Biomedical subjects
Publications and source records attributed to M Sela.
Treatment of intraoral squamous cell carcinomas is guided by the clinical stage of the disease and includes surgical resection. The resulting defect may be closed surgically or prosthodontically. This article describes a technique for provisional closure of a surgical defect. The interim obturator permits normal oral functioning until permanent rehabilitation is performed.
Choanal atresia, a congenital narrowing or obstruction of the nasal airway caused by significant respiratory distress in neonates, may require emergency intervention. Although atresia can be repaired surgically, restenosis is a common complication with this procedure. To prevent this, tubes are inserted into the nasal cavity immediately after surgery. This article describes a technique for preparing individual surgical splints designed to prevent postsurgical obstruction of the nasal cavity.
Glatiramer acetate (GA) previously known as Copolymer 1 (Cop 1), a synthetic amino acid copolymer, suppresses experimental autoimmune encephalomyelitis (EAE) and shows a beneficial effect in relapsing-remitting type of multiple sclerosis (MS). GA acts as a specific immunomodulator by binding to MHC Class II molecules, inducing specific T suppressor (Ts) cells and interfering with T cell responses to myelin antigens. MS patients treated with GA developed GA reactive antibodies, which peaked at three months and decreased at six months. In order to find out whether anti-GA antibodies may neutralize the therapeutic effect of GA, we tested both polyclonal (mouse and human) and monoclonal GA specific antibodies for their ability to interfere with the biological activity of GA in several assay systems. None of the antibodies interfered with GA activities either in vitro (binding to MHC molecules and T cell stimulation) or in vivo (blocking of EAE). Furthermore, 53 samples of sera obtained from 34 MS patients that participated in the open label trial in Israel, and all developed GA specific antibodies, were tested for their ability to inhibit the proliferation response of GA specific Ts cell clone and to interfere with GA competitive inhibition of the response to peptide 84-102 of myelin basic protein (MBP). None of the sera inhibited and some even enhanced the in vitro activities of GA. Furthermore, representative MS sera with high titer of GA reactive antibodies did not neutralize the biological activities of GA and did not inhibit Th2 cytokine secretion by human GA specific clone. These results are consistent with the findings that the therapeutic effect of GA is not affected by GA reactive antibodies and is sustained upon long term treatment.
On the basis of this preliminary report series of patients, it seems that the achievement of fixed anchorage for nail prostheses is feasible using the process of osseointegration, the use of standard dental implants, and abutment and maxillofacial rehabilitation laboratory to build the superstructure system. The osseointegrated procedure is relatively simple, cost-effective, and less time-consuming compared with other reconstruction techniques. Using local anesthesia and day-care facilities the operative time was only 35 minutes for the first stage and 15 minutes for the second stage. The attachment should be lifelong, as in the face. Loosening and infection are infrequent.
Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T-cell regulated, antibody-mediated diseases. Peptides p195-212 and p259-271 of the human acetylcholine receptor (AChR) alpha-subunit, were previously shown to be immunodominant T cell epitopes in MG patients as well as in SJL and BALB/c mice, respectively. A dual altered peptide ligand (APL) composed of the two single amino acid analogs of the myasthenogenic peptides was shown to inhibit, in vitro and in vivo, MG-associated autoimmune responses. Furthermore, the dual APL was shown to down-regulate the clinical manifestations of an established EAMG in C57BL/6 mice injected with Torpedo AChR (TAChR). In the present study we attempted the elucidation of the mechanism(s) by which the dual APL down-regulates EAMG-associated responses. It is shown here that the dual APL acts by actively suppressing, in a specific manner, myasthenogenic T cell responses. The active suppression is mediated, at least partially, by the up-regulation of the secretion of TGF-beta following administration of the dual APL. The up-regulated secretion of TGF-beta is accompanied by down-regulation of IFN-gamma and IL-2 [T helper (Th) 1-type cytokine] secretion and by an up-regulation of IL-10 secretion (Th2-type cytokine). Furthermore, the inhibitory effect of the dual APL could be adoptively transferred to p195-212 or TAChR-immunized mice. The down-regulation of IL-2 secretion and the ability of recombinant IL-2 to rescue lymph node cells of mice treated with the dual APL from a state of unresponsiveness suggests that the dual APL acts also, at least partially, by causing the cells to undergo anergy.
