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M Prete

Publications and source records attributed to M Prete.

11 recordsLinked to original sources

Biological therapy with monoclonal antibodies: a novel treatment approach to autoimmune disease.

Most autoimmune diseases (ADs) are still associated with high morbidity and mortality despite the use of a wide range of drugs that can delay their progression, control their symptoms, but never bring about a complete cure. This failure has aroused interest in new forms of monoclonal antibody-based experimental immunotherapy (IT), aiming at targeting cellular antigens or cytokines involved in the pathogenesis of ADs. The first part of this review offers a general overview of the molecular mechanisms that mediate the immune response and the molecule regarded as potential IT targets. A critical evaluation will then be made of some forms of IT, with particular emphasis on TNF-alpha and CD20-blocking reagents. Lastly an account will be given of active IT whereby an endogenous response against antigens regarded as the target of passive IT can be induced by anti-idiotype or peptides.

Antibodies, Monoclonal↗

Beta-2 microglobulin-free HLA class I heavy chain (FHC) A3 and/or A30 soluble products contribute only minimally to serum FHC expression.

No monoclonal antibodies (mAbs) are presently available to measure the total amount of beta2-microglobulin-free HLA class I heavy chain (FHC) in sera. The available ELISA-based double determinant immunoassay (DDIA), established to measure FHC, uses two mAbs (TP25.99 and HC-10) that recognize a monomorphic determinant expressed on all HLA-B/C FHC products and a determinant expressed only on some HLA-A FHC products. This restricted reactivity implies that, in addition to HLA-B/C, HLA-A FHC products are also detected in individuals bearing HLA A3 and/or A30 allotypes. The aim of this study was to establish whether such restriction results in the detection of low FHC levels in individuals lacking HLA A3 and/or A30 allospecificities. The FHC mean concentration (+/- SD) in 294 healthy blood/bone marrow donors (HBDs) was 0.24 (+/- 0.2) mg/l. The grouping of HBDs according to their HLA-A FHC product reactivity with one, both or no mAbs did not result in any statistically significant differences (Mann-Whitney test: P > 0.05) between their median FHC concentrations. Since the absence of differences in their FHC levels was not attributable to a difference in the percentage distribution of HLA allotypes associated with high or low HLA-B/C FHC expression, our results indicate that FHC HLA A3 and/or A30 products detected in DDIA by these two mAbs only minimally contribute to FHC serum expression and that the assay is not limited by the failure to detect HLA-A FHC products in A3- and/or A30- individuals.

Enzyme-Linked Immunosorbent Assay↗

Human CD4 internal antigen anti-idiotypic monoclonal antibody. immunochemical and sequence analysis.

The mouse mAb2 16D7 recognizes the paratope of the syngeneic anti-human CD4 mAb HP2/6 (mAb1 of our idiotypic cascade) and mimics CD4 in xenogeneic settings in humans. Immunochemical and sequence analyses were performed to define the minimum structural requirement for this mimicry. Binding assay of mAb1 with isolated naive 16D7 H and L chains showed that only the second reacted with mAb1. Specificity was indicated by the lack of reactivity of mAb1 with the L chain of mAb2 14D6, which also recognizes mAb1-paratope. It is likely that the 16D7-L mAb1-specific epitope is "sequence-dependent", since fully denatured 16D7-L still reacted with mAb1. Sequence analysis of 16D7 and mAb1 showed a high degree of homology of their VH. as both were coded by the same gene family (V/II), whereas CDR3 showed the greatest diversity. Alignment of 16D7-H CDR3 with CD4, however, produced no similarity. In contrast, analyses of the 16D7 VL sequence (XX/V) defined a CDR3 6-mer peptide with a 50% identity (83% of similarity) to the CD4 stretch 218-223. This peptide seems a suitable replacement for 16D7 in active immunotherapy as it did not match any protein fragment retrieved from the n-r database (NCBI) and both the peptide and the corresponding CD4 amino acid stretch are surface accessible. Based on their immunochemical profiles and similarity to CD4, four additional 16D7-derived peptides were designed for synthesis. The data indicate that CD4 mimicry by mAb2 can be obtained at the level of primary structure and provide useful information for the synthesis of peptide(s) with bioactive potential.

Amino Acid Sequence↗

Implementing emergency department observation units within a multihospital network.

