Cerebral Endothelial Expression of Adhesion Molecules in Mice with Chronic Graft-Versus-Host Disease

Abstract

Background and Purpose-Graft-versus-host disease (GvHD) is a major complication after allogeneic bone marrow transplantation (BMT). The theory that the central nervous system (in addition to the peripheral nervous system) participates in GvHD has been supported by detection of cerebral lymphomononuclear infiltrates in experimental GvHD and the observation of cerebral angiitis-like disease in patients with chronic GvHD. Methods-In a murine BMT model, we investigated the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on cerebral endothelium after allogeneic and syngeneic transplantation. Through the use of ICAM-1-knockout mice, the effect of ICAM-1 deficiency on cellular infiltration was evaluated. As an indicator of enhanced apoptotic cell death, we examined the cerebral expression of Fas antigen (Fas), the occurrence of the poly-ADP ribose polymerase p85 fragment, and the distribution of TUNEL positive-stained cells. Results-In close correlation with earlier findings of cerebral infiltration in the same animals, we found cerebral endothelial upregulation of ICAM-1 and especially of VCAM-1 in allogeneic recipients compared with syngeneic animals without GvHD and unmanipulated controls. In ICAM-1-knockout mice, leukocytic infiltration did not differ from that in wild-type animals. Neither cerebral histopathologic changes nor an apoptotic effect of cellular infiltrates on brain parenchyma could be detected. Key Words: immunohistochemistry Ⅲ cerebrovascular disorders Ⅲ endothelium, vascular Ⅲ graft-versus-host disease Ⅲ cell adhesion molecules N eurologic complications can occur in up to 70% of allogeneic bone marrow recipients, 1 and involvement of the central nervous system (CNS) has been reported because of the neurotoxicity of the conditioning regimen, neurovascular complications, and side effects of immunosuppression. Chronic graft-versus-host disease (GvHD), a systemic complication after allogeneic bone marrow transplantation (BMT), is known to cause peripheral neuromuscular disorders, 2,3 and there is growing evidence that it can also affect the CNS. In animal models of chronic GvHD, cerebral perivascular and parenchymal lymphomononuclear infiltrations and upregulation of major histocompatibility (MHC) class I and II antigens have been reported. 4 Chronic GvHD has also been considered a possible cause of cerebral ischemic and hemorrhagic complications in patients after allogeneic transplantation. 5 Because cellular adhesion molecules (CAMs) play a major role in the recruitment of leukocytes into the brain, we investigated the endothelial expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the brains of mice with chronic GvHD. The same animals were described earlier to have cerebral cellular infiltrations 6 ; we therefore sought to correlate these earlier findings with our results on vascular CAM expression. Through the use of ICAM-1-knockout mice, the influence of ICAM-1 deficiency on leukocyte infl...

Cerebral angiitis in four patients with chronic GVHD

“…24 In addition, we have described an upregulation of adhesion molecules on cerebral vessels in the same mouse model of GVHD. 15 Adhesion molecules and chemokines control homing of leukocytes to the CNS in inflammatory brain conditions. Here, we could further show that a high proportion of the leukocytic infiltrates in humans expressed CD11a, which is part of the adhesion receptor leukocyte function-associated Ag-1 .…”

“…15 The following primary Abs were used: mouse anti-human LCA (leukocyte common Ag, also stains activated microglia), cluster of differentiation (CD) 3 (pan T-cell marker), CD8 (cytotoxic T-cell marker), CD68 (marker for monocytes and microglia), Granzyme B, glial fibrillary acidic protein (all obtained from DAKO, Hamburg, Germany) and CCR5 (chemokine receptor-5, clone MC5; kindly provided by M Mack, University of Regensburg, Regensburg, Germany); rabbit anti-human CD11a (subunit of the leukocyte functionassociated Ag-1) and CCR1 (both from Abcam, Cambridge, UK). In one patient, IHC against UHCL (memory T-cell Ag) was performed on first neuropathological examination; reevaluation using LCA, CD3 and CD8 IHC could not be carried out because of lack of tissue specimen.…”

The importance of neovascularization and its inhibition for allogeneic hematopoietic stem cell transplantation

“…The vasculature is sequentially affected during GVHD ( Figure 1). Endothelial damage is caused (1) initially by the conditioning regimen, (2) in the second phase neovascularization and recruitment of inflammatory cells occur, and (3) in the third phase alloreactive T cells target the endothelium and blood vessels are destroyed. Studies on neovascularization during GVHD are summarized in Table 1.…”

Host interleukin 6 production regulates inflammation but not tryptophan metabolism in the brain during murine GVHD

“…Traditional approaches for the treatment of these GVHD complications have involved antidepressant or anxiolytic agents that are used empirically and have not been validated in well-designed studies. Prior studies in animal models have demonstrated that alloreactive donor T cells are able to infiltrate the CNS and are associated with neuronal cell death (18,19), suggesting that donor T cells can mediate pathological damage in the brain, similar to other GVHD target tissues. Furthermore, T cell-mediated inflammation has been correlated with behavioral abnormalities (18), similar to what has been reported in humans undergoing allogeneic HSCT (20,21).…”