. Towards a new methodology for measuring overall cytokine production in human in vivo.

A patient with plasma cell leukemia was treated with anti-interleukin (IL)-6 monoclonal antibodies (mAb) for 2 months. Using chromatography on protein A-Sepharose, anti-murine-IgG-Sepharose, anti-IL-6-mAb-Sepharose and gel filtration at pH 2.3, we have demonstrated that the anti-IL-6 mAb, by preventing the binding of IL-6 to its cell membrane receptor and its renal elimination, has induced huge amounts of IL-6 to circulate in the form of monomeric immune complexes. By using this observation, we have developed a mathematical modelling that allows the determination of the overall daily production of IL-6 in this patient, which was in the range of 15 micrograms per day. Overall in vivo production of cytokines has never been evaluated in animals or in humans before.

Antibodies, Monoclonal↗
PubMed1992

Treatment of rheumatoid arthritis with anti CD4 monoclonal antibody. Open study of 25 patients with the B-F5 clone.

Twenty-five defined severe RA patients (pts) (17 F, 8 M) were treated in an open study with a CD4 murine monoclonal antibody (Mab) (B-F5 clone, IgG1). Mab's daily dose was 10 mg (1 pt), 15 mg (2 pts), 20 mg (17 pts), 30 mg (4 pts) and 50 mg (1 pt) for 10 days. Tolerance was fair. Clinical improvement occurred during treatment period or within the first month in all but 2 patients, irrespective of Mab dosage. Improvement duration was variable (1 to 12 months), half of the patients still show signs of improvement at month 4. Biological parameters (CRP) improved parallel to the clinical. At day 180, 25% of the patients showed a reduction of 50% or more of the initial CRP values. There is no modification of RF titers, renal and hepatic parameters. Sequential evaluation showed a decrease of B, TCD3, CD4, CD8 lymphocytes and monocytes two hours after Mab infusion and return to baseline in 20 hours. Xenogenic immunization occurred in 6 patients without influence upon clinical response. These modifications are moderate and transient and do not account for the more prolonged effect in some cases, nor do they offer any prediction of further clinical response.

Adult↗
PubMed1992

Down-regulation of cell surface CD4 molecule expression induced by anti-CD4 antibodies in human T lymphocytes.

Antigenic modulation was defined as the down-regulation of a cell surface antigen expression induced by exposure to specific antibody. We investigated the modulation of CD4 surface expression in human peripheral blood lymphocytes incubated in vitro with anti-CD4 monoclonal antibodies (mAbs). Modulation of surface CD4 was achieved at 37 degrees C, but not at 4 degrees C, with five different murine anti-CD4 mAbs of IgG1 and IgG2a subclasses, with different epitope specificities. Modulation was dose dependent with a maximum at nonsaturating mAb concentration. It was reversible upon culture in mAb-free medium. It was accelerated and amplified in the presence of monocytes or after cross-linking of anti-CD4 mAbs. It could be induced with solid phase anti-CD4 mAbs, but not with soluble F(ab')2 fragments. Its magnitude was identical on all CD4+ lymphocytes. It was associated with a moderate down-regulation of CD2 and CD3 but not of CD8 and HLA class I surface expression. Modulation was slightly augmented by addition of inhibitors of the endosome/lysosome pathway but not by protein synthesis inhibitors. The anti-CD4 mAb initially bound to cell surface was no longer detectable after 24 hr of culture. Most of surface CD4 proteins complexed with antibody were rapidly internalized and transiently replaced by CD4 from an intracytoplasmic pool and then no longer were expressed. CD4 mRNA was moderately decreased in cells incubated with anti-CD4 mAb while beta-actin and beta 2-microglobulin mRNAs remained at stable levels. It was concluded that down-regulation of CD4 surface expression induced by anti-CD4 mAb concerned only a part of CD4 molecules and was associated with a decreased synthesis. The delay required to achieve maximal modulation is likely to reflect exhaustion of the intracytoplasmic recycling pool of CD4 molecules.

Animals↗
PubMed1992

Down-regulation of lymphocyte CD4 antigen expression by administration of anti-CD4 monoclonal antibody.

