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International audience; Belatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 (n=5), a selective pegylated Fab9 antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept (n=5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid-resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell-specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro, FR104 controlled the proliferative response of human preex-isting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.

Unlabelled Near-infrared spectroscopy has been used to monitor cerebral oxygen saturation during cerebral circulatory arrest and carotid clamping. However, its utility has not been demonstrated in more complex situations, such as in patients with head injuries. The authors tested this method during conditions that may alter the arteriovenous partition of cerebral blood in different ways. Methods The authors compared changes in measured cerebral oxygen saturation and other hemodynamic parameters, including jugular venous oxygen saturation, in nine patients with severe closed head injury during manipulation of arterial carbon dioxide partial pressure and after mean arterial pressure was altered by vasopressors. Results The Bland and Altman representation of cerebral oxygen saturation versus jugular oxygen saturation showed a uniform scatter. Values for changing arterial carbon dioxide partial pressure were: bias = 1.1%, 2 SD = +/-21%, absolute value; and those for alterations in mean arterial pressure: bias = 3.7%, 2 SD = +/-24%, absolute value. However, a Bland and Altman plot of changes in cerebral oxygen saturation versus changes in jugular oxygen saturation had a negative slope (alteration in arterial carbon dioxide partial pressure: bias = 2.4%, 2 SD = +/-17%, absolute value; alteration in mean arterial pressure: bias = -4.9%, 2 SD = +/-31%, absolute value). Regression analysis showed that changes in cerebral oxygen saturation were positively correlated with changes in jugular venous oxygen saturation during the carbon dioxide challenge, whereas correlation was negative during the arterial pressure challenge. Conclusions Cerebral oxygen saturation assessed by near-infrared spectroscopy does not adequately reflect changes in jugular venous oxygen saturation in patients with severe head injury. Changes in arteriovenous partitioning, infrared-spectroscopy contamination by extracerebral signal, algorithm errors, and dissimilar tissue sampling may explain these findings.