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K M Debatin

Publications and source records attributed to K M Debatin.

142 records · Page 8Linked to original sources
PubMed1989

Lack of interleukin-2 (IL-2) dependent growth of TAC positive T-ALL/NHL cells is due to the expression of only low affinity receptors for IL-2.

Binding of interleukin-2 (IL-2) to high affinity receptors on activated normal T cells was shown to be the essential step in induction of proliferation of such cells. The finding of abundant IL-2 receptors on malignant T cells in adult T cell leukemia suggested a deregulation of the IL-2/IL-2 receptor system and was assumed to account for aberrant growth in malignant disorders of T cells. In this study we use malignant T cells from nine patients with the clinical diagnosis of T-ALL or T-NHL and did not detect IL-2 dependent growth under conditions in which normal T cells responded to IL-2. IL-2 receptors comparable in numbers to activated T cells were found on T-ALL/T-NHL cells stimulated with PHA and PMA. However, binding studies using radiolabeled IL-2 indicated that the receptors present on malignant T cells were not able to bind to IL-2 with high affinity. Therefore, if IL-2 is involved in the proliferation of malignant T cells, its mechanism of growth regulation may be different from the one for normal T cells. Alternatively, IL-2 may not play a role in the regulation of growth of malignant T cells in vitro.

Adolescent↗
PubMed1984

Activation of macrophages by lymphokines from T-cell clones: evidence for different macrophage-activating factors.

The data reported in this paper demonstrate that macrophage-activating factors (MAFs) are a heterogeneous group of T-cell-derived lymphokines. Two long-term T-cell clones, Cl 96 and PK 7.1.2E8, were potent sources of MAFs (MAF96 and MAF7.1.2E8). These MAFs could be distinguished by differential activation of macrophages. Activation of resident murine macrophages with MAF7.1.2E8 enhanced RNA and glycoprotein synthesis, hexosemonophosphate shunt (HMPS) activity, release of oxygen metabolites (O-2 and H2O2), pinocytosis and tumor cytostasis, whereas no effect on schistosomula killing and tumor cytolysis could be observed. In contrast, MAF96 enhanced glycoprotein synthesis, HMPS activity, release of oxygen metabolites and prostaglandin E, schistosomula killing, and tumor cytostasis and cytolysis, while RNA synthesis and pinocytosis were decreased. These findings show that MAFs from both T-cell clones share some properties but markedly differ in others. In addition, the macrophage-activating properties of MAF96 but not of MAF7.1.2E8 could selectively be inhibited by a rabbit anti-lymphokine antiserum. This demonstrates a serological difference between MAF activities from both clones. Although at optimal concns both MAFs were active in the absence of lipopolysaccharide (LPS), the activity of suboptimal doses of MAF96 but not of MAF7.1.2E8 could be enhanced by LPS. These findings show that different MAFs from T-cell clones may be useful to clarify molecular mechanisms of macrophage activation.

Animals↗
PubMed1983

Macrophage-activating factors from different T cell clones induce distinct macrophage functions.

The data reported in this paper are the first demonstration that different T cell clones (PC-AKR-CI 96, clone 96; PK 7.1.2 E8, clone 7.1.2 E8) secrete different macrophage-activating factors (MAF) that induce distinct macrophage activities. Incubation of resident murine macrophages with MAF 7.1.2 E8 increased RNA, protein, and glycoprotein synthesis, hexosemonophosphate shunt (HMPS) activity, release of oxygen metabolites (O-2, H2O2), pinocytosis, phagocytosis, and tumor cytostasis, whereas no effect on prostaglandin E (PGE) release, schistosomula killing, and tumor cytolysis could be observed. In contrast, MAF 96 increased glycoprotein synthesis, HMPS activity, release of oxygen metabolites and PGE, schistosomula killing, and tumor cytostasis and cytolysis, whereas RNA and protein synthesis and pinocytosis were decreased and phagocytosis remained unaffected. Thus, MAF from both T cell clones share some macrophage-activating properties but differ in others. Most importantly, both MAF could be differentiated serologically by a rabbit anti-lymphokine antiserum that selectively inhibited MAF 96 but not MAF 7.1.2 E8 activity. At optimal concentrations, MAF 96 and 7.1.2 E8 were active in the absence of lipopolysaccharide (LPS) whereas LPS enhanced the activity of suboptimal doses of MAF 96 but not of MAF 7.1.2 E8. These data are discussed with respect to the possibility that the functional dichotomy of T cell clones might reflect different activities of normal T cell subpopulations.

Animals↗
PubMed1981

Depressed mediator release by inflammatory exudate cells in immunized rats following antigen challenge.

The aim of the present study was to characterize leukocytes present in a local inflammatory reaction with respect to production of prostaglandin E (PGE) and the release of factors affecting lymphocyte function, which are produced by macrophages (interleukin-1) or stimulated lymphocytes (interleukin-2). Lewis rats immunized against bovine serum albumin (BSA) were challenged by intraperitoneal injection of antigen. The PGE release by peritoneal cells (PEC) was tested in vitro and found to be enhanced in immunized rats before BSA challenge. However, PEC harvested after the injection of antigen showed a marked reduction in prostaglandin production during the first 24 hr. When these cells were tested for the secretion of lymphokines (IL-1, IL-2) the same depression was found.