BACKGROUND: Copolymer 1 (Cop 1) was previously shown to prevent graft-versus-host disease and interfere in various manifestations of immune rejection. In this study, we tested whether Cop 1 can also hinder the reactivity of host against graft and inhibit graft rejection. METHODS: Cop 1 was tested in two transplantation systems: skin and thyroid grafting assays. The effect of Cop 1 on T cell reactivity was investigated by proliferation and cytokine secretion of spleen and lymph node cells from transplanted mice, as well as the T cell lines generated therefrom. RESULTS: Cop 1 treatment prolonged skin graft survival and inhibited the functional deterioration of thyroid grafts, in various strain combinations, across minor and major histocompatibility barriers, similarly to the potent immunosuppressive drug FK506. Cop 1 inhibited the proliferation of graft-specific T cell lines, as well as their interleukin (IL)-2 and interferon-gamma (IFN-gamma) secretion, when incubated in vitro with the stimulating allogeneic cells. Spleen and lymph node cells from Cop 1-treated mice, as well as the T cell lines generated from them, demonstrated a pronounced inhibition of proliferation and secretion of T helper (Th)1 cytokines in response to graft cells. In addition, cells from Cop 1-treated mice secreted high amounts of Th2 cytokines in response to Cop 1 and small but significant amounts of Th2 cytokines, mainly IL-10, in response to allograft cells. CONCLUSIONS: Cop 1 treatment inhibited the Th1 response to graft and induced a Th2 cytokines secretion in response to both Cop 1 and graft cells, leading to improved survival and function of the transplanted grafts.
Humoral and cellular immune responses were followed in multiple sclerosis patients treated with Copolymer 1 (Cop1, glatiramer acetate, Copaxone) who participated in three different clinical trials. All patients (130) developed Cop1 reactive antibodies, which peaked at 3 months after initiation of treatment, decreasing at 6 months and remaining low. IgG1 antibody levels were 2-3-fold higher than those of IgG2. The proliferative response of Peripheral Blood Mononuclear Cells (PBMC) to Cop1 was initially high and gradually decreased during treatment. Antibodies and T cell responses to MBP were low and did not change significantly during the treatment. The humoral and cellular immunological responses to Cop1 do not correlate with the side effects and do not affect its therapeutic activity. The preferential production of IgG1 over IgG2 antibodies may indicate that Th2 responses are involved in mediating the clinical effect of Cop1.
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Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoimmune disease. Immunization with two myasthenogenic peptides, p195-212 and p259-271, which are sequences of the human acetylcholine receptor, resulted in MG-associated immune responses. A dual altered peptide ligand (APL) composed of the two APLs of the myasthenogenic peptides inhibited, in vitro and in vivo, those responses. This study was aimed at understanding the mechanism(s) underlying the in vivo inhibitory properties of the dual APL. To this end, we analyzed T cells of mice that were immunized with p259-271 for their adhesiveness toward vascular cell adhesion molecule 1, for the activity of their secreted matrix metalloproteinases (MMPs), and for their intracellular phospholipase C (PLC) activity. Immunization with p259-271 triggered the above three activities and in vivo administration of the dual APL inhibited the latter. Thus, treatment of mice with the dual APL interferes with functions required for T cells to migrate and interact with the self-AChR. This is the first indication that very late antigen 4, MMP-9, and PLC are targets for immunomodulation of autoreactive T cells by altered peptide ligands.
