Molgramostim to treat SS-sickle cell leg ulcers.
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Administration, Topical↗
Biomedical subjects
A J Duits
Publications and source records attributed to A J Duits.
Skewed distribution of IgG Fc receptor IIa (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients.
OBJECTIVE: Fc gamma receptors of class IIa (Fc gamma RIIa) occur in 2 allelic forms, with either a low (IIa-R131) or a high (IIa-H131) affinity for complexed IgG2 and IgG3. This polymorphism might have implications for the handling of immune complexes. Therefore, we determined the distribution of the Fc gamma RIIa allotypes in patients with systemic lupus erythematosus (SLE), with or without a history of lupus nephritis. METHODS: We studied 95 unrelated white European patients with SLE, as defined by the American College of Rheumatology criteria, 50 of whom had a history of lupus nephritis, and 69 healthy white European control subjects. Fc gamma RIIa allotypes were determined by immunophenotyping of blood monocytes. RESULTS: It was found that lupus nephritis was significantly associated with the "low affinity" Fc gamma RIIa R/R131 allotype and with the R131 allele, compared with healthy controls. No significant association was found upon comparison of groups with and without nephritis. CONCLUSION: SLE patients with a history of lupus nephritis have an abnormal distribution of Fc gamma RIIa allotypes. Fc gamma RIIa may well play a role in the pathogenesis of lupus nephritis, since IIa-R/R131 SLE patients seem to have a higher incidence of developing this complication.
Adult↗
CD8 T cell activation after intravenous administration of CD3 x CD19 bispecific antibody in patients with non-Hodgkin lymphoma.
A bispecific antibody directed to T and B cells (CD3 x CD19 bsAb) was daily infused intravenously in escalating doses from 10 micrograms up to 5 mg in three patients with chemotherapy-resistant non-Hodgkin lymphoma; in this way we aimed to activate T cells to kill the malignant B cells. Only limited toxicity was observed, consisting of moderate fever preceded by chills or shivers and mild thrombocytopenia. No human anti-(mouse Ig) antibodies were found. Pharmacokinetics showed a t1/2 of 10.5 h with peak levels of 200-300 ng/ml after infusion of 2.5 mg bsAb. bsAb in serum was functionally active in vitro. After bsAb infusion a rise in serum tumour necrosis factor alpha was observed, accompanied by an increase in soluble CD8 and to some extent in soluble interleukin-2 receptor (IL-2R), but not in interferon gamma. IL-4 or soluble CD4. No evidence was found for monocyte activation (no increases in IL-6, IL-8 or IL-1 beta in serum). No gross changes in histology or number of IL-2R+, CD4+ or CD8+ cells were found in the lymph nodes after therapy, but one patient showed activated CD8+ T cells within the tumour nodules. In conclusion, after intravenously administered CD3 x CD19 bsAb only moderate toxicity was found, probably due to CD8+ T cell activation and cytokine release, without CD4+ T cell activation.
Adult↗
Antisense oligonucleotides, a novel tool for the control of cytokine effects on human cartilage. Focus on interleukins 1 and 6 and proteoglycan synthesis.
OBJECTIVE: To prevent the negative effects of interleukin-1 (IL-1) and IL-1-induced IL-6 on cartilage proteoglycan (PG) synthesis, we used an antisense oligonucleotide (ASO) specific for IL-6 messenger RNA (mRNA) to inhibit IL-6 production. METHODS: Explants of human articular cartilage were cultured in the presence or absence of IL-6-ASO, IL-1, and exogenous IL-6. As metabolic parameters, cartilage production of IL-6 was determined in the B9 bioassay and PG as incorporation of 35SO4. RESULTS: The IL-6-ASO prevented IL-1-induced production of IL-6 in the cartilage explants, as well as IL-1-induced inhibition of PG synthesis. This inhibition was restored, despite the presence of IL-6-ASO, when exogenous IL-6 was added. A control ASO (not specific for IL-6 mRNA) was not effective. CONCLUSION: The IL-6-ASO used can penetrate the extracellular matrix of articular cartilage, enter the chondrocytes, and inhibit the IL-1-induced production of IL-6. Furthermore, IL-6-ASO can prevent the IL-1-induced inhibition of cartilage PG synthesis. The effect of exogenous IL-6 shows that IL-1 requires IL-6 for inhibition of PG synthesis.