BACKGROUND: The proportion of emergency department (ED) chest pain patients who undergo an extended "rule out MI (myocardial infarction)" evaluation beyond the ED determines both the quality and cost of patient care. The higher an organization's rate of such evaluations, the lower the average miss rate for MI. Five of the 13 hospitals in the Voluntary Hospital Association Northeast multihospital network implemented ED observation units by June 1997 for outpatient rule out MI evaluations. RESULTS: Compared with historical and case controls, the five hospitals with ED observation units had a higher observation rate (16% versus 0% [p < .001] and 2% [p < .001]) and a higher rule out MI evaluation rate (61% versus 46% [p < .01] and 45% [p < .01]), without a significantly higher admission rate (47% versus 46% and 45%). For the three hospitals with observation units that collected charge data during 1997 on a consecutive series of chest pain patients who had negative rule out MI evaluations, charges for patient services were lower for patients evaluated in the ED observation unit ($2,214.80 +/- $80.40) than in the hospital ($5,464.30 +/- $393.60). CONCLUSIONS: ED observation units represent a cost-effective restructuring of the diagnostic approach to patients with acute chest pain. In an improvement of quality of patient care, a larger proportion of ED chest pain patients receive an extended evaluation than is possible with hospital admission as the only ED disposition option.

Chest Pain↗

False-negative and false-positive errors in abdominal pain evaluation: failure to diagnose acute appendicitis and unnecessary surgery.

OBJECTIVES: To test the hypothesis that physician errors (failure to diagnose appendicitis at initial evaluation) correlate with adverse outcome. The authors also postulated that physician errors would correlate with delays in surgery, delays in surgery would correlate with adverse outcomes, and physician errors would occur on patients with atypical presentations. METHODS: This was a retrospective two-arm observational cohort study at 12 acute care hospitals: 1) consecutive patients who had an appendectomy for appendicitis and 2) consecutive emergency department abdominal pain patients. Outcome measures were adverse events (perforation, abscess) and physician diagnostic performance (false-positive decisions, false-negative decisions). RESULTS: The appendectomy arm of the study included 1, 026 patients with 110 (10.5%) false-positive decisions (range by hospital 4.7% to 19.5%). Of the 916 patients with appendicitis, 170 (18.6%) false-negative decisions were made (range by hospital 10.6% to 27.8%). Patients who had false-negative decisions had increased risks of perforation (r = 0.59, p = 0.058) and of abscess formation (r = 0.81, p = 0.002). For admitted patients, when the inhospital delay before surgery was >20 hours, the risk of perforation was increased [2.9 odds ratio (OR) 95% CI = 1.8 to 4.8]. The amount of delay from initial physician evaluation until surgery varied with physician diagnostic performance: 7.0 hours (95% CI = 6.7 to 7.4) if the initial physician made the diagnosis, 72.4 hours (95% CI = 51.2 to 93.7) if the initial office physician missed the diagnosis, and 63.1 hours (95% CI = 47.9 to 78.4) if the initial emergency physician missed the diagnosis. Patients whose diagnosis was initially missed by the physician had fewer signs and symptoms of appendicitis than patients whose diagnosis was made initially [appendicitis score 2.0 (95% CI = 1.6 to 2.3) vs 6.5 (95% CI = 6.4 to 6.7)]. Older patients (>41 years old) had more false-negative decisions and a higher risk of perforation or abscess (3.5 OR 95% CI = 2.4 to 5.1). False-positive decisions were made for patients who had signs and symptoms similar to those of appendicitis patients [appendicitis score 5.7 (95% CI = 5.2 to 6.1) vs 6.5 (95% CI = 6.4 to 6.7)]. Female patients had an increased risk of false-positive surgery (2.3 OR 95% CI = 1.5 to 3.4). The abdominal pain arm of the study included 1,118 consecutive patients submitted by eight hospitals, with 44 patients having appendicitis. Hospitals with observation units compared with hospitals without observation units had a higher "rule out appendicitis" evaluation rate [33.7% (95% CI = 27 to 38) vs 24.7% (95% CI = 23 to 27)] and a similar hospital admission rate (27.6% vs 24.7%, p = NS). There was a lower miss-diagnosis rate (15.1% vs 19.4%, p = NS power 0.02), lower perforation rate (19.0% vs 20.6%, p = NS power 0.05), and lower abscess rate (5.6% vs 6.9%, p = NS power 0.06), but these did not reach statistical significance. CONCLUSIONS: Errors in physician diagnostic decisions correlated with patient clinical findings, i.e., the missed diagnoses were on appendicitis patients with few clinical findings and unnecessary surgeries were on non-appendicitis patients with clinical findings similar to those of patients with appendicitis. Adverse events (perforation, abscess formation) correlated with physician false-negative decisions.

Abdominal Pain↗

Serum levels of beta-2-microglobulin-free heavy chain of HLA class I antigen in healthy individuals: relationship to their class I allotype.