This review article summarises the initial preclinical studies as well as the different stages of clinical trials in multiple sclerosis (MS) with Copolymer 1 (Cop 1), recently denoted glatiramer acetate. Experimental studies on autoimmune encephalomyelitis (EAE), the animal model of MS, as well as studies on the mechanism of action in both animals and humans are discussed. The review describes the early clinical trials which were followed by Phase II and III trials, culminating in FDA approval in 1996 for the treatment of relapsing-remitting MS. The accumulated experience with glatiramer acetate indicates that its efficacy is apparently increased as a function of usage time while the favourable side effect profile is sustained. MRI studies revealed that treatment with glatiramer acetate resulted in a significant reduction of gadolinium (Gd)-enhancing lesions. Ongoing clinical trials which might extend its usage or change its mode of delivery are also described. Glatiramer acetate appears to be a treatment of choice for the relapsing-remitting type of MS.
Hypernephroma is one of the most common tumours to spread by extranodal metastases to the head and neck. We herein report on six patients with unusual metastatic hypernephroma to the head and neck area. In two of the six cases, the metastatic tumour in the head and neck was the presenting symptom, and the renal tumour was secondarily detected. Metastatic hypernephroma to the head and neck area has been demonstrated mostly in the paranasal sinuses, parotid gland, and the mandible. Among the six cases presented, four belong to the above-mentioned group, but the other two are rather rare cases, one metastatic to the nasopharynx and soft palate and the other to both lobes of the thyroid gland. Hypernephroma should be sought and excluded whenever a metastatic lesion is encountered in the head and neck area, even if the metastatic lesion is the first clinical presentation. The diagnosis of metastatic hypernephroma should be suspected in any patient with even a remote history of renal cell carcinoma.
Polyacetal resin (Delrin) is well known material in many medical fields as for artificial heart valves and artificial hip joints. In dentistry the material is known as Dental D, and among its other applications, is used for removable partial dentures. The article presents a cleft lip and palate patient with missing teeth (12 and 22). The patient underwent on operations for closure of the cleft, but even so some sinus tracts from the nasal cavity to the soft and hard palate exist. The patient was rehabilitated 10 years ago with chrome-cobalt removable partial denture, but lately, episodes of swelling and burning sensation were reported. The patient was diagnosed (by the allergy clinic in Hadassah hospital) as allergic to chrome-cobalt. Some optional treatment plans were offered to the patient (fixed, which involved an operation of closing the fistulas, and then a fixed restoration, another option was removable denture with Dental D). The patient chose to be rehabilitated with Dental D removable partial denture, which closes the fistulas and reconstructs the missing teeth. Due to the physical properties of the Dental D, its biocompatibility and the improved esthetics results, the Dental D can be a good alternative for the chrome-cobalt removable partial denture. The esthetic results with the Dental D, as far better than the conventional partial denture.
Overexpression of ErbB-2, a coreceptor for stroma-derived growth factors, is involved in malignancies of epithelial tissues, and a humanized antibody to ErbB-2 was shown to be therapeutic in a clinical setting. In an effort to understand and enhance immunotherapy, the laboratory has raised several tumor inhibitory monoclonal antibodies (mAb), including mAb L26 that blocks inter-receptor interactions. Here the application of the phage display methodology for the isolation of a phage clone that specifically recognizes mAb L26 is described. The isolated mimetic peptide (mimotope) specifically inhibited the binding of mAb L26 to ErbB-2 overexpressing cells. No sequence homology was found between the mimotope and ErbB-2. implying that it mimics a conformational structure of the receptor. Preliminary studies showed that the lead peptide can be truncated by removal of two to three amino acids from either the N- or C-terminal end without drastically affecting the inhibitory properties of the mimotope. A tryptophan'glycine residue at the C-terminus and a lysine at the N-terminus of the peptide seemed to play a role in its ability to compete with L26 antibody for binding to ErbB-2 overexpressing cells. These results highlight the potential of active immunization with conformation mimicking peptides in ErbB-2 overexpressing tumors.
