The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for hematologic malignancies, bone marrow failure syndromes, and inherited immunodeficiencies and metabolic diseases. Graft-versus-host disease (GVHD) is the major life-threatening complication after allogeneic HCT. New insights into the pathophysiology of GVHD garnered from our understanding of the immunological pathways within animal models have been pivotal in driving new therapeutic paradigms in the clinic. Successful clinical translations include histocompatibility matching, GVHD prophylaxis using cyclosporine and methotrexate, posttransplant cyclophosphamide, and the use of broad kinase inhibitors that inhibit cytokine signaling (e.g. ruxolitinib). New approaches focus on naïve T cell depletion, targeted cytokine modulation and the inhibition of co-stimulation. This review highlights the use of animal transplantation models to guide new therapeutic principles.

Milestones in acute GVHD pathophysiology

“…Major milestones from the early ages of hematopoietic stem cell transplantation deserve first to be mentioned. Pioneers in the field included Van Bekkum, Thomas, and Santos [reviewed in ( 4 , 12 – 14 )]. In parallel, in this period, the major histocompatibility complexes (MHC) in the mice ( 15 ) and humans ( 16 ) were discovered.…”

“…Ten years later, Matheí and colleagues reported the first patient who underwent allogeneic bone marrow transplantation (BMT) who developed lethal GVHD ( 3 ). The outcomes of patients transplanted at this early age were poor [reviewed in ( 4 )]. This mainly resulted from the poor knowledge of histocompatibility, the need for immunosuppressive drugs post-transplant, and advanced stage of the hematological malignancies.…”

Inflammatory CD4/CD8 double-positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

“…While all the validated GVHD biomarkers to date have been plasma based, the direct investigation of T cell subsets as biomarkers has been another area of active investigation (27)(28)(29)(30). Both CD4 and CD8 T cells can respond to allogeneic antigens, but while CD8 T cells may be directly responsible for cellular cytotoxicity, CD4 T cells have been the primary focus of the field (31)(32)(33). The CD4 population is unique in its capacity to polarize into a variety of different subsets, based on the cytokine environment it finds itself, to drive an inflammatory response (34)(35)(36)(37)(38)(39)(40).…”

Editorial: Endocrinological sequelae of hematopoietic stem cell transplantation

“…Transplant-related complications, including severe myelosuppression, graft failure, and graft versus host disease (GvHD), are the major causes of poor outcomes post-HSCT and reduced quality of life. Among other challenges, GvHD-related symptoms and disorders (such as bronchiolitis obliterans organizing pneumonia with decreased pulmonary function or sclerodermatous-like chronic GvHD) and secondary cancers significantly impact post-HSCT outcomes ( 2 ). Moreover, long-term survivors may experience early and late endocrine disorders, which may occur as different clinical manifestations of the GvHD-related immune dysregulation, or may independently arise as late effects of pre-transplant induction and/or conditioning regimens ( 3 ).…”