Modulation of surface CD4 antigen expression was assessed by flow cytometry after calibration with 125I-labeled anti-CD4 monoclonal antibodies (mAbs). Three patients with severe psoriasis treated with BB14 (anti-CD4 mouse IgG1) and five patients with rheumatoid arthritis treated with BL4 (anti-CD4 mouse IgG2a) were analyzed for sequential changes in surface CD4 expression on CD4+ blood lymphocytes. Anti-CD4 mAb treatment induced a decrease of 50 to 80% of CD4 expression, with slow and partial recovery after cessation of mAb administration. CD4 modulation was related to mAb dosage and mAb concentration in plasma. It was achieved at nonsaturating concentration. In vitro incubation of blood mononuclear cells induced CD4 modulation of similar kinetics and magnitude, associated with decrease of 5-10% of CD3 expression. CD4 modulation required both an intact Fc part of the antibody and the presence of monocytes. The possible role of CD4 modulation should be considered along with other functional activities of anti-CD4 mAbs in analyzing the mechanisms of the clinical effects of these antibodies.

Antibodies, Monoclonal↗
PubMed1992

Anti-CD4 monoclonal antibody therapy in severe psoriasis.

We report here the treatment of psoriasis, a chronic inflammatory skin disease characterized by uncontrolled keratinocyte proliferation, with BB14, a CD4 murine IgG1 antibody. Three patients with severe psoriasis were treated with anti-CD4 mAb infusions (0.2 mg/kg/day for the first patient, 0.4 mg/kg/day for 2 days and 0.8 mg/kg/day during the following days for the 2 others) for 7 or 8 days, without other therapy. Rapid clinical improvement, with major reduction of the Psoriasis Area Severity Index, was observed during 1 month after treatment. Moderate decreases in CD4+ blood cells occurred in the last two patients but not in the first one. Circulating T cells coated with anti-CD4 mAb were detectable during the first 48 h in the first patient and from day 1/2 to day 7/8 in the two others. The density of CD4 molecules on the surfaces of peripheral blood lymphocytes was decreased in all patients and remained low as long as anti-CD4 mAb was detectable in patient serum. The maximal 24 h residual mAb levels ranged from 0.3 microgram/ml in the first patient to 3.8 and 7.0 microgram/ml in the two others. The three patients produced IgM antibodies against the anti-CD4 mAb at day 7/8 or 15 and two patients had IgG antibodies at day 15. Lesional skin samples demonstrated (1) gradual improvement in parakeratosis, papillomatosis and acanthosis, (2) decreased expression of ICAM-1 and HLA-DR by keratinocytes, (3) an increase in CD1a+ Langerhans cell number, (4) partial decrease in epidermal T cell infiltrate and (5) no major change in the dermal infiltrate composed of CD3+, TcR alpha beta+, CD45Ro+, HLA-DR+ T cells. We conclude that anti-CD4 mAb administration can induce a rapid and major improvement in psoriatic lesions, with immunohistochemical changes different from those induced by cyclosporin A or 8-methoxypsoralen plus long wave UV light (PUVA) therapy. Our data provide strong evidence for a critical role of CD4+ lymphocytes in psoriasis.

Adult↗
PubMed1992

B-B10 (anti-CD25)-saporin immunotoxin--a possible tool in graft-versus-host disease treatment.

An immunotoxin containing the B-B10 MoAb, directed against the CD25 determinant, and the ribosome-inactivating protein saporin, inhibits 3H-TdR incorporation in phytohemagglutin, allogeneic-stimulated lymphocytes (primary and secondary mixed-lymphocyte reaction), and in an alloreactive T cell clone. A lower degree of inhibition was obtained with the B-B10 MoAb, which is known to inhibit IL-2 activity, as well as with the unconjugated compounds. These results suggest that the in vivo administration of the conjugate might be a more effective tool in the treatment of patients affected by graft-versus-host disease than B-B10 alone, by inducing an efficient killing of allogeneic-reacting T lymphocytes.

Antibodies, Monoclonal↗