The brain may devise laws for the blood

In this issue of Blood, Adams and colleagues have explored the impact of monoclonal antibody blockade of colony-stimulating factor 1 receptor (CSF1R) in models of central nervous system (CNS) chronic graft-versus-host disease (cGVHD).¹ Chronic GVHD is a pervasive syndrome of destructive donor-derived immune activation, uncontrolled acute and chronic inflammation, and progressive organ dysfunction following allogeneic stem cell transplantation. Overall, cGVHD is a major cause of mortality and morbidity following allogeneic stem cell transplantation and the major cause of impairment of activities of daily living and reduced quality-of-life measures.^2,3 Prior modeling from the same laboratory as the current article has determined that CNS cGVHD is driven by a unique population of CSF1-dependent, brain-infiltrating, bone marrow-derived major histocompatibility complex (MHC) class II-positive macrophages (BMDM), which promote a late CD4⁺ T-cell CNS infiltration and interferon gamma (IFN-γ)-dependent chronic neuroinflammation, impaired neurological synapse function, and impaired behavior.⁴ 

Given the recent and promising development of a clinical strategy using CSF1R-directed monoclonal antibody axatilimab to deplete donor-derived inflammatory macrophages and thereby reverse sclerodermatous skin GVHD,⁵ the authors hypothesized that therapeutic use of CSF1R-blockade and subsequent depletion of CNS BMDM could also prevent or improve the onset of CNS cGVHD. Surprisingly, in this model system, anti-CSF1R therapy was found to exacerbate behavioral and anatomic features of CNS acute GVHD when administered in the early posttransplant period. Cellular changes within the CNS included depletion of microglia, a finding that was duplicated, along with acute GVHD behaviors, even in untransplanted control subjects treated with anti-CSF1R therapy. When anti-CSF1R therapy was used in the setting of established CNS cGVHD, therapeutic efficacy was limited as measured by nondepletion of BMDM and nonreversal of cGVHD-associated behaviors. All of these findings were reproduced by conditional depletion of CSF1R expression on BMDM, highlighting the regulatory role of the CSF1R pathway in the activation and proinflammatory status of BMDM. Importantly, when IFN-γ receptor-deficient grafts were used in these model systems, decreased expression of MHC class II on BMDM was observed and the animals did not develop neurological inflammation, reiterating the importance of IFN-γ in the pathogenicity of CNS GVHD and the possible opportunities to disrupt this pathway with anticytokine strategies including the JAK-inhibitor ruxolitinib or IFN-γ blockade with emapalumab. No doubt these agents will be the subject of future experiments using the model established by Adams and colleagues.

How, then, are we to interpret these model systems in clinical practice considerations of the prevention and management of cGVHD, particularly in the setting of the development of novel immune-modifying therapies such as anti-CSF1R monoclonal antibodies?

The apparent separation in the onset of beneficial treatment of systemic cGVHD while exacerbating CNS GVHD serves as a potentially cautionary tale in the development and monitoring of new anti-GVHD therapies. Neurotoxicity in allogeneic transplantation is a protean and multifactorial complication and may reflect the accumulated treatment burden of prior chemotherapy, nutritional deficiencies, polypharmacy, biochemical perturbations, chronic infections, and the psychological burden of chronic illness in addition to the potential vascular and immune-inflammatory effects of GVHD. Manifestation of neurological pathology is recorded in a third of transplant recipients acutely and in 60% of cases in long-term follow-up patients who often report symptoms of fatigue, decreased cognition, or impaired memory.⁶ In most instances the causes of neurological symptoms are not definitively identified, and the possibility of CNS GVHD remains part of the differential diagnosis. Reported symptoms do not necessarily imply the presence of CNS cGVHD. In particular, fatigue alone does not appear to be associated with specific features of neuroinflammation,⁷ and cognitive decline has shown evidence of CNS immune activation.⁸ Collectively, although both the importance of identifying GVHD in the development of neurological sequelae of allogeneic transplant and the knowledge gaps of how best to incorporate and report CNS GVHD in prospective studies has been recognized in consensus GVHD documents,^9,10 specific diagnostic criteria remain elusive. This highlights the need for the development of CNS GVHD-specific biomarkers and prospective radiological criteria and the incorporation of neuropsychological testing and patient-reported outcomes measures to better delineate the clinical manifestations of CNS GVHD and its response (or deterioration) to treatment. The enhanced neuroinflammation observed on CSF1R-blocking therapy highlights the important concept of compartmentalization of GVHD in which some organ systems (CNS included) may be profoundly affected but others remain unscathed by GVHD. Overall, the findings from Adams and colleagues have laid down a challenge to the transplant community in which the development and monitoring new therapies for GVHD must give consideration to the unique pathobiology of CNS GVHD while simultaneously developing the capacity to accurately monitor for and diagnose its onset.

Conflict-of-interest disclosure: The author declares no competing financial interests.