An ELISA-based double determinant immunoassay has been established to measure the soluble beta2-microglobulin (beta2m)-free heavy chain (FHC) of the HLA-B, -C (and HLA-A3, -A28 and -A30) class I molecular complex in sera from 212 HLA-typed healthy unrelated individuals. FHC was calculated by means of a standard curve constructed using serial concentrations of beta2m-associated HLA-class I heavy chain (HLA-I)/FHC purified from cultured human lymphoid cell C1R-sB7-supernatant. The mean FHC concentration (+/-SD) was 0.25 mg/l (+/-0.2). Its median concentration did not statistically differ between males and females, though the male/female ratio was greater in the high secretor (FHC >0.45 mg/l; mean + 1SD) than in the low secretor group (FHC < 0.05 mg/l; mean - 1SD). FHC < 0.05 mg/l was statistically (Fisher's exact test) associated with HLA-B17 (p = 0.003); FHC > 0.45 mg/l was statistically associated with HLA-B35 (p = 0.003) and -Cw4 (p = 0.002). None of these allele-positive groups showed a mean FHC concentration 1.5 times higher than that of the corresponding allele-negative ones. This allotype-dependent HLA-B and C FHC enhancement was less marked than that previously reported for HLA-I in individuals carrying HLA-A9 (and its splits). These results indicate that FHC could be a more valuable marker when its levels are compared among individuals carrying different allotypes. Moreover the lack of correlation between FHC and HLA-I levels measured in 52 HLA-A3, -A28 or -A30 positive individuals suggests that the two molecules may be regulated by different metabolic pathways and their serum expression may have a different biological significance.

Alleles↗

Increased serum levels of beta2m-free HLA class I heavy chain in multiple myeloma.

Serum levels of beta2-microglobulin (beta2m)-free HLA class I heavy chain (FHC) in 94 patients with multiple myeloma (MM) were higher than in 29 patients with monoclonal gammopathy of undetermined significance (MGUS) (P = 0.023) and in 97 sex- and age-matched healthy controls (P < 0.0001). Spearman correlation analysis indicated that in MM, FHC correlated with beta2m (r = 0.31, P = 0. 003) and the percentage of bone marrow plasma cells (BMPC%) (r = 0. 36, P = 0.002), whereas beta2m, in addition to BMPC% (r = 0.43, P = 0.0003), also correlated with creatinine levels (r = 0.63, P < 0.0001), haemoglobin levels (r = -0.35, P = 0.0007) and patient age (r = 0.34, P < 0.0011). Furthermore, MM patients with poor prognosis (beta2m >/= 6 mg/l) displayed higher FHC levels than those with a better prognosis (beta2m < 6mg/l) (P < 0.021). At variance from beta2m, these levels were not influenced by renal failure, as indicated by the lack of Spearman correlation of FHC with creatinine concentration and of statistical significance between the median FHC concentration of MM patients with creatinine < 176.6 micromol/l and those with creatinine >/= 176.6 micromol/l (P = 0.3). Stratification of patients according to disease activity and stage showed that FHC levels were only statistically different (P = 0.04) for disease activity, whereas beta2m and C-reactive protein were not. Taken together, our data indicate that serum FHC may be a useful disease marker in MM.

Aged↗

Does activity of pulmonary sarcoidosis depend on disease duration? A correlation between bronchoalveolar lavage, scintigraphic, radiologic, and physiologic parameters and time of onset of the disease.

In pulmonary sarcoidosis the alveolitis is thought to precede and modulate granuloma formation and fibrosis. Thus, patients with early disease may have a more active pulmonary process, while patients with long standing sarcoidosis are thought to have fibrotic, stabilized lesions. The aim of the present study is to correlate radiographic stage, alveolitis activity, and respiratory function changes with the length of the disease. For this purpose 116 patients with biopsy-proven untreated pulmonary sarcoidosis have been divided in three groups according to time of onset of the illness: group A (48 patients with sarcoidosis duration less than or equal to 3 months), group B (25 patients with sarcoidosis duration greater than 3 less than or equal to 6 months), and group C (43 patients with sarcoidosis duration greater than 6 months less than or equal to 3 years). We found a progression with time from roentgenographic stage I to III, but no correlation was present between the disease duration and T lymphocytes of BAL, results of gallium lung scans, and respiratory function values. Our results suggest that the activity of alveolitis and the derangement of respiratory function in pulmonary sarcoidosis are unrelated to the time of onset of the disease.

Adolescent↗

Monoclonal antibodies in the immunotherapy of autoimmune diseases.

The present report critically reviews the rationale, clinical effectiveness and limits of monoclonal antibody-based immunotherapy in the treatment of autoimmune diseases, with particular emphasis on tumor necrosis factor-alpha blocking reagents. Reference will also be made to active immunotherapy whereby an endogenous response induced by anti-idiotypic monoclonal antibodies or peptides toward molecules regarded as passive immunotherapy targets, is expected to mediate the therapeutic effects.

Antibodies, Monoclonal↗