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Ferrata Storti Foundation
Haematologica 2020 Volume 105(11):2550-2560
Translational and clinical advances in acute graft-versus-host disease
Mahasweta Gooptu and John Koreth
Dana-Farber Cancer Institute, Boston, MA, USA
ABSTRACT
Acute graft-versus-host disease (aGvHD) is induced by immunocompe- tent alloreactive T lymphocytes in the donor graft responding to polymorphic and non-polymorphic host antigens and causing inflam- mation in primarily the skin, gastrointestinal tract and liver. aGvHD remains an important toxicity of allogeneic transplantation, and the search for better prophylactic and therapeutic strategies is critical to improve transplant out- comes. In this review, we discuss the significant translational and clinical advances in the field which have evolved based on a better understanding of transplant immunology. Prophylactic advances have been primarily focused on the depletion of T lymphocytes and modulation of T-cell activation, pro- liferation, effector and regulatory functions. Therapeutic strategies beyond corticosteroids have focused on inhibiting key cytokine pathways, lympho- cyte trafficking, and immunologic tolerance. We also briefly discuss impor- tant future trends in the field, the role of the intestinal microbiome and dys- biosis, as well as prognostic biomarkers for aGvHD which may improve stratification-based application of preventive and therapeutic strategies.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) remains one of the most important curative modalities for marrow failure and various advanced/aggressive hematologic malignancies. Acute graft-versus-host disease (aGvHD) remains an impor- tant HSCT toxicity with significant associated morbidity and mortality. aGvHD clinical manifestations typically involve skin (rash), upper (nausea, anorexia) or lower (diarrhea, abdominal pain) gastrointestinal (GI) tract, or liver dysfunction (elevated bilirubin, transaminases).1 Its pathology is typically induced by immunocompetent effector T lymphocytes responding to donor/recipient polymorphic and non-polymorphic anti- gens on host tissues, with activation, inflammation and eventual cytolytic activity.
Despite advances in HSCT, such as high resolution HLA genotyping and the rou- tine use of calcineurin-inhibitor (CNI)-based prophylaxis, aGvHD incidence remains in the 30-35% range with HLA-matched donors. While aGvHD outcomes have improved (largely due to advances in supportive care, e.g., infectious disease inter- ventions), patients with severe and steroid-refractory (SR) aGvHD still have impaired survival, estimated to be in the 5-30% range.
aGvHD control is a cornerstone of successful transplantation. Effective interven- tions should not cause excessive toxicity, impair the curative graft-versus-leukemia (GvL) effect of allotransplantation, or contribute to graft failure. In this review, we summarize aGvHD pathogenesis and discuss novel advances in the prevention and treatment of aGvHD that have evolved as our understanding of pathogenesis has grown. In addition, we highlight areas of burgeoning interest in the field: microbiota dysbiosis, and the development of aGvHD biomarkers.
Biology of acute graft-versus-host disease
In an early model of aGvHD, Antin and Ferrara described a three-step process com- prising: (i) host tissue injury due to the conditioning regimen, with the production of inflammatory cytokines; (ii) stimulation and proliferation of effector T lymphocytes (Teff); and, finally, (iii) recruitment and activation of additional mononuclear effectors and amplification of a ‘cytokine storm’.2 This basic model has stood the test of time, although it has been refined thanks to a deeper and more sophisticated understand-
Correspondence:
JOHN KORETH
john_koreth@dfci.harvard.edu
Received: May 3, 2020.
Accepted: July 29, 2020. Pre-published: September 17, 2020.
doi:10.3324/haematol.2019.240309 ©2020 Ferrata Storti Foundation
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