Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia

Abstract

Immune mechanisms contribute to cerebral ischemic injury. Therapeutic immunosuppressive options are limited due to systemic side effects. We attempted to achieve immunosuppression in the brain through oral tolerance to myelin basic protein (MBP). Lewis rats were fed low-dose bovine MBP or ovalbumin (1 mg, five times) before 3 h of middle cerebral artery occlusion (MCAO). A third group of animals was sensitized to MBP but did not survive the post-stroke period. Infarct size at 24 and 96 h after ischemia was significantly less in tolerized animals. Tolerance to MBP was confirmed in vivo by a decrease in delayed-type hypersensitivity to MBP. Systemic immune responses, characterized in vitro by spleen cell proliferation to Con A, lipopolysaccharide, and MBP, again confirmed antigen-specific immunologic tolerance. Immunohistochemistry revealed transforming growth factor ␤1 production by T cells in the brains of tolerized but not control animals. Systemic transforming growth factor ␤1 levels were equivalent in both groups. Corticosterone levels 24 h after surgery were elevated in all sham-operated animals and ischemic control animals but not in ischemic tolerized animals. These results demonstrate that antigen-specific modulation of the immune response decreases infarct size after focal cerebral ischemia and that sensitization to the same antigen may actually worsen outcome.

T- and B-Cell-Deficient Mice with Experimental Stroke have Reduced Lesion Size and Inflammation

“…Activated T cells have the capacity to infiltrate brain, and could contribute to expansion of the ischemic penumbra, an area that already contains infiltrating neutrophils. The functionality of this response has received much interest because of reports that tolerance to brain antigens can be induced with beneficial effects on stroke severity (Becker et al, 1997). The context of lymphocyte activation is likely important, as proinflammatory CD4 + CD28À lymphocyte subsets in blood are well recognized in clinical ischemic stroke, and rising CD4 + CD28À counts are associated with increased risk of stroke recurrence and death (Nadareishvili et al, 2004).…”

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

“…Because this protective effect only occurred when RTL551 was linked to a neuroantigen, rather than a nonneuronantigen (Subramanian et al, 2009), it suggests that an adaptive immune response to brain antigens occurred following stroke, and that classical T-cell activation may indeed have contributed to postischemic brain damage. Moreover, tolerance against brain antigens by mucosal administration of the antigen before stroke has been reported to improve outcome after stroke (Becker et al, 1997(Becker et al, , 2003Frenkel et al, 2005;Gee et al, 2008), further suggesting that antigen-dependent lymphocyte activation occurs following stroke, and that it contributes to brain injury. Therefore, the contribution of antigen-dependent T-cell activation in the damaging effects of T cells acutely poststroke remains unclear.…”

Inflammation and spinal cord injury: Infiltrating leukocytes as determinants of injury and repair processes

“…They play a prominent role in demyelinating disorders (78) and participate in brain and spinal cord injury. There is an abundance of myelin reactive T-cells in spinal cord injured and stroke patients (79)(80)(81) . Experimental studies are only now beginning to explore their function in spinal cord injury.…”