Lymphocyte Subsets Show Different Response Patterns to In Vivo Bound Natalizumab—A Flow Cytometric Study on Patients with Multiple Sclerosis

Natalizumab is an effective monoclonal antibody therapy for the treatment of relapsing- remitting multiple sclerosis (RRMS) and interferes with immune cell migration into the central nervous system by blocking the α4 subunit of very-late activation antigen-4 (VLA-4). Although well tolerated and very effective, some patients still suffer from relapses in spite of natalizumab therapy or from unwanted side effects like progressive multifocal leukoencephalopathy (PML). In search of a routine-qualified biomarker on the effectiveness of natalizumab therapy we applied flow cytometry and analyzed natalizumab binding to α4 and α4 integrin surface levels on T-cells, B-cells, natural killer (NK) cells, and NKT cells from 26 RRMS patients under up to 72 weeks of therapy. Four-weekly infusions of natalizumab resulted in a significant and sustained increase of lymphocyte-bound natalizumab (p<0.001) which was paralleled by a significant decrease in detectability of the α4 integrin subunit on all lymphocyte subsets (p<0.001). We observed pronounced natalizumab accumulations on T and B cells at single measurements in all patients who reported clinical disease activity (n = 4). The natalizumab binding capacity of in vitro saturated lymphocytes collected during therapy was strongly diminished compared to treatment-naive cells indicating a therapy-induced reduction of α4. Summing up, this pilot study shows that flow cytometry is a useful method to monitor natalizumab binding to lymphocytes from RRMS patients under therapy. Investigating natalizumab binding provides an opportunity to evaluate the molecular level of effectiveness of natalizumab therapy in individual patients. In combination with natalizumab saturation experiments, it possibly even provides a means of studying the feasability of patient-tailored infusion intervals. A routine-qualified biomarker on the basis of individual natalizumab saturation on lymphocyte subsets might be an effective tool to improve treatment safety

Immunological mechanism of action and clinical profile of disease-modifying treatments in multiple sclerosis.

Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials

Signos, convención y verdad

Semántica; Wittgenstein; Austin; lenguaje y verdad

El juicio predicativo simple en Frege y Husserl: Una confrontación

The doctrine on predicative judgment sustained by Frege and Husserl reopens a discussion already present in the philosophical tradition: Does predicative judgment consist in a “composition” of concepts made by the understanding, or in an “assent” to a propositional content? For Frege, the “thought”, i. e., the sense of the proposition, as expresion of the judgment, presents such unity that it cannot be explained by a “composition” of previous elements; Husserl on the contrary, sustains that, although the propositional content of judgments in composed judgments do present a unity, in the case of the simple predicative judgment this unity arises due to a “synthesis”. Thus, for Frege the act of judging consists in “recognizing the truth-value of a thought”, which agrees with the doctrine of an “assent” to a propositional content. For Husserl, on the contrary, the basic act of judging consists in a “synthesis” of basic representations, which is very close to Aristotle’s doctrine

La verdad práctica en Tomás de Aquino

This paper analyses two texts of Aquinas (Summa theologiae, I-II, q. 57, a. 5, ad 3, and Expositio libri peryermeneias I, 3, 107 ss.) where the truth of practical intellect is defined in accordance with Aristotle’s account in Nicomachean Ethics, 1139a27-31. The proposed interpreta-tion tries to show that both texts are arguably not incompatible. A last important claim is that according to the definition of practical truth practical intellect is supposed to work as a mesure for reality

Determinismo o libertad. La idea de libertad en Schelling

Millán-Puelles' theory of freedom is radically separated from all other views that attribute an absolute character to human freedon. One of these theses is precisely that of Schelling, according to whom "the essence of the self is freedom"

La verdad práctica en Tomás de Aquino

This paper analyses two texts of Aquinas (Summa theologiae, I-II, q. 57, a. 5, ad 3, and Expositio libri peryermeneias I, 3, 107 ss.) where the truth of practical intellect is defined in accordance with Aristotle’s account in Nicomachean Ethics, 1139a27-31. The proposed interpreta-tion tries to show that both texts are arguably not incompatible. A last important claim is that according to the definition of practical truth practical intellect is supposed to work as a mesure for reality