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.

Keywords: animal models; graft-versus-host disease; history; pathophysiology; treatment.

Figure 1

Timeline of major experimental concepts that have translated into clinical practice. GVHD was initially described as a wasting syndrome in transplanted mice in 1956. Early clinical bone marrow transplantation was associated with high mortality due to GVHD, infection and relapse. Recognition of T cells as the mediators of GVHD and GVL and initiating rudimentary tissue-typing. Conditioning and GVHD prophylaxis regimens were developed in dog models in the 1980s that led to reduced intensity and non-myeloablative conditioning in the 1990s. Stem cell mobilization following cytokine administration was developed in the early 1990s and gained widespread clinical translation. New approaches to GVHD prophylaxis, including post-transplant cyclophosphamide (PT-Cy) and naïve T (Tn) cell depletion developed in the 2000s and are increasingly utilized in the clinic. In the last decade the widespread use of gene editing, initially in T cells, has been widely translated to modulate GVHD and GVL. Figure generated with biorender.com.