The central nervous system is a target of acute graft versus host disease in mice

Abstract

Key Points The central nervous system can be a direct target of alloreactive T cells during GVHD. Central nervous system damage in mouse models of GVHD lead to deficits in learning and increased anxiety behavior.

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

“…A number of preclinical studies, however, provide support for the premise that alloreactive donor T cells can infiltrate the brain during GVHD and be associated with behavioral abnormalities. Hartrampf et al (18) reported that the CNS was a target organ during GVHD in murine models and was associated with anxiogenic behavior and learning -/-animals transplanted with B10.BR BM and spleen cells (▲, n = 8) in the forced swim test 14 days after transplantation. Results are from 2 experiments in all panels.…”

“…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).…”

Bone marrow T-cell infiltration during acute GVHD is associated with delayed B-cell recovery and function after HSCT

“…More recently, the lung, thymus, and central nervous system were described as target organs as well. [25][26][27] Little is known about human BM as a target of T-cell infiltration and stromal cell destruction after allo-HSCT.…”

The importance of bone marrow involvement in GVHD

“…HSC transplantation, and, in some conditions, gene therapy, effectively cure patients with genetic HSC-derived disease including many primary immunodeficiencies, hemoglobinopathies, or other inborn errors. 2,3 In the most serious immunodeficiencies (SCID), transplantation or gene therapy should be performed as soon as possible in the first year of life. For inborn errors, such as Hurler disease, earlier treatment leads to a better outcome, with preservation of neurologic function.…”

“…The pervasive nature of acute GVHD is becoming increasingly apparent, as the list of potential targets has expanded beyond the skin, liver, and gastrointestinal tract to include the lungs, central nervous system, and thymus. [2][3][4] Myelosuppression has long been appreciated clinically in patients experiencing GVHD, and recent data from mouse models have indicated that the bone marrow itself may be a target of acute GVHD, leading to impaired hematopoiesis due to damage of the bone marrow niche. 5,6 Similar to the thymus's role in T-cell development, the bone marrow is an important site of immune reconstitution after transplant, in this case for B-cell development.…”