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Biomedical subjects

J F Bach

Publications and source records attributed to J F Bach.

At least 235 records · Page 13Linked to original sources
PubMed1992

Thymic abnormalities in fetuses aborted from human immunodeficiency virus type 1 seropositive women.

Pathological abnormalities of the thymus were found in 3 of 37 fetuses aborted from human immunodeficiency virus (HIV)-infected mothers. These lesions were located predominantly in the thymic cortex, which contains mostly immature lymphocytes. Areas of focal lymphocyte depletion were infiltrated with CD4+ macrophages and were associated with abnormalities of the epithelial stromal network. No evidence of extensive HIV infection in any of the 37 thymuses was detected by either immunofluorescence or in situ hybridization techniques, although rare cells that expressed HIV antigens were found in 3 fetuses. Although less extensive, this thymic fetopathy was similar to that described in postnatal acquired immunodeficiency syndrome thymuses, strongly suggesting that the lesions were related to HIV infection. Thymic fetopathy might represent the initial injury to the lymphoid system in HIV-infected infants in whom early and severe immunosuppression develops.

Abortion, Induced↗
PubMed1991

[Acute clinical syndrome associated with OKT3 administration. Prevention by single injection of an anti-human TNF monoclonal antibody].

This study analyzed the capacity of an anti-human tumour necrosis factor (TNF) monoclonal antibody, CB006 (murine IgG1, Celltech), to prevent the OKT3-induced acute clinical syndrome. Fourteen renal allograft recipients undergoing prophylactic OKT3 therapy were included. CB006 was administered as a single i.v. injection, 0.4 mg/kg (Group I, 7 patients) and 2 mg/kg (Group II, 7 patients), one hour prior to the first OKT3 administration. Nineteen consecutive patients that were part of a randomized multicenter trial constituted the historical control group. In all patients CB006 was perfectly well tolerated and significantly decreased the frequency of the common OKT3-associated acute symptoms. None of the CB006 pretreated patients showed severe life threatening symptoms (hypotension, respiratory distress or neurotoxicity), observed in 10 per cent of historical controls. At variance with controls, in CB006 treated patients gastrointestinal symptoms (vomiting, diarrhea) and pyrexia (body temperature greater than or equal to 39 degrees C) appeared in low frequency, were mild and short lasting, never promoting major prostration of the patients due to electrolytes and fluid loss. Importantly, the presence in some patients of these mild symptoms, correlated with detectable bioactive TNF in the circulation thus reflecting incomplete blockade by CB006 of OKT3-induced TNF. CB006 pharmacokinetics data further stressed the need for adequate dosage adaptation. CB006 did not affect the biological or clinical effectiveness of OKT3. None of the patients showed evidence of anti-CB006 xeno-sensitization.

Antibodies, Monoclonal↗
PubMed1991

Identification and functional activity of prolactin receptors in thymic epithelial cells.

Thymic epithelial cells (TECs), the major component of the thymic microenvironment, can be modulated by pituitary hormones. We have shown previously that prolactin (PRL) can influence the endocrine activity of TECs and stimulate TEC proliferation as well as cytokeratin expression, suggesting the existence of PRL receptors on TECs. Using a series of monoclonal antibodies (mAbs) to the extracellular domain of the rat liver PRL receptor, we have demonstrate that rat TECs bear specific receptors for PRL, as assessed by immunoblotting as well as by immunocytochemistry experiments. Using a probe specific for the long form of PRL receptor, mRNAs of 6.7 and 10.1 kilobases were detected, although by immunoblot the major protein in TECs had a molecular mass of 43 kDa. Functionally, these mAbs were able to modulate thymulin secretion, as well as TEC proliferation. Moreover, the mAbs cross-reacted with human TECs and were able to mimic the action of PRL on these cells. These data bring further support for the general concept of the neuroendocrine immune circuit and extend the notion for a pleiotropic role of PRL as an immunomodulatory hormone.

Animals↗
PubMed1991

Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non-obese diabetic mice.

