This prospective multicentre cohort shows that CT-P13 is safe and effective in the induction of clinical remission and response in both CD and UC. Patients with previous infliximab exposure exhibited decreased response rates and were more likely to develop allergic reactions.
Although a strong clinical response to fontolizumab was not observed, significant decreases in C-reactive protein levels suggest a biological effect. Fontolizumab was well tolerated, and further studies to assess its efficacy are warranted.
Assembly and mutual proximities of ␣, , and ␥ c subunits of the interleukin 2 receptors (IL-2R) in plasma membranes of Kit 225 K6 T lymphoma cells were investigated by f luorescence resonance energy transfer (FRET) using f luorescein isothiocyanate-and Cy3-conjugated monoclonal antibodies (mAbs) that were directed against the IL-2R␣, IL-2R, and ␥ c subunits of IL-2R. The cell-surface distribution of subunits was analyzed at the nanometer scale (2-10 nm) by FRET on a cell-by-cell basis. Immune responses are regulated by a series of proteins termed cytokines. Cytokines exhibit a high degree of redundancy and pleiotropy controlling a wide range of functions in various cell types. The redundancy is explained in part by the sharing of common receptor subunits among members of the cytokine receptor superfamily. Each cytokine has its own private receptor but may share public receptors with other cytokines. The multisubunit interleukin 2 receptor (IL-2R) includes three elements: the 55-kDa IL-2R␣, the 70-to 75-kDa IL-2R, and the 64-kDa IL-2R␥ subunits (1-7). There are three forms of cellular receptors for IL-2 based on their affinity for ligand and receptor subunit utilization: one with a very high affinity (IL-2R␣␥, K d 10 Ϫ11
Subunits (a, b and c) of the interleukin-2 receptor complex (IL-2R) are involved in both proliferative and activationinduced cell death (AICD) signaling of T cells. In addition, the signaling b and c chains are shared by other cytokines (e.g. . However, the molecular mechanisms responsible for recruiting/sorting the a chains to the signaling chains at the cell surface are not clear. Here we show, in four cell lines of human adult T cell lymphoma/leukemia origin, that the three IL-2R subunits are compartmented together with HLA glycoproteins and CD48 molecules in the plasma membrane, by means of fluorescence resonance energy transfer (FRET), confocal microscopy and immunobiochemical techniques. In addition to the b and c c chains constitutively expressed in detergent-resistant membrane fractions (DRMs) of T cells, IL-2Ra (CD25) was also found in DRMs, independently of its ligand-occupation. Association of CD25 with rafts was also confirmed by its colocalization with GM-1 ganglioside. Depletion of membrane cholesterol using methyl-b-cyclodextrin substantially reduced co-clustering of CD25 with CD48 and HLA-DR, as well as the IL-2 stimulated tyrosine-phosphorylation of STATs (signal transducer and activator of transcription). These data indicate a GPI-microdomain (raft)-assisted recruitment of CD25 to the vicinity of the signaling b and c c chains. Rafts may promote rapid formation of a high affinity IL-2R complex, even at low levels of IL-2 stimulus, and may also form a platform for the regulation of IL-2 induced signals by GPI-proteins (e.g. CD48). Based on these data, the integrity of these GPI-microdomains seems critical in signal transduction through the IL-2R complex. Recent FRET data, in contrast to an earlier Ôsequential subunit-organizationÕ (affinity conversion) model [10], suggested a preassembly of the three IL-2R subunits, even in the absence of their relevant cytokine ligands in the plasma membrane of T lymphoma cells. Binding of the physiological ligands (IL-2, IL-7, IL-15) was reported to selectively modulate the mutual molecular proximities/ interactions of the IL-2R a, b and c c chains [11]. Microscopic (confocal fluorescence and immunogold labeling-based electron microscopy) studies revealed large scale (% 4-800 nm) overlapping clusters of CD25 and HLA molecules on T cell lines [12]. These observations all suggest that the above membrane proteins are somewhat compartmentalized in T cell plasma membranes.
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