Biomedical subjects
Publications and source records attributed to H Deicher.
Study design and preliminary data of a prospective randomized trial with monthly administration of intravenous cyclophosphamide in so far 12 patients with systemic lupus erythematosus (SLE) and nephritis are presented.
Immunoglobulin heavy chains (G1m, G2m, G3m, A2m) and kappa light chain (Km) allotype and phenotype frequencies were examined in 323 central European Caucasian patients with systemic lupus erythematosus (SLE). No significant differences were found between the different allotype or phenotype frequencies of the SLE patients and a control group of healthy individuals. Our results indicate that Gm, A2m and Km allotypes do not represent susceptibility factors for SLE in Caucasians.
Quantitative analysis of nailfold capillary morphology was performed in age and sex matched groups of 29 patients with systemic lupus erythematosus (SLE) presenting Raynaud phenomenon (RP), 29 RP negative patients with SLE with the same duration of the disease, and 29 healthy controls. Percentages of tortuous, meandering and bushy capillaries were significantly increased in both groups of patients without influence of RP. Capillary density was lower, mean diameters of the capillary loops were higher in patients, especially when RP was present (at the venular branch in microns, mean +/- SD: controls: 15.0 +/- 2.0, RP negative patients with SLE: 17.6 +/- 3.6, RP positive patients with SLE: 20.5 +/- 6.3). In a subgroup of 13 patients with frequent Raynaud's attacks (more than 1/week), diameters were still higher (22.1 +/- 7.1, p to controls less than 0.0005; p to RP negative patients less than 0.05). In patients with SLE, the prevalence of RP seems not to be associated with the increased number of abnormal capillaries but with capillary enlargement, correlating with the frequency of attacks.
A group of proliferative diseases of the epidermal Langerhans' cells are commonly referred to as Langerhans' cell histiocytosis (LCH). A small number of the patients with this disease face an unfavorable disease course despite chemotherapy and radiation therapy. In LCH patients with a poor prognosis, allogeneic bone marrow transplantation (BMT) could be the appropriate treatment with proven antiproliferative effects and may be able to repopulate the recipient with stem cell-derived Langerhans' cells from the donor or correct the presumed underlying immunodeficiency. An LCH was diagnosed in a 15-year-old boy with multiple osteolytic lesions, anemia, and diabetes insipidus centralis. Repeated flare-ups of the disease had necessitated several courses of conventional chemotherapy including cyclophosphamide (CY), prednisolone (P), 6-mercaptopurine (6-MP), vincristine (VCR), and additional local irradiation without stable remission. Three years after first being diagnosed with LCH the patient underwent high-dose chemotherapy-radiation therapy followed by allogeneic BMT from his human lymphocyte antigen (HLA)-identical brother. Currently, he is alive and well and has been disease-free for more than 41 months after BMT.
The investigation of in vitro platelet functions from patients with SLE and rheumatoid arthritis (RA) revealed a distinctly reduced aggregation mass after both collagen und ADP induction. The platelet serotonin contents were significantly decreased in both groups. An "aspirin-like" platelet defect could be excluded by finding a normal malonyldialdehyde release of patients' platelets upon thrombin stimulation. Significantly increased platelet associated IgG was also detected, whereas platelet associated IgM remained within normal limits. These results are interpreted as indicating an ongoing platelet release reaction induced by IgG platelet antibodies, which induce the observed impairment of platelet functions and may also lead to the release of proinflammatory platelet mediators.
