The Cns in Acute GVHD: Development and Effects

Graft-versus-host disease (GVHD) is a severe complication of multiple organ systems in allogeneic hematopoietic stem cell transplantation (HSCT). An association between neurological complications and GVHD has been reported in patients after allogeneic HSCT. In a murine MHC-disparate allogeneic transplantation model (BM and T cells from C57BL/6 into lethally irradiated BALB/c) we studied whether the CNS is a target organ of acute GVHD. CNS infiltrating lymphocytes were isolated from brains after complete perfusion of the animals. We found increasing numbers of CNS-infiltrating donor derived CD4 and CD8 alloreactive T cells on day 7, 14, and 21 (p<0.001) in brains from allo-HSCT recipients, but almost none in syngeneic transplanted controls. The majority of infiltrating lymphocytes were effector memory T cells (CD44highCD62Llow). P-selectin-glycoprotein-1, Lymphocyte-function-associated-antigen-1 and a4-Integrin were broadly and CXCR-3 was less frequently expressed, while Lymphocyte-Peyer-patch-adhesion-molecule was absent, the latter distinguishing CNS infiltrating T cells from peripheral T cells. Histological analysis and immunohistochemistry for CD3 and CD4 in situ showed infiltration of Cortex, Hippocampus, Basal ganglia, Thalamus, Hypothalamus, Cerebellum, and Medulla oblongata in allogeneic HSCT recipients, consistent with lymphocytic multifocal meningoencephalitis. Syngeneic transplanted controls showed no pathology and T cells were virtually undetectable (p<0.01). Apoptotic cell death by TUNEL staining was only observed in allogeneic transplanted controls. We performed behavioral tests 14 to 20 days after HSCT to test whether these findings were associated with cognitive deficits. Mice were tested before the onset of severe GVHD. We found no differences between allogeneic- versus syngeneic- or non-transplanted mice in locomotor activity, motor coordination, strength and neuromuscular function. However, allogeneic transplanted animals demonstrated increased anxious behavior and decreased exploratory activity (p<0.01). Importantly, spatial learning was impaired in allogeneic transplanted animals as compared to both controls (p<0.0001). In conclusion, we observed in our experimental GVHD models that allo-HSCT recipients incur a lymphocytic meningoencephalitis during the early stages of acute GVHD, which is associated with significant infiltration of donor effector memory T cells in the CNS and certain cognitive defects, such as spatial memory loss.