Aged↗
Elevated synovial fluid levels of interleukin-6 and tumor necrosis factor associated with early experimental canine osteoarthritis.
OBJECTIVE: To measure levels of cytokines, proteases, and glycosaminoglycans (GAG) in synovial fluid (SF) from the knees of animals with experimental osteoarthritis (OA) and from their contralateral (control) knees, and to compare and correlate these values with each other as well as with measures of proteoglycan synthesis in the corresponding articular cartilage. This study will help to identify cytokines of potential importance in the early stages of the development of OA. METHODS: OA was induced in 12 mature animals by sectioning the anterior cruciate ligament. After 3 months, SF from the operated and contralateral (control) knee joints was assayed for interleukin-6 (IL-6), tumor necrosis factor (TNF), IL-1, latent metalloproteinase, and sulfated GAG. Proteoglycan synthesis in the corresponding articular cartilage was also measured. RESULTS: IL-6 levels in SF from the operated joint compared with the control joint were significantly elevated in 11 of 12 animals. TNF levels were also elevated in 10 of 11 SF samples from operated joints, but to a lesser extent than those of IL-6. IL-1 and IL-1 inhibitors were undetectable in either the operated or control joint SF. The GAG concentration was elevated in SF from experimental OA joints. This elevation correlated with that of TNF, but not IL-6. There was no significant difference in the concentration of APMA-activatable metalloproteinase. The rate of proteoglycan synthesis was higher in the cartilage from the operated joint in 8 of 12 animals, and the mean rate of synthesis was significantly higher than in the control joint. There was a positive correlation between this increase in cartilage proteoglycan synthesis (operated versus control) and the increase in SF IL-6, but there was no correlation with the levels of TNF or GAG. CONCLUSION: This is the first study of SF levels of cytokines in early experimental OA. Our results show surprisingly high levels of IL-6 in operated joints, where the cytokine could act directly on the chondrocytes, and thus play a role in mediating their responses to cartilage injury.
Animals↗
Leukocyte adhesion deficiency in a Dutch Holstein calf: a case with a clear-cut family history.
A leukocyte adhesion deficiency characterized by recurrent (predominantly bacterial) infections, lack of extravascular polymorphonuclear leukocyte (PMN) and pus formation has been described first in humans and then in dogs, and recently also in cattle. Because of important clinical similarities, a unitary explanation for the leukocyte adhesion deficiency (LAD) syndrome in mammals is proposed, inasmuch that an intrinsic leukocyte defect (i.e. mutations in genes encoding the common CD18 subunit), is thought to cause the disease. However, thus far, the hallmark of such intrinsic leukocyte defects, notably their heritability (or familial incidence), has not (yet) been unequivocally demonstrated. This is the first report to describe the occurrence of four Dutch bovine LAD (BLAD) cases with the clearest familial clustering observed to date. The diagnosis was based on the clinical features of very poor thriving, in general, of the calves, hyperneutrocytosis without appreciable left shift, and the absence of PMN CD11a, or CD11b, or CD11c using monoclonal antibodies (mAb) and/or Concanavalin A binding activity of PMN lysates in immunoblots. Interestingly, a familial clustering was observed also for below-normal PMN CD11c expression. Thus, a cow with low CD11c expression (50.4%) and delivering three of the study BLAD calves, also had a healthy descendant with low (44.9%) PMN CD11c expression. These findings suggested the possibility that both subnormal expression and lack of PMN CD11 expression are inheritable factors in cattle. Furthermore, a large prospective study using the present mAb for selecting relatives expressing the complete spectrum (0 to > or = 90%) of PMN CD11/CD18 expression would create a comprehensive study population for understanding both the role of genetic factors and of survival strategies in BLAD.
