The rationale for the potential of CD28 superagonistic antibodies as immunomodulatory drugs for the treatment of autoimmune diseases had stemmed from the observations in animals that ligation of the T-cell-expressed CD28 molecule with superagonistic antibodies, in the absence of concurrent T-cell receptor binding, led to the preferential expansion of the regulatory T-cell subset. So, why did this antibody have the opposite effect when tested in humans? Now, using JJ316 (the rat functional equivalent of TGN1412 that had been used in the preclinical work) Reichardt and colleagues suggest that this is possibly due to the ability of the antibody to elicit two functionally distinct phases of T-cell activation.
The authors show that, similar to TGN1412 in the human volunteers, JJ316 initially (within the first 10 hours after administration) caused rapid profound lymphopaenia in rats. They further report that this lymphopaenia is a consequence of the JJ316-induced redistribution of T cells to secondary lymphoid organs and the arrest of T-cell motility within these. However, because of the short duration of this T-cell arrest (a couple of minutes) relative to the duration of the lymphopaenia (over 24 hours), the authors sought other potential contributing factors and found that T-cell cytoskeletal rearrangements, enhanced T-cell adhesion and interference with lymphocyte egress from the spleen could all be responsible for impaired T-cell recirculation.
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