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The murine Mx-1 protein is one of the best biochemically and functionally characterized interferon (IFN)-induced proteins that is necessary, and sufficient, for providing resistance to murine cells against viral influenza infection. Recently an intracellular human protein homologous to the murine Mx-1 protein has been identified by means of a specific monoclonal antibody. The restricted induction of this intracellular protein in human mononuclear cells (MNC) by various cytokines was investigated. MNC from 26 of 28 healthy people and 35 of 36 cancer patients before IFN-alpha therapy had no detectable Mx-homologous protein. Incubation of human MNC with IFN-alpha and IFN-beta for 24 h at different concentrations led to a dose-dependent induction of the Mx-homologous protein. All IFN-alpha or IFN-beta preparations tested were equally effective in eliciting this intracellular protein. IFN-gamma induced only 1% of the Mx amount elicited by type-1 IFN compared on a weight basis. Neither interleukin (IL) 1 nor IL3, IL4, IL5, IL6, tumor necrosis factor-alpha/beta, granulocyte colony-stimulating factor (CSF) or granulocyte macrophage-CSF at any of the concentrations tested were capable of eliciting any detectable amount of the Mx homolog, while IL2 was a poor Mx-homologous protein inducer. In the presence of high-titered IFN-alpha antisera both IL2 and IFN-gamma were unable to stimulate this protein, proving that IFN-gamma and IL2 indirectly induce the Mx homolog via IFN-alpha. Therefore, the human Mx-homologous protein is a strictly by type I IFN-regulated protein in human peripheral blood lymphocytes.
Twenty-six people with symptomatic HIV-1 infection were screened for the presence of interferon (IFN) alpha and IFN alpha antibodies in their sera and the presence of the IFN-induced intracellular Mx-homologous protein in their peripheral blood leukocytes. Eleven people had measurable IFN alpha levels ranging from 1 to 40 IU/ml. None of the sera tested was positive for IFN alpha binding or IFN alpha neutralizing antibodies in the assays employed. Twenty-five of the 26 people had significant levels of the Mx-homologous protein in their peripheral mononuclear cells. The Mx concentrations varied from 0.3 to 6 U/ml in the people studied. IFN alpha-positive people had significantly higher levels of the Mx homolog than IFN alpha-negative people (P less than 0.03). Furthermore, the Mx homolog content in Walter-Reed class 2 people was significantly lower than in Walter-Reed class 5/6 people (P less than 0.01). Our results suggest that the IFN system is activated in more than 90% of the people with lymphadenopathy-associated syndrome, AIDS-related complex and AIDS. Since acid-labile IFN alpha can induce the Mx homolog in vitro endogenously produced IFN alpha seems likely to be responsible for the high Mx homolog levels detected.
The human interferon-induced intracellular protein homologous to the murine Mx-protein has recently been identified by means of a specific monoclonal antibody. Three of six melanoma cell lines elicited this intracellular human Mx-homolog upon incubation with IFN-alpha or IFN-gamma, yet all six melanoma cell lines tested were susceptible to the antiproliferative effect of IFN-alpha and IFN-gamma. Compared per antiviral unit, IFN-gamma had weaker Mx-inducing but stronger antiproliferative activity than IFN-alpha. These data suggest that the IFN-induced Mx-homologous protein is not involved in the antiproliferative action of IFN on malignant melanoma cell lines. Furthermore, 51 patients with advanced malignant melanoma were treated thrice weekly with 10 x 10(6) IU rIFN-alpha-2b and 6 x 10(6) nIFN-alpha, respectively. Nine of the 51 patients experienced systemic objective tumor responses (3 complete response, 6 partial response), but had Mx concentrations in their mononuclear cells equal to the Mx levels of non-responders during IFN-alpha therapy. Therefore, the level of Mx-homologous protein induced during IFN therapy is not a predictive marker for an antitumor response in malignant melanoma.
136 untreated multiple myeloma patients of stage II and III were collected in the study. 37/51 stage II patients had progressive disease and were treated with melphalan and prednisone (MP). 85 patients were of stage III and randomized into MP and vincristine, BCNU, adriamycin, melphalan and dexamethasone (VBAMDex) treatment groups. 55% of MP treated patients responded versus 75% of the VBAMDex group. Since the study has been activated only 16 months ago, no difference in survival could be observed.
277 untreated multiple myeloma patients of stage 1 (n = 33), II (n = 106) and III (n = 138) entered the study. Patients of stage II presenting a progressive tumor (n = 64) initially or during observation (n = 14) were treated with MivP (remissions: 61%). 138 patients of stage III were randomized to receive MivP or VBAMDex treatment. 51% of MivP treated patients responded versus 70% of the VBAMDex group. 71 responders of stage II and III with stable disease were randomized on Ifn-alpha maintenance versus no maintenance treatment. The relapse rate in both groups was 50% after 7 months. 75% survival was greater than 36 months in stage II and 11 months in stage III patients.