A rodent oncogenic mutant of the Neu receptor tyrosine kinase is a useful experimental model because overexpression of the respective receptor, namely HER2/ErbB-2, in human malignancies is associated with relatively aggressive diseases. Here we show that the oncogenic form of Neu is constitutively associated with the product of the c-cbl proto-oncogene and is part of a large complex that includes the phosphoinositide 3-kinase and Shc. Ectopic expression of c-Cbl, a ubiquitin-protein isopeptide ligase specific to activated tyrosine kinases, causes rapid removal of Neu from the cell surface and severely reduces signaling downstream of oncogenic Neu. c-Cbl-induced down-regulation of Neu involves covalent attachment of ubiquitin molecules and requires the carboxyl-terminal domain of Neu. The negative effect of c-Cbl is antagonized by v-Cbl, a virus-encoded oncogenic truncated form of c-Cbl. In an in vivo model, infection of a Neu-transformed neuroblastoma with a c-Cbl-encoding retrovirus caused enhanced down-regulation of Neu and correlated with tumor retardation. Our results implicate c-Cbl in negative regulation of Neu and offer a potential target for treatment of HER2/ErbB-2-positive human malignancies.
This study addresses the issue of the effect of immunomodulating therapies in the target organ-the central nervous system (CNS)-in the case of multiple sclerosis. Copolymer 1 (Cop 1, Copaxone, glatiramer acetate), an approved drug for the treatment of multiple sclerosis, is a potent inducer of Th2 regulatory cells in both mice and humans. Highly reactive Cop 1-specific T cell lines that secrete IL-4, IL-5, IL-6, IL-10, and transforming growth factor-beta in response to Cop 1 and crossreact with myelin basic protein (MBP) at the level of Th2 cytokine secretion were established from both brains and spinal cords of Cop 1-treated mice. In contrast, no reactivity to the control antigen lysozyme could be obtained in lymphocytes isolated from CNS of mice injected with lysozyme. Adoptively transferred labeled Cop 1-specific suppressor cells were found in brain sections 7 and 10 days after their injection to the periphery, whereas lysozyme-specific cells were absent in the CNS. Hence, Cop 1-induced Th2 cells cross the blood-brain barrier and accumulate in the CNS, where they can be stimulated in situ by MBP and thereby exert therapeutic effects in the diseased organ. This therapeutic effect was manifested, in brains of experimental autoimmune encephalomyelitis-induced mice, by a decrease in the inflammatory cytokine interferon-gamma and by secretion of the anti-inflammatory cytokine IL-10 in response to the autoantigen MBP.
Overexpression of HER-2/ErbB-2, a homologue of the epidermal growth factor receptor, is associated with poor prognosis, and an ErbB-2-specific antibody is therapeutic when administered to patients with metastatic breast cancer. To understand the mechanism underlying immunotherapy, we concentrated on antibody- and epidermal growth factor-induced degradation of ErbB-2. We show that enhanced degradation is preceded by poly-ubiquitination of ErbB-2. This process necessitates recruitment of the c-Cbl ubiquitin ligase to tyrosine 1112 of ErbB-2. Consequently, mutagenesis of this site retards antibody-induced degradation. Thus, the therapeutic potential of certain antibodies may be due to their ability to direct ErbB-2 to a c-Cbl-regulated proteolytic pathway.
We recently reported that the posttraumatic spread of degeneration in the damaged optic nerve can be attenuated by the adoptive transfer of autoimmune T cells specific to myelin basic protein. However, it would be desirable to obtain immune neuroprotection free of any possible autoimmune disease. In an attempt to obtain disease-free immune neuroprotection, we used the synthetic four-amino acid polymer copolymer 1 (Cop-1), which is known not to be encephalitogenic despite its cross-reactivity with myelin basic protein. We show here that active immunization with Cop-1 administered in adjuvant, as well as adoptive transfer of T cells reactive to Cop-1, can inhibit the progression of secondary degeneration after crush injury of the rat optic nerve. These results have implications for the treatment of optic neuropathies.