Pathogenesis of Acute Graft-Versus-Host Disease: Cytokines and Cellular Effectors

Abstract

The pathogenesis of acute graft versus host disease (GVHD) is multistep process. This review considers acute GVHD in three sequential steps: conditioning regimen, donor T cell activation, and effector mechanisms. In step one, the conditioning regimen simultaneously damages and activates host tissues, amplifying antigen presentation to allogeneic donor T cells. In step two, donor T cells, activated by host alloantigens, proliferate and secrete a variety of cytokines. Type 1 cytokines (interleukin-2 and interferon-y) are critical for acute GVHD, but several regulatory mechanisms of tissue damage include inflammatory cytokines and cytolytic cellular effectors. The gastrointestinal (GI) tract is a principal target organ because damage to the GI mucosa can release inflammatory mediators such as endotoxin that amplify systemic disease. The inflammatory processes of acute GVHD can be considered as a distortion of the cellular responses to viral and bacterial infections. Cell-mediated toxicity is critical to other GVHD target organs, particularly the liver, where Fas-mediated injury predominates. The cytolytic pathways (e.g., perforin) clearly intensify acute GVHD, although they are not necessary for systemic disease in several model systems. Many of these insights come from animal models using mutant mouse strains that can clarify the role of individual proteins or cell types in the disease process. These insights should allow the testing of new classes of drugs and inhibitors in clinical bone marrow transplantation.

The number of infused CD34+ cells does not influence the incidence of GVHD or the outcome of allogeneic PBSC transplantation, using reduced-intensity conditioning and antithymocyte globulin

“…25 Preparative regimens of low intensity are associated with mild extramedullary toxicity, thus resulting in less tissue damage, especially of the gastrointestinal mucosa, hence with anticipated milder 'cytokine storm' that normally can provoke the GVHD process. 26 Taking this observation into consideration, it is reasonable to assume that in the latter studies the impact of the high CD34 þ cell doses on the GVHD was counterbalanced by an opposite impact of the lower intensity of the preparative regimen.…”

The effect of hematopoietic growth factors on the risk of graft-vs-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis

“…28 Thus, it was expected that drugs which induce a Th2-polarization, such as G-CSF, would reduce acute GVHD risk, and GM-CSF, which favors Th1-polarization, would have the opposite effect. Animal studies, however, have failed to confirm this hypothesis.…”

G-CSF-primed haploidentical marrow transplantation without ex vivo T cell depletion: an excellent alternative for high-risk leukemia

“…17 Th-1 type responses are critical for acute GVHD. 18 Treatment that induces Th2 response reduces GVHD. 19 G-CSF polarizes T cell differentiation from Th1 to Th2 type cells and induces Th2 responses, with the production of IL-4 and IL-10.…”