Use of monoclonal antibodies in vivo as a therapeutic strategy for alloimmune or autoimmune reactivity: the Besançon experience.
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Biomedical subjects
Publications and source records attributed to D Wendling.
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The level of soluble interleukin-2 receptors (SIL2-R), which reflects lymphocyte activation, is often described as a useful parameter for evaluating disease activity and progression in patients with inflammatory conditions. Serum SIL2-R was assayed using a sandwich ELISA method in 98 subjects including 38 controls (C), 36 patients with ankylosing spondylarthropathy (AS) and 24 patients with rheumatoid arthritis (RA). SIL2-R levels were higher in RA patients than in controls and AS patients (p < 10(-4)), whereas the difference between AS patients and controls was small (p = 0.02). In RA patients, SIL2-R levels were not correlated with any of the clinical or biological parameters studied and remained unchanged during clinical improvements. In the AS group, SIL2-R levels showed no correlations with inflammation parameters (CRP, IgA) and was similar in patients with and without HLA B27 or appendicular joint involvement. This study failed to provide any evidence that SIL2-R levels are helpful for monitoring patients with inflammatory joint disease.
The authors present a case of intramedullary neurinoma. A 44 years old patient was admitted for lumbar pain and bilateral sciatica. Neurological examination was normal except for dysuria and diminution of Achilles tendon reflexes. Lumbar spine X-rays and spinal cord angiogram were normal, but myelogram and myelo-scan revealed a fusiform enlargement of the conus medullaris. MRI confirmed this aspect. Total removal of an intramedullary tumor was done, using ultrasonography, operating microscope and ultrasonic aspiration. The post-operative course was uneventful, with, as sequelae a perineal hypoesthesia. Histological examination of the excised tumor revealed a neurinoma. The epidemiology, clinical features, radiology, and surgical treatment of such rare intramedullary tumors are discussed.
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The authors report 20 cases of primary oxalosis with bone involvement, late revealed in adults in 19 cases. They have studied the clinical, radiological and histological manifestations of this bone oxalosis. 19 cases had an end stage chronic renal failure, either treated by maintenance hemodialysis, or by renal (or liver-renal) graft. 17 patients complained of bone pain after starting hemodialysis; 3 had vertebral crush fractures, and 1 multiple spontaneous fractures. Diffuse bone sclerosis (with a homogeneous pattern on axial skeleton and a patchy appearance on the peripherical skeleton), bone translucency, subperiosteal phalangeal resorption were the main radiological symptoms. Oxalate crystals surrounded by a giant cells granuloma were always observed on bone biopsy (16 cases). Bone resorption was observed in 9 cases, hyperparathyroidism in 14 cases and osteomalacia in 7 cases. Hyperparathyroidism does'nt explain all the clinical and radiological manifestations (especially bone resorption). Bone resorption as other radiological and clinical manifestations can be found without hyperparathyroidism and can increase despite parathyroidectomy; so, bone resorption seems to be partly due to the granulomatous reaction around oxalate crystals rather than hyperparathyroidism.
The phagocyte oxydative metabolism function was measured using chemiluminescence in microamounts of whole blood in 15 ankylosing spondylitis (AS) patients (10 were B27 positive), and in 17 controls. It was obtained from cells at rest, and following stimulation (latex, zymosan, fMLP), with luminol and lucigenin as amplifiers. The maximal light intensity was significantly higher (P less than 0.01) in AS compared to the controls in resting cells as well as in those after stimulation. There was no difference between HLA-B27 positive or negative AS patients. The increase in oxidative metabolism of the phagocyte system in AS was more evident in the luminol dependent assay, suggesting an activation of the myeloperoxydase system.
A 57 year old woman presented with clinical and biological features of adult onset Still's disease. A kidney biopsy was performed at the onset of the condition and was found to be normal. Four years later, in view of a nephrotic syndrome, histopathological examination of a new kidney biopsy specimen was made and showed typical amyloid deposition. Renal amyloidosis was suspected in five previously reported cases but demonstrated by kidney biopsy in only two of them. In the present case renal amyloidosis was recorded after disease of four years' duration. The normality of the first renal biopsy specimen suggests the possibility of a direct relation between amyloidosis and adult onset Still's disease.
Ten patients with severe rheumatoid arthritis were treated with a murine monoclonal anti-CD4 (B-F5) antibody in an open study (one with 10 mg/day, 2 with 15 mg/day, 7 with 20 mg/day) for 10 consecutive days. Tolerance was excellent. All patients improved during treatment clinically (Ritchie's index, morning stiffness, pain scale) (p = 0.005), as well as biologically C-reactive protein (p = 0.008) with an average 60% reduction of each of these variables at Day 15, and clinical benefit lasted over 6 months in some patients. No significative depletion was noted in total lymphocyte or CD3, CD4, CD8, CD20, positive cells after treatment. Evidence of murine immunization was found in only 2 patients.
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Ten patients (6 women and 4 men), with a group mean age of 65 years, defined as severe and with a mean follow-up period of 9 years and refractory to conventional treatments, were treated with monoclonal anti-CD4 antibodies in an open study. The monoclonal antibodies, of murine origin, were administered by intravenous route for ten consecutive days at a dose of 10 mg (1 patient), 15 mg (2 patients) or 20 mg (7 patients). Local and systemic tolerability were excellent. Clinical improvement was rapid (pain, morning stiffness, Ritchie index, p = 0.005 between D0 and D15), as was the paraclinical improvement (C-reacting protein, p = 0.008), although without achieving complete remission. The outcome revealed that the effect was more prolonged in patients treated with 20 mg per day than in the others, suggesting a dose-effect relationship. The improvement obtained may persist for more than 9 months in some patients. No significant change in immunological parameters was found at the end of the treatment (lymphocyte populations, immunoglobulins, complement). Only 2 out of 10 patients developed anti-mouse antibodies. As a result of its excellent tolerability and rapid effectiveness, this antibody appears to offer fresh therapeutic prospects in rheumatoid arthritis.
The tibial tuberosity may be affected by enthesitis in seronegative spondylarthropathies, especially in childhood. Three personal cases illustrate this possibility. Data from the literature seem to confirm that enthesitis is more common in juvenile forms (where it may occur as the first manifestation) than in adult forms. Enthesitis is manifested mainly by clinical symptoms. Roentgenographic changes are inconsistent and variable; ossification may develop. Osgood Schlatter disease is the main differential diagnosis. Persistent enthesitis of the tibial tuberosity in a young boy should suggest spondylarthropathy.
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Two patients with adult Still's disease and abnormal urinalysis underwent kidney biopsy 2 to 21 years after onset of the disease. Unexpectedly, mesangial glomerulonephritis was discovered. Even if a fortuitous association could not be excluded, the real prevalence of glomerular involvement in ASD should be determined by further studies in view of a potential immune complex pathogenesis of this condition.
Bronchoalveolar lavage and bronchial biopsies were performed in 15 patients with ankylosing spondylitis (AS) and 17 control subjects. There was no difference in total cell count, number of lymphocytes, CD4+/CD8+ ratio, or beta 2 microglobulin concentrations in bronchoalveolar lavage fluid between these two groups. Bronchoalveolar lavage IgA concentrations were not increased, but bronchial IgA deposits were more common in AS. This study failed to show any subclinical alveolitis in AS.
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