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.
Highlights
Specialty section: This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology
New insights into the pathophysiology of Graft-versus-host disease (GVHD) garnered from our understanding of the immunological pathways within animal models have been pivotal in driving new therapeutic paradigms in the clinic
In 1956, two groups observed that mice exposed to lethal dose of total body irradiation (TBI) and administered allogeneic splenocytes survived for a shorter time than those transplanted with syngeneic splenocytes [1,2,3]
Summary
In 1956, two groups observed that mice exposed to lethal dose of total body irradiation (TBI) and administered allogeneic splenocytes survived for a shorter time than those transplanted with syngeneic splenocytes [1,2,3]. In 1963, Mathé and colleagues reported the first case of a human allogeneic bone marrow transplantation (BMT) recipient that survived beyond a year This patient had complete engraftment and the development of a lethal “secondary disease” was described [5]. Studies of allogeneic BMT in Seattle using dog models in the 1980s provided the scientific groundwork for the field leading to the concepts of histocompatibility matching, Pathophysiology and Treatment of GVHD conditioning regimens and pharmacological GVHD prophylaxis [9,10,11,12,13] These findings were soon translated to the clinic and successful clinical BMT was established [14], subsequently leading to E. For a detailed discussion of the various mouse models of GVHD currently available and the penetrance of disease therein, we refer the reader to some of the excellent reviews on this subject [15,16,17]
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