Biomedical subjects

E M Fallon

Publications and source records attributed to E M Fallon.

4 recordsLinked to original sources

PubMed2000

Increased endosomal sorting of ligand to recycling enhances potency of an interleukin-2 analog.

An interleukin-2 (IL-2) variant containing adjacent point mutations (L18M/L19S, termed 2D1) displaying binding affinity to the heterotrimeric IL-2 receptor similar to that of wild-type IL-2 (WT) had been previously found to surprisingly exhibit increased bioactivity in a peripheral blood lymphocyte proliferation assay. In order to provide an explanatory mechanism for this unexpected potency enhancement, we hypothesize that altered endocytic trafficking of the 2D1 variant might be responsible by increasing the number of ligand-receptor complexes. We demonstrate here that the internalization kinetics of 2D1 via the high affinity IL-2 receptor are equivalent to those of WT but that a significantly increased fraction of internalized 2D1 is sorted to recycling instead of to lysosomal degradation. We further find a reduced pH sensitivity of binding to IL-2 receptor alpha relative to IL-2 receptor beta compared with WT, which could be responsible for the altered sorting behavior of 2D1 in the acidic endosomal compartment. Accordingly, the 2D1 variant displays a half-life 36 h longer than that of IL-2 in T-lymphocyte culture at concentrations equal to the K(D) of the IL-2 receptor. The extended half-life of intact 2D1 provides enhanced mitogenesis as compared with IL-2. In addition, 2D1 stimulates natural killer cells to a lesser degree than IL-2 at equal concentrations. We conclude that this IL-2 variant provides increased mitogenic stimulation that could not be easily predicted from its cell surface receptor binding affinity while minimizing undesired stimulation of natural killer cells. This concept of altering trafficking dynamics may offer a generalizable approach to generating improvements in the pharmacological efficacy of therapeutic cytokines.

Cell Line↗

PubMed1998

Scratching the (cell) surface: cytokine engineering for improved ligand/receptor trafficking dynamics.

Cytokines can be engineered for greater potency in stimulating cellular functions. An obvious test criterion for an improved cytokine is receptor-binding affinity, but this does not always correlate with improved biological response. By combining protein-engineering techniques with studies of receptor trafficking and signaling, it might be possible to identify the ligand receptor-binding properties that should be sought.

Cytokines↗

PubMed1997

Acute chest pain.

Chest pain is the initial symptom of many life-threatening disease processes. Pain may arise from any structure located in the thoracic cavity. Cardiac causes of chest pain usually have anginal symptoms. Noncardiac causes have a variety of chest pain characteristics. Diseases that require immediate attention and intervention are myocardial infarction/unstable angina, dissecting aortic aneurysm, pericarditis, pulmonary embolism, pneumothorax, pneumonia, and acute chest syndrome. In order to evaluate a patient with the complaint of chest pain, the advanced practice nurse must be familiar with the differential diagnosis approach to acute chest pain.

Acute Disease↗

PubMedDate not supplied

Computational model for effects of ligand/receptor binding properties on interleukin-2 trafficking dynamics and T cell proliferation response.

Multisubunit cytokine receptors such as the heterotrimeric receptor for interleukin-2 (IL-2) are ubiquitous in hematopoeitic cell types of importance in biotechnology and are crucial regulators of cell proliferation and differentiation behavior. Dynamics of cytokine/receptor endocytic trafficking can significantly impact cell responses through effects of receptor down-regulation and ligand depletion, and in turn are governed by ligand/receptor binding properties. We describe here a computational model for trafficking dynamics of the IL-2 receptor (IL-2R) system, which is able to predict T cell proliferation responses to IL-2. This model comprises kinetic equations describing binding, internalization, and postendocytic sorting of IL-2 and IL-2R, including an experimentally derived dependence of cell proliferation rate on these properties. Computational results from this model predict that IL-2 depletion can be reduced by decreasing its binding affinity for the IL-2R betagamma subunit relative to the alpha subunit at endosomal pH, as a result of enhanced ligand sorting to recycling vis-à-vis degradation, and that an IL-2 analogue with such altered binding properties should exhibit increased potency for stimulating the T cell proliferation response. These results are in agreement with our recent experimental findings for the IL-2 analogue termed 2D1 [Fallon, E. M. et al. J. Biol. Chem. 2000, 275, 6790-6797]. Thus, this type of model may enable prediction of beneficial cytokine/receptor binding properties to aid development of molecular design criteria for improvements in applications such as in vivo cytokine therapies and in vitro hematopoietic cell bioreactors.

Biological Transport↗