Insulin-dependent diabetes mellitus (IDDM) is a polygenic disease caused by autoimmune destruction of insulin-producing beta cells in the islets of Langerhans. Its onset is preceded by a long and variable period in which lymphoid cells infiltrate the pancreas but first remain outside the islets (peri-insulitis) before invading them (insulitis). Among susceptibility loci, only the major histocompatibility complex (MHC) has been clearly assigned. Genetic study of the nonobese diabetic (NOD) mouse model for insulin-dependent diabetes mellitus has revealed genetic linkage of insulitis and of early onset diabetes with two non-MHC loci mapping to chromosome 3 and 11 respectively. Here we report a close association of periinsulitis with a third non-MHC locus mapping to chromosome 1. Successive stages in the progression of diabetic disease thus appear to be controlled by distinct genes or sets of genes.

Alleles↗
PubMed1991

CD8+ T cell homing to the pancreas in the nonobese diabetic mouse is CD4+ T cell-dependent.

The adoptive transfer of type I diabetes in nonobese diabetic mice requires the contribution of both CD4+ and CD8+ T cells. To further elucidate the cellular pathway(s) of beta-cell destruction and the responsibility of each subset, high doses of committed T cells from diabetic mice purified to single subsets, were injected into syngeneic nonobese diabetic neonates. The recipients of single or mixed subsets were followed for clinical manifestations of diabetes and examined at 30 days of age for in situ lesions. None of the animals injected with either CD4+ or CD8+ T cells became overtly diabetic during the 30 days of observation whereas 8 of 23 mice inoculated with a mixture of the two subsets developed glycosuria and hyperglycemia. However, insulitis was found in 6 of the 13 mice injected with CD4+ T cells whereas only 1 of the 9 mice injected with CD8+ T cells showed marginal infiltration of the pancreas. The lesions initiated by CD4+ T cells alone were considerably less severe than those induced by the mixture of both subsets, corroborating the fact that overt disease did not occur in the former group. Together, these results suggest a distinct function for each diabetogenic T cell subset. CD4+ T cells, which have the capacity to home to the pancreas, promote in turn the influx of CD8+ effector T cells that do not by themselves accumulate in this organ. These results illustrate a novel form of T-T cell interactions leading to organ specific autoimmune lesions.

Animals↗
PubMed1991

Anti-alpha/beta T cell receptor monoclonal antibody provides an efficient therapy for autoimmune diabetes in nonobese diabetic (NOD) mice.

The nonobese diabetic (NOD) mouse is a relevant model for studying human insulin-dependent diabetes mellitus (IDDM). The selective destruction of insulin-secreting cells in this model is subsequent to an autoimmune reaction directed towards the beta cells inside the islets of Langerhans of the pancreas. Given the key role played by T cells in the development of IDDM, we investigated a model of IDDM prevention in NOD mice by administration of a monoclonal antibody to the alpha/beta dimer of the T cell receptor for antigen. Our data provide evidence that aiming at the T cell receptor protects against both spontaneous and cyclophosphamide-induced diabetes in the NOD mouse. Interestingly, potential clinical application is suggested by the efficient and durable reversal of recent onset diabetes in mice treated with anti-alpha/beta monoclonal antibody within 1 week following the clinical discovery of IDDM.

Animals↗
PubMed1991

Cascade modulation by anti-tumor necrosis factor monoclonal antibody of interferon-gamma, interleukin 3 and interleukin 6 release after triggering of the CD3/T cell receptor activation pathway.

In addition to being potent immunosuppressants, anti-CD3 monoclonal antibodies (mAb) are powerful mitogens in both humans and mice. The first antibody injection consistently induced an initial monocyte-dependent T cell activation with subsequent release of both monocyte- and T cell-derived cytokines [mainly tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin (IL) 2, IL 3 and IL 6) into the circulation. This cytokine release is associated with a self-limiting, often severe, acute physical reaction in both patients and mice. We report here that a single injection of anti-TNF mAb prior to anti-CD3 administration not only neutralizes the biological activity of TNF but also strongly affects the release of other cytokines, with notably an up-regulation of IFN-gamma release and a down-regulation of IL 3 and IL 6 release. Conversely, pretreatment with anti-IFN-gamma mAb increases IL 3 and IL 6 production but does not affect TNF levels. Taken together, these data point to a pivotal role of IFN-gamma in the anti-CD3-induced cytokine cascade and reveal new regulatory pathways between TNF and IFN-gamma. With regard to the clinical implications of these findings, as anti-TNF mAb prevents anti-CD3-induced sickness in mice, whereas anti-IFN-gamma does not, such a therapeutic approach might be of value in OKT3-treated patients.

