Acute Graft-Versus-Host Disease, Infections, Vascular Events and Drug Toxicities Affecting the Central Nervous System

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.

Case report: Autoimmune encephalomyelitis following cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation

“…Clinical manifestations of CNS-GVHD include seizures, vision loss, aphasia, and cognitive impairment. The symptoms are similar to multiple sclerosis or Guillain-Barre syndrome (6,8). Transplantation-associated thrombotic microangiopathy (TA-TMA) has been shown to be another rare potential neurological complication of allogeneic stem cell transplantation (9).…”

A three‐year‐old with central nervous system graft versus host disease: A rare cause of posthematopoietic stem cell transplant encephalopathy

“…10 T-cell infiltration through blood-brain barrier leads to IL-6 and indoleamine 2,3 deoxygenase production. 11 This likely has central role in CNS GvHD due to its action on host microglial cells. Hence, therapies that suppress T-cell infiltration and block IL-6 could reverse neuroinflammation.…”

Autoimmune Limbic Encephalitis in Patients with Hematologic Malignancies after Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide

“…While typical manifestations of acute GVHD and other NRM are thought to involve the skin, gastrointestinal tract, and liver, more recent reports have suggested that symptoms arising from central nervous system derangements may be a significant complication of immune therapies such as HSCT. Of these, a recent case report identified autoimmune limbic encephalitis (LE) as a complication of allogeneic HSCT [ 6 ]. LE is an inflammatory disease of the medial temporal lobes mediated by autoantibodies such as antibodies to N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR) or human herpesvirus 6 (HHV-6) and has often been reported as a paraneoplastic syndrome [ 7 , 8 , 9 ].…”