Animals↗
Immunoadjuvant activity of a liposomal IL-6 formulation.
The adjuvant effect of interleukin 6 (IL-6) entrapped in liposomes was evaluated using a 65 kDa heat shock protein as a model antigen. The secondary humoral immune response either to antigen alone, or incorporated into liposomes, and the effect of IL-6 entrapped in liposomes, on this response were studied in Balb/c mice. The adjuvanticity of these formulations was compared with that of potent adjuvants such as Ribi and dimethyldioctadecylammoniumbromide (DDA). The importance of IL-6 during adjuvant activity was supported by the observation that high serum IL-6 levels were induced in Balb/c mice by all members of a panel of adjuvants tested. Following incorporation into liposomes, IL-6 retained its full biological activity, as shown by its capacity to sustain growth of the IL-6-dependent B9 cell line. At antigen dosages where Ribi and DDA gave minimal or no secondary antibody titres, incorporation of antigen into liposomes resulted in measurable secondary antibody titres. Interestingly, this adjuvant activity was significantly enhanced when liposomes containing IL-6 were co-injected with the liposomal antigen formulation. These results illustrate the potential adjuvant properties of this formulation, which seem especially useful for vaccines containing weak or non-immunogenic antigens.
Adjuvants, Immunologic↗
Isotype-specific cross-linking of select human Fc gamma R isoforms triggers release of IL-6.
Anti-CD3 MoAbs are widely used in T cell activation studies, and are effective in immunosuppressive therapy. We used a panel of mouse (m) anti-CD3 switch variant MoAbs of five different isotypes to study IL-6 release from accessory cells. Incubation of human (h) mononuclear cells with anti-CD3 MoAbs resulted in increased IL-6 levels with MoAbs of mIgG1 and mIgG2a isotypes, with no effect of mIgG2b or mIgA. This suggested involvement of IgG Fc receptors (Fc gamma R) in triggering IL-6 production. To evaluate the role of different Fc gamma R molecules individually we used a panel of hFc gamma R-transfected mouse fibroblasts, and Jurkat T cells as a model. IL-6 secretion by CD32 transfectants expressing the hFc gamma RIIa high-responder (HR) allelic form was triggered by mIgG1 anti-CD3 MoAb, with no effect of four other isotypes. None of the anti-CD3 MoAbs induced IL-6 secretion by CD32 transfectants expressing either a variant of this receptor, containing only a single intracellular amino acid (CT-), the hFc gamma RIIa low-responder (LR) allelic form, or hFc gamma RIIb1. hFc gamma RI (CD64) transfectants exhibited IL-6 production after incubation with mIgG2a anti-CD3 MoAb, and to a lesser extent with mIgG2b, and mIgG1 MoAb. Indirect involvement of T cells in triggering IL-6 secretion could be excluded by experiments in which transfectants were cultured with immobilized anti-CD3 MoAb. These data indicate that cross-linking of either hFc gamma RI, or hFc gamma RIIaHR by appropriate anti-CD3 MoAbs triggers IL-6 production of accessory cells, and not T cells. This may also take place in vivo during immunosuppressive therapy with anti-CD3 MoAbs, and related antibody-mediated immune responses.
3T3 Cells↗
Synergism of interleukin 6 and 1 alpha,25-dihydroxyvitamin D3 in induction of myeloid differentiation of human leukemic cell lines.