Animals↗
PubMedDate not supplied

Pharmacokinetics of orally administered zidovudine in HIV-infected children and adults.

The pharmacokinetics of oral zidovudine in HIV-infected children and adults are reported. Fourty-six patients were investigated. For data analysis three groups of similar size were formed: young children 4 months-4 years, n = 15 (group 1), older children up to 13 years, n = 16 (group 2) and young adults, n = 15 (group 3). After a single oral dose repeated blood samples were taken 1/2 hourly during a period of 4 hours and zidovudine concentrations in plasma were determined by high performance liquid chromatography. For better comparison of dose dependent parameters peak concentrations (Cmax) and the area under the time-concentration curves (AUC) were normalized either to the dose/body weight (bw) or the dose/body surface area (bs), respectively. Time to reach peak concentrations and mean terminal elimination half-life times (t1/2 beta = 63.4 +/- 47.6, 74.9 +/- 54.9 and 56.9 +/- 16.4 min in group 1, 2 and 3, respectively, mean +/- SD) were not significantly different between the three groups. With normalization to dose/bw young children in comparison to adults had significantly lower Cmax (2.7 +/- 1.3 vs. 4.6 +/- 2.4 mumol/l, p = 0.016) and AUC (226 +/- 108 vs. 373 +/- 224 mumol.min/l, p = 0.038). Group 2 gave intermediate values. However, with normalization to dose/bs differences in Cmax (6.5 +/- 3.3, 7.3 +/- 4.2 and 6.8 +/- 3.6 mumol/l, in group 1, 2, and 3, respectively) and AUC (563 +/- 313, 691 +/- 351 and 555 +/- 342 mumol.min/l, in group 1, 2 and 3) were not significant between the three groups. It is likely that changes in body water content with age may account for most of these differences observed. In conclusion, a similar pharmacokinetic profile was found in children older than 3 months as compared to older children or adults.

Administration, Oral↗
PubMedDate not supplied

[Lipodystrophies].

The lipodystrophy syndromes are rare disorders characterized by the loss of adipose tissue. The loss of fat tissue can have genetic, immune, or infectious/drug-associated causes. With the extent of fat loss metabolic complications, such as insulin resistance, diabetes mellitus, hypertriglyceridemia, and fatty liver increase in severity. Lipodystrophies can be divided into two subtypes: familial and acquired. Causative mutations have recently been identified in one form of familial lipodystrophy as well as in one form of acquired lipodystrophy. Several mouse models might help understanding the development of these syndrome. In this review article, the recently introduced classification of lipodystrophy syndromes is presented as well as new insights into pathogenesis and therapeutic strategies.

Adipose Tissue↗
PubMedDate not supplied

IGF-I- and IGFBP-3-expression in cultured human preadipocytes and adipocytes.

The expression and secretion of IGF-I and IGFBP-3 were investigated in cultured human preadipocytes and in in vitro differentiated adipocytes derived from human subcutaneous adipose tissue under chemically defined culture conditions. Human preadipocytes expressed mRNAs for IGF-I and IGFBP-3 and secreted the corresponding proteins into the culture medium as measured by sensitive radioimmunoassays. In human adipocytes; specific mRNA-expression was comparable to that found in preadipocytes, but IGF-I secretion was increased 10-fold (3.87 +/- 0.69 vs. 0.41 +/- 0.11 ng/ml/10(6) cells/48 hrs, p < 0.05) and IGFBP-3 secretion 2.5-fold (7.34+/-1.15 vs. 3.27+/-0.38 ng/ml/10(6) cells/48 hrs, p<0.05) in the presence of adipogenic medium probably resulting in an increase of unbound IGF-I. Under serum-free, chemically defined conditions human growth hormone (hGH) and insulin were found to be positive regulators and cortisol was found to be a negative regulator of IGF-I and IGFBP-3 secretion in preadipocytes. In cultured human adipocytes, hGH showed no effect on IGF-I and IGFBP-3 secretion, whereas insulin stimulated and cortisol inhibited the secretion of both proteins. We conclude that IGF-I and IGFBP-3 may not only exert their actions in human adipose tissue via circulation, but also in an auto/paracrine way.

Adipocytes↗
PubMedDate not supplied

[Local recurrence of mediastinal non-Hodgkin lymphomas in childhood].

Local relapses in mediastinal non-Hodgkin's lymphomas in childhood are rare. Of the 15 children treated in our hospital during the last 11 years, 2 had early local or pleural relapses. At presentation both had extensive pleural effusions, and after completion of induction therapy still some fluid in the pleural space was present. A local irradiation was not performed initially. Be review of the literature for risks and benefit of local irradiation in mediastinal non-Hodgkin's lymphoma, local irradiation in children receiving aggressive chemotherapy should only be considered in few patients; preferentially in those, with incomplete disappearance of the mediastinal tumor or, as we may conclude from our patients, incomplete disappearance of pleural effusion.

