Severe Human Traumatic Brain Injury, but Not Cyclosporin A Treatment, Depresses Activated T Lymphocytes Early after Injury

Abstract

Severe traumatic brain injury (TBI) leads to an immunocompromised state responsible for an increased morbidity and mortality. Our understanding of the mechanisms responsible for this brain damage is incomplete. Damage maybe mediated by a complex cascade of neuroinflammation, and cytokine activation. In addition, translocation and accumulation of T cells in the brain parenchyma could take place and be related to detrimental effects. Our aims in this prospective randomized pilot study, were to detect the early effect of severe TBI upon cell-mediated immunity, to verify if early immunologic impairment correlates with neurologic outcome, and finally, to test the effect of early administration of iv infusion of cyclosporin A upon cell-mediated immunologic function. Forty-nine patients with severe TBI were studied. Thirty-six of these patients received a 24-h intravenous infusion of Cyclosporin A, or two 24-h infusions of the drug. 10 patients were in the placebo group. Three patients, not enrolled in the cyclosporin trial, were studied only for the relationship between cellular immunity, neurological outcome, and infection rate. T cell counts and microbiological cultures were performed in all patients. Sixty-five percent of patients demonstrated reduced T lymphocyte counts on admission. Furthermore, reduction of T cell numbers was related with significantly worse neurologic outcome and an increase in pulmonary infection. There was no significant difference between the placebo and CsA treated patients for the studied immunological parameters, or for incidence of infection. We also observed sequestration/diapedesis of T cells into the brain parenchyma, around contusions, after human TBI and we speculate that this could be responsible for further brain damage.

Safety and Tolerability of Cyclosporin A in Severe Traumatic Brain Injury Patients: Results from a Prospective Randomized Trial

“…These findings mirror those reported in a previous article, in which we clearly demonstrated that no significant difference exists in the studied immunologic parameters in the placeboversus CsA-treated groups at any time point (Mazzeo et al, 2006). Furthermore, we could not demonstrate any other significant covariable factors in the incidence of lung infections after admission, other than the early impairment of T-cell activation secondary to injury that was not due to the administration of CsA (Mazzeo et al, 2006).…”

“…The administration of any medication that might induce further immunological suppression should therefore be undertaken with caution, in order to avoid any additional or synergistic suppression of immune function after severe TBI. We have previously reported that there were no significant differences between the placebo-and CsAtreated patients in this clinical trial with regard to immunological parameters, such as total lymphocyte count and phenotypic cell subsets (CD3 þ mature T cells, CD4 þ helper= inducer T cells, and CD8 þ suppressor=cytotoxic T cells), or the incidence of infection (Mazzeo et al, 2006). No significant difference was seen in the incidence of infection or sepsis between the two study groups detailed here.…”

“…The safety and tolerability of CsA are reported here. Other aspects of drug administration, such as its effects on cellmediated immunological function, and brain neurochemistry and cerebral and systemic hemodynamics, have been reported previously (Mazzeo et al, 2006(Mazzeo et al, , 2008.…”

Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury

“…The importance of noninvasive methods to detect and quantify axonal injury is underscored by ongoing trials of neuroprotectants such as cyclosporin A (Empey et al, 2006;Mazzeo et al, 2006) and hypothermia (Adelson et al, 2005) that are aimed at least in part at reducing axonal injury Koizumi and Povlishock, 1998;Okonkwo et al, 1999;Scheff and Sullivan, 1999). Stratification of patients based on the presence or severity of axonal injury could significantly improve the design of such trials.…”

Mitochondrial Damage: A Target for New Therapeutic Horizons

“…Encouraged by these laboratory data, further studies were performed to provide pharmacological guidelines to further clinical studies 19,20 and to establish the safety of the drug in respect with its immunosuppressive properties. 20,21 Based on these data, a prospective randomized and placebo-controlled, double-blinded two-center clinical study was performed in severe human TBI. During the study, patients suffering some severe TBI were enrolled and received 5 mg/kg during a 24-hour period, delivered within 12 hours from injury.…”