Acute graft-versus-host disease: from the bench to the bedside

Abstract

During the past decade, progress in basic immunology has been impressive. In parallel, whereas our understanding of the pathophysiology of acute graft-versushost disease (GVHD) has greatly improved, so has our knowledge of the complexities of the immune system. Much of the immunobiology of acute GVHD has been gleaned from preclinical models and far less from correlations with clinical observations or therapeutic interventions. In this review, we summarize some of the major advances in GVHD pathophysiology, including the translation of these from the bench to the bedside, and discuss preclinical approaches that warrant further exploration in the clinic. IntroductionMuch of our understanding of the biology of graft-versus-host disease (GVHD) has developed from 2 preclinical animal models, the mouse and the dog (reviewed in Welniak et al, 1 Ferrara et al, 2 Shlomchik, 3 van den Brink and Burakoff, 4 Feinstein et al, 5 and Schleuning 6 ). Because the inbred mouse model has been used as the basis for much of our knowledge of the immunologic mechanisms of GVHD, this review will focus on murine models but also will highlight several aspects of the canine model. Because there are significant species differences between humans and mice, 5 points are important to consider when drawing conclusions from studies with animal models and before correlation to the clinical allogeneic hematopoietic stem cell transplantation (HSCT) scenario (Table 1).GVHD is a complex disease resulting from donor T-cell recognition of a genetically disparate recipient that is unable to reject donor cells after allogeneic HSCT. The classical scheme of GVHD 1,2,7 development includes 5 basic steps.Step 1: priming of the immune response. Cytoreductive conditioning induces tissