Neutralizing antibodies explain the poor clinical response to Interferon beta in a small proportion of patients with Multiple Sclerosis: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Neutralizing antibodies (NAbs) against Interferon beta (IFNβ) are reported to be associated with poor clinical response to therapy in multiple sclerosis (MS) patients. We aimed to quantify the contribution of NAbs to the sub-optimal response of IFNβ treatment.</p> <p>Methods</p> <p>We studied the prevalence of NAbs in MS patients grouped according to their clinical response to IFNβ during the treatment period. Patients were classified as: group A, developing ≥ 1 relapse after the first 6 months of therapy; group B, exhibiting confirmed disability progression after the first 6 months of therapy, with or without superimposed relapses; group C, presenting a stable disease course during therapy. A cytopathic effect assay tested the presence of NAbs in a cohort of ambulatory MS patients treated with one of the available IFNβ formulations for at least one year. NAbs positivity was defined as NAbs titre ≥ 20 TRU.</p> <p>Results</p> <p>Seventeen patients (12.1%) were NAbs positive. NAbs positivity correlated with poorer clinical response (<it>p </it>< 0.04). As expected, the prevalence of NAbs was significantly lower in Group C (2.1%) than in Group A (17.0%) and Group B (17.0%). However, in the groups of patients with a poor clinical response (A, B), NAbs positivity was found only in a small proportion of patients.</p> <p>Conclusion</p> <p>The majority of patients with poor clinical response are NAbs negative suggesting that NAbs explains only partially the sub-optimal response to IFNβ.</p

Cellular issues relating to the resistance of HIV to antiretroviral agents

It has been proposed that the declining efficiency of antiretroviral agents in human immunodeficiency virus (HIV) infection may also depend on cellular factors at their site of action. Two in particular have been proposed: (i) the defective intracellular metabolism of NRTI in target cells and the altered uptake; and (ii) efflux of nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI) by cellular transporter molecules. Several studies have shown that: changes in the activities of various purine and pyrimidine biosynthetic enzymes may occur in lymphocytes of HIV-infected patients; HIV-infected patients on prolonged treatment with nucleoside analogues, e.g. zidovudine, show significantly decreased activity of thymidine kinase (TK) compared with untreated HIV-infected people; and NRTI and PI are substrates for the multidrug membrane transporters. With regard to the latter issue, it is known that the ATP-binding cassette transporter proteins such as the P-glycoprotein (MDR), and the newly discovered family of multidrug resistance-associated proteins (MRP1-6), promote the active extracellular efflux of a wide variety of therapeutics drugs and overexpression of some of them lowers intracellular concentration of PI. In the very near future such mechanisms, also called 'cellular drug resistance', might be taken into account, together with other immunological, virological and behavioural factors, to explain the 'drug failure' and/or the variability of response in HIV patients undergoing antiretroviral treatment

Fate of neutralizing and binding antibodies to IFN beta in MS patients treated with IFN beta for 6 years

An increasing number of evidence is showing that during prolonged treatment of relapsing-remitting multiple sclerosis (RRMS) with interferon (IFN) beta 1a or IFN beta 1b, the patients may develop serum anti-IFN antibody. It has been argued that some of the RRMS patients receiving IFN beta, who developed antibodies to IFN, lose them over time even though the treatment continues. To gain further insights into this issue, we performed a study to establish what happened to binding antibodies (BAB) and neutralizing antibodies (NAB) in 42 RRMS patients treated for 6 years with IFN beta 1a and/or IFN beta 1b. While the data of BAB analysis did not allow to reach definite conclusions, the results on NAB development confirm that the presence of this type of antibodies is transitory; in fact, most of the positive patients reverted to seronegative, although the IFN treatment is still ongoing; the only patients who were positive for NAB at 6 years of treatment are those whose serum contains high concentration of them. The paper also shows that patients lose antibodies to IFN independently on the type of IFN used for the treatment. In conclusion, the data indicate that the disappearance of the anti-IFN antibodies from the serum while the patients are still undergoing IFN treatment depends on the titer of antibodies but not on the type of IFN administered. (C) 2003 Elsevier Science B.V. All rights reserved

Multimodal MRI-based tissue classification in breast ductal carcinoma

In this paper we propose a pipeline to integrate breast diffusion and perfusion MRI for diagnosis, surgical planning and follow-up. Dynamic contrast enhanced (DCE) and diffusion weighted (DWI) MRI provide complementary information on the tissue structure and properties: while DCE-MRI allows the characterization of the lesion angiogenesis, DWI techniques can probe the apparent diffusion coefficient (ADC) and therefore assess the nature and cellularity of the lesions. Here we propose a two-step process for the integration of these modalities. First, dissimilarity-based clustering is performed on DCE-MRI to identify the different tumoral subregions. These are then mapped onto the DWI images following inter-modal registration. The probability density functions (PDFs) of the so-identified subregions in the ADC map are extracted and compared through non-parametric testing. Results show that subregions corresponding to different clusters hold statistically different PDFs, indicating a degree of consistency in the information obtained from the two modalities while providing a posterior validation of the registration method. This enables the efficient integration of the information brought by DCE and DWI, respectively, while taking advantage of their complementarity

Proteolytic balance in patients with multiple sclerosis during interferon treatment

Multiple sclerosis (MS) is a progressive, inflammatory, demyelinating disease. An altered cytokine network has been reported to occur during the disease, and its pathogenetic role has been hypothesized. To date, interferon-beta (IFN-beta) is the most effective and reliable therapy in the majority of MS patients, although the mechanisms underlying its therapeutic effects are not fully understood. Breakdown of the blood-brain barrier (BBB) with consequent extravasation of the T cells and their invasion of the brain parenchyma seems to be one of the most important steps in the pathogenesis of the disease. Matrix metalloproteinease-2 (MMP-2) and MMP-9 are enzymes with proteolytic activities toward extracellular matrix ECM components. They are physiologically balanced by the MMP tissue inhibitors TIMP-2 and TIMP-1, so that proteolysis occurs as the result of increased MMP or decreased TIMP levels. In 38 patients with MS, MMP-2 and TIMP-1 levels were similar before and after 9 months of IFN-beta therapy, whereas MMP-9 levels significantly decreased and TIMP-2 levels significantly increased in comparison to values obtained before treatment. These results suggest that IFN-beta modulates T cell activities, including MMP and TIMP production, thus contributing either to maintaining the integrity of the BBB or to slowing the progression of the disease

The effects of prolonged treatment with zidovudine, lamivudine and abacavir on a t- lymphoblastoid cell line

A human T-lymphoblastoid cell line that is resistant to the antiviral activity of zidovudine (ZDV) and moderately resistant to lamivudine (3TC) has been obtained as a result of prolonged treatment with a combination of three nucleoside analogues (NA), ZDV, 3TC, and abacavir (ABV). These cells, called CEM(ZLA), are fully sensitive to ABV. The cellular resistance of the CEM(ZLA) cells to ZDV correlates with significant reductions in thymidine kinase (TK) activity and in the amount of intracellular TK protein. Interestingly, the reduction in TK activity led to impairment of the ability of CEM(ZLA) to accumulate the triphosphate metabolite of ZDV. However, the moderately 3TC-resistant phenotype of CEM(ZLA) cannot be ascribed to a similar reduction in deoxycytidine kinase activity. Compared to the parental CEM cells, CEM(ZLA) cells express a high level of multidrug resistance protein 4 (MRP4), which could reduce the intracellular concentration of 3TC. This study shows that the exposure of cells to a combination of NAs is capable of simultaneously affecting more than one target site to confer resistance and that NAs display differing abilities to select cellular resistance mechanisms

Endometrial cancer: an overview of novelties in treatment and related imaging keypoints for local staging

Abstract Endometrial cancer is the most common gynaecologic malignancy in developed countries and its incidence is increasing. First-level treatment, if no contraindicated, is based on surgery. Pre-operative imaging is needed for evaluation of local extent and detection of distant metastases in order to guide treatment planning. Radiological evaluation, based on transvaginal ultrasound, MR and CT, can make the difference in disease management, paying special attention to assessment of entity of myometrial invasion, cervical stromal extension, and assessment of lymph nodal involvement and distant metastases