Adolescent↗
PubMedDate not supplied

Betulinic acid: a new chemotherapeutic agent in the treatment of neuroectodermal tumors.

We identified betulinic acid (BetA) as a new cytotoxic agent active against neuroectodermal tumor cells including neuroblastoma, medulloblastoma, glioblastoma and Ewing's sarcoma cells representing the most common solid tumors of childhood. BetA induced apoptosis independent of wild-type p53 protein and accumulation of death-inducing ligand/receptor systems such as CD95. BetA had a direct effect on mitochondria resulting in the release of soluble apoptogenic factors such as cytochrome c or AIF from mitochondria into the cytosol where they induced activation of caspases. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-XL that blocked loss of the mitochondrial membrane potential and cytochrome c release from mitochondria conferred resistance to BetA at the level of mitochondrial dysfunction, protease activation and nuclear fragmentation. Neuroblastoma cells resistant to CD95- or doxorubicin-triggered apoptosis remained sensitive to treatment with BetA suggesting that BetA may bypass some forms of resistance. Moreover, BetA exhibited potent antitumor activity on primary tumor cell cultures from all neuroblastoma (4/4), all medulloblastoma (4/4) and most glioblastoma patients (20/24) ex vivo. These findings suggest that BetA may be a promising new agent in the treatment of neuroectodermal tumors in vivo.

Antineoplastic Agents, Phytogenic↗
PubMedDate not supplied

Molecular determinants of apoptosis induced by cytotoxic drugs.

Recent experimental evidence suggests that apoptosis pathways such as the CD95 system are an important mediator of chemotherapy-induced apoptosis in various tumor cell lines. Therapeutic concentrations of cytotoxic drugs induce CD95 and CD95-L that mediates apoptosis via an autocrine/paracrine loop by crosslinking CD95. Interfering with CD95-L/receptor interaction by antagonistic antibodies to the receptor or by inhibition of CD95-L expression strongly reduces apoptosis. Drug-induced apoptosis critically depends on activation of caspases since apoptosis is almost completely abrogated by the caspase inhibitor zVAD-fmk. The receptor apical caspase FLICE/MACH (caspase-8) and the downstream caspase CPP32 (caspase-3) are cleaved resulting in processing of substrates such as the nuclear enzyme PARP. In addition, the response to cytotoxic drugs is modulated by pro- and antiapoptotic proteins of the Bcl-2 family and p53. Defects in apoptosis pathways, e.g. deficient upregulation of CD95-L, downregulation of CD95 expression or blockade of caspase activation may confer resistance to cytotoxic drug treatment. Thus, chemosensitivity of tumor cells depends on intact apoptosis pathways such as the CD95 system that are activated by chemotherapeutic drugs. These findings may have implications for drug sensitivity and resistance of tumor cells.

Antineoplastic Agents↗
PubMedDate not supplied

[The role of CD95 (APO-1/Fas) mutations in lymphoproliferative and malignant lymphatic diseases].

CD95 (APO-1/Fas)-mediated apoptosis plays a major role in normal lymphocyte regulation. CD95 mutations cause a benign autoimmune lymphoproliferation syndrome (ALPS) in mice and humans. CD95 is mutated in some de novo T-lineage acute lymphoblastic leukemia of childhood and these mutations might be of biological significance. The resistance toward CD95-mediated apoptosis observed in most B-lineage ALL is not caused by mutations of CD95. CD95 mutations have been associated with Hodgkin's and Non-Hodgkin's lymphoma and have been described in multiple myeloma. The relevance of CD95 mutations for chemoresistance of ALL requires further study.

Animals↗
PubMedDate not supplied

Autocrine growth factors secreted by the malignant human B-cell-line BJAB are distinct from other known cytokines.

BJAB, a EBV-negative Burkitt-like lymphoma, did not grow under suboptimal culture conditions in low concentrations of serum unless appropriate cytokines were added. A subclone of BJAB, Clone 13, however, could be kept in long-term culture under such conditions without added cytokines. This suggested that growth of BJAB-Clone 13 was supported by autocrine growth factors (AGF). In fact, the supernatant of Clone 13 stimulated growth of the parental BJAB line and showed IL-1-like activity. Of several cytokines tested only AGF and IL-1 stimulated growth of BJAB. IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, GM-CSF, TNF-alpha, LT, IFN-gamma and TGF beta did not have this effect. The IL-1-like activity was completely neutralized by anti-IL-1 alpha antibodies. In contrast, AGF-activity was not affected by anti-IL-1 alpha. Rabbit antibodies produced against fractions enriched for AGF inhibited growth of BJAB. This inhibition was overcome by Clone 13-AGF, but not by IL-1 alpha. These data suggest that Clone 13-AGF is distinct from IL-1 alpha and might be a new cytokine.

Antibodies↗