Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for patients with hematological malignancies. Acute Graft versus host diseases (GVHD) is a major immune mediated side effect of allo-HCT that can affect the central nervous system (CNS) in addition to post-allo-HCT vascular events, drug toxicity or infections. Here we summarize and discuss recent preclinical data on the CNS as a target of acute GVHD and the known mechanisms contributing to neurotoxicity with a focus on microglia and T cells. We also discuss open questions in the field and place the findings made in mouse models in a clinical context. While in mice the neurological deficits can be assessed in a controlled fashion, in patients the etiology of the CNS damage is difficult to attribute to acute GVHD versus infections, vascular events, and drug-induced toxicity. Ultimately, we discuss novel therapies for GVHD of the CNS. Our understanding of the biological mechanisms that lead to neurotoxicity after allo-HCT increased over the last decade. This review provides insights into CNS manifestations of GVHD versus other etiologies of CNS damage in mice and patients.
Highlights
Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation
Preclinical studies have shown that allogeneic T cells infiltrate the central nervous system (CNS) during GVHD and activate different cell types including microglia and other myeloid cells
While CNS-GVHD accounts for some of the neurological symptoms observed after allo-HCT it is important to consider infections, vascular events, and drug-induced toxicity
Summary
Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). In line with the findings, an increase in the expression of c-fos was noted in several cortical regions including occipital and olfactory regions in a rat GVHD model [27] Such inflammatory effects were not observed upon transfer of syngeneic T cells [27]. Allogeneic virus-specific T cells were shown to be effective against CMV and EBV [65,66,67] and could be used to treat neurological symptoms caused by virus infections This strategy will be most relevant for allo-HCT patients with drug-refractory CMV infection that lack virus-specific T cells. Thrombocytopenia induces vascular complications ranging from subdural hematoma, hemorrhages and infarct along with increased infection rate in patients post allo-HCT [49]. A plethora of infections, vascular events, and drug-induced toxicities can cause neurogical symptoms that need to be ruled out before diagnosing CNS-GVHD
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