Animals↗
PubMed1991

Intravenous gamma-globulin in myasthenia gravis: interaction with anti-acetylcholine receptor autoantibodies.

Clinical improvement has been observed in myasthenia gravis patients treated by intravenous immunoglobulin (IVIg). In order to investigate the mechanism of action of these IVIg, we looked for an in vitro interaction between IVIg and the anti-acetylcholine receptor autoantibodies. Significant inhibition by IVIg of anti-acetylcholine receptor autoantibody activity from 30 MG sera was observed and binding of anti-acetylcholine receptor autoantibodies on IVIg was found for four of five myasthenia gravis sera. These observations suggest that IVIg contains Ig directly binding to and inhibiting pathogenic autoantibodies.

Adolescent↗
PubMed1991

Autoantibodies in D-penicillamine-induced myasthenia gravis: a comparison with idiopathic myasthenia and rheumatoid arthritis.

The distribution of autoantibodies was studied in patients with rheumatoid arthritis (RA) treated by D-penicillamine and who developed myasthenia gravis (MG). The anti-human acetylcholine receptor (AChR) antibodies were specifically associated with clinical symptoms of MG without any difference in the pattern of specificities in idiopathic (id-MG) or in induced MG (DPen-MG). Conversely, anti-nuclear antibodies were elevated in DPen-MG sera compared to id-MG sera (P less than 0.001) but were also compared to patients with RA treated by D-penicillamine (or thiopronine) and who did not develop MG. Anti-denatured DNA antibodies were enhanced in sera from treated patients, whether they had presented or not a MG disease. Anti-histone antibodies were associated with RA. These observations suggest that the immunological imbalance in RA patients, can be increased by a drug treatment which may trigger the appearance of a second autoimmune disease such as MG, where anti-AChR antibodies are associated with anti-nuclear antibodies.

Adult↗
PubMed1991

Benzodiazepine anesthesia in humans modulates the interleukin-1 beta, tumor necrosis factor-alpha and interleukin-6 responses of blood monocytes.

The influence of sedative and anxiolytic benzodiazepines on human monocyte function was assessed in 11 patients undergoing anesthesia prior to control endoscopy of the urinary tract. A single i.v. injection of 0.08 mg/kg midazolam induced a marked and delayed inhibition of the lipopolysaccharide-induced production of interleukin-1 beta, tumor necrosis factor-alpha and interleukin-6 by monocytes isolated from peripheral blood. Corticosteroids were not responsible for the observed immunosuppression. These studies demonstrate that, when administered in man, benzodiazepines markedly alter the capacity of monocytes to synthetize major mediators of the host inflammatory response.

Anesthesia↗
PubMed1991

The contribution of non-MHC genes to susceptibility to autoimmune diseases.

Genetic studies of experimental models of autoimmune diseases, including systemic lupus-like syndromes and organ-specific autoimmunity, provide major information on genetic control of autoimmune diseases. In addition to genes known to be linked to the major histocompatibility complex (MHC), these studies point to multiple genes located outside the MHC that influence the onset and the progression of autoimmune diseases. Identification of these genes and of their interrelationships is now a major task that will be facilitated by recent progress in molecular biology and gene mapping. Among candidate genes, antigen-receptor genes (i.e., immunoglobulin- and T-cell receptor genes) most likely contribute an important part of the autoimmune susceptibility in several of these animal models. Available linkage data suggest a similar involvement of these antigen-receptor genes in several human autoimmune diseases. In addition to a better understanding of pathogenic mechanisms associated with autoimmunity, the knowledge of these disease-predisposing genes is expected to permit a better classification of often complex syndromes as well as the design of new treatments.

Animals↗