Chapter 109 - Graft-Versus-Host Disease and Graft-Versus-Leukemia Responses

Abstract

The graft-versus-leukemia (GVL) response fundamentally underpins the ability of allogeneic transplantation to irradicate treatment-resistant hematologic malignancies. Graft-versus-host disease (GVHD) presents a formidable immunological barrier limiting higher rates of cure due to its considerable morbidities. The manifestations of GVHD reflect dysregulation among cellular effectors of the innate and adaptive immune system arising from genetic disparities between the donor and host, tissue injury, and heightened levels of inflammation. Over the past half century, knowledge of GVL and GVHD responses has evolved exponentially from the initial seminal discoveries of Human Leukocyte Antigen (HLA) system towards a refined understanding that accounts for additional major and minor histocompatibility antigens. Numerous cytokines/chemokines, intracellular signal transduction pathways, epigenetic modifiers, microbiome alterations, and post-translational modifications act in the complex regulation of GVHD/GVL through amplifying or ameliorating inflammatory signals in the host. These observations have yielded actionable targets for clinical transplantation particularly in the early diagnosis, treatment, and prevention of GVHD. In recent years, advances in the understanding of transplant conditioning and immune prophylaxis have led to expansion of HLA disparate haploidentical and cord blood donors. These improvements importantly provide a deeper understanding that will enable more elegant dissection of the tight linkage between GVL and GVHD responses. Improving the therapeutic potential of allogeneic transplant will likely require multiple contributions from improved molecular-based donor selection, selective GVHD prophylaxis, and cellular graft engineering to promote GVL responses without provoking GVHD. This chapter reviews the immunobiology and clinical features of GVHD and GVL responses, examines critical outstanding questions, and highlights emerging clinical approaches that attempt to optimally balance these interrelated effects after allogeneic transplantation.