Interleukin 6 (IL-6) is a multifunctional cytokine with an important role in immunity. We analyzed the effect of recombinant human IL-6 in combination with 1 alpha,25-dihydroxyvitamin D3 (Vit. D3) on differentiation of the human myeloid leukemic cell lines U937 and HL-60 with respect to alterations in antigen expression and functional activity. Of a panel of antigens analyzed, only CD11b (the alpha chain of CR3), and CD14 (a cell surface protein recognizing the lipopolysaccharide-binding protein-lipopolysaccharide complex) had significantly increased expression. Expression of ICAM-1 (CD54), a ligand for LFA-1, was also found to be enhanced with a concomitant increase of ICAM-1 mRNA levels. Enhanced nonspecific esterase levels and induction of respiratory burst activity confirmed that cell differentiation was induced. Furthermore, IL-6 and Vit. D3 had a profound effect on functional activities, as shown by enhancement of rosetting between sheep erythrocytes, sensitized with C3bi (EAC), and either U937 or HL-60 cells. Also, phorbol myristate acetate-induced homotypic adhesion of U937, which is ICAM-1 dependent, was markedly induced by these agents. These results indicate an important role of IL-6 and Vit. D3 in myeloid cell function and development.
Antigens, CD↗
Selective enhancement of Leu-CAM expression by interleukin 6 during differentiation of human promonocytic U937 cells.
Interleukin 6 (IL-6) is a cytokine with multiple biological activities on various tissues and cells. We have investigated the effect of recombinant human IL-6 (rhIL-6) on growth and differentiation of U937. Recombinant human IL-6 induced a dose-dependent growth inhibition, apparent around day 4, of up to 50% by day 8 of culture. Concomitant with this, changes in cytochemical activities were observed, indicative of differentiation. A panel of U937 antigens was analysed after culture with rhIL-6. Expression of the majority of these membrane antigens was unaffected, with the exception of two classes. First, rhIL-6 had a profound effect on members of the leucocytic cell adhesion molecules (Leu-CAM) family. Expression of the alpha-chain of CR3 (complement receptor 3; CD11b) was enhanced in a dose-dependent fashion, with maximal expression around day 7. Parallel to this a simultaneous increase in beta-chain (CD18) expression was found. Furthermore, enhanced expression of CR3 was, accompanied by increased rosetting with sheep erythrocytes sensitized with C3bi. A much lower, but significant, enhancement was observed for the alpha-chain of the p150,95 antigen (CD11c). Expression of leucocyte function-associated antigen-1, (LFA-1), (CD11a/CD18) remained unchanged. Remarkably, however, expression of a ligand of LFA-1, intercellular adhesion molecule-1 (ICAM-1; CD54), was enhanced with similar kinetics as CR3 and p150,95. A specific anti-rhIL-6 antiserum completely inhibited the IL-6 effect. These observations provide further support for an important role of IL-6 in the regulation of myeloid cell development in man.
Antibodies, Monoclonal↗
Differential expression of the gene encoding the novel pituitary polypeptide 7B2 in human lung cancer cells.
The protein designated 7B2 is a recently discovered pituitary polypeptide which is selectively expressed in cells containing secretory granules, such as neurons and endocrine cells. Northern blot analysis of 7B2 gene expression in small cell lung carcinoma (SCLC) cell lines revealed that 7B2 was expressed in all nine cell lines of the classic type tested, but in six of seven SCLC cell lines of the variant type, 7B2 expression could not be detected. In only one of four non-SCLC cell lines tested, 7B2 was expressed. Furthermore, in 16 primary human non-SCLCs, no or only very low expression of 7B2 was found. In the eight primary human SCLCs tested, expression of 7B2 appeared variable: three exhibited a high level of expression; three a low level; while in two cases, expression was very low or not detectable at all. Finally, the three carcinoid tumors tested expressed very high levels of 7B2 mRNA. These data indicate that the 7B2 gene is a useful marker not only to discriminate between classic and variant types of SCLC cell lines, but also in human lung cancer diagnosis.
Carcinoma, Non-Small-Cell Lung↗
Plasma homocysteine levels in sickle cell disease and the need for folate supplementation.
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Adolescent↗