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We performed positron emission tomography (PET) using 18F-labeled 2-F-2-deoxyglucose in 13 patients with systemic lupus erythematosus (SLE). Ten of them had clinical signs of central nervous system involvement (NP-SLE). All patients with neurologic symptoms showed pathologic changes on PET, always in accordance with the clinical state. Three patients without neuropsychiatric manifestations had normal PETs. Computed tomography of the brain and magnetic resonance imaging proved to be less sensitive to both presence and localization of CNS lesions. We conclude that the combination of PET and MRI constitutes the most useful diagnostic procedure for NP-SLE.
Pulmonary infection with mycobacterium tuberculosis and clonal B-cell expansion is described in a 26-year-old woman with granulomatous disease of lung, liver, and bone marrow as well as a late onset common variable immunodeficiency syndrome (CVID).
The human Mx, an interferon (IFN)-alpha- and IFN-beta-induced 76-kd protein, is a homolog (Mx-homolog) to the murine Mx protein, which is necessary and sufficient to provide adequate resistance against influenza virus in murine cells and in mice. Leukocytes from 36 patients with tumors (chronic myelogenic leukemia, hairy cell leukemia, and malignant melanoma) were monitored for their Mx-homolog content before, during, and after rIFN-alpha-2b therapy. Before therapy, only one patient was slightly positive for Mx-homolog. All 36 patients showed a significant increase of Mx-homolog in their mononuclear cells within the first day of IFN therapy. During therapy, the Mx-homolog levels remained elevated. After cessation of treatment, the Mx-homolog content in the mononuclear cells decreased slowly; within 2 weeks, it was about 20-30% of its value during therapy. However, even after 3 weeks, the Mx-homolog was still detectable. The maximally induced Mx-homolog concentration showed a significant correlation to the IFN dose given in vivo. These data indicate that the Mx-homolog is an excellent marker for monitoring the activity of IFN during IFN therapy. In addition, the in vivo endogenous activation of the IFN system might be detectable by the determination of the Mx-homolog despite the lack of circulating IFN.
The Fc gamma RIII (CD16) Ag on human NK cells involved in antibody-dependent cellular cytotoxicity has been demonstrated to be an important activation structure. The present studies were carried out to further characterize the functional role of the CD16 Ag and the mechanisms whereby cytotoxicity is activated by using human NK clones. In phenotypic studies Fc gamma RIII was found to be expressed heterogeneously on various human cloned NK cells. Expression on CD3- and CD3+ clones varied with the donor and mAb used for detection. Functional data demonstrated that cytotoxicity against NK-resistant target cells can be induced in CD3-CD16+ NK clones and CD3+CD16+ clones with NK activity when various CD16 mAb were used. CD16 antibodies but not reactive isotype control antibodies induced cytotoxicity. In contrast to complete CD16 antibodies F(ab')2 fragments were not able to activate the cytotoxic mechanism. Both an antibody against FcR on the target cell (Fc gamma RII) and a CD11a antibody blocked induction of cytotoxicity. These results suggest that three steps are critical for activation of CD16+ cells via Fc gamma RIII: 1) specific binding of CD16 antibodies to Fc gamma RIII on effector cells irrespective of the epitope recognized; 2) cross-linking of effector cell CD16 Ag through binding of the Fc site of CD16 antibodies via corresponding FcR on the target cell membrane; and 3) interaction of CD11a/18 molecules with the target cell membrane.
In three female patients with metastasising malignant melanoma psoriasis exacerbated during the third week of treatment with recombinant interferon-alpha-2b, at a weekly dosage of three times 10 million IU. The psoriatic lesions vanished almost completely after discontinuing the drug and systemic administration of corticosteroids. It appears that induction of psoriasis exacerbation is yet another important side effect of interferon, at least at elevated doses, whereas low alpha-interferon dosage levels may improve psoriasis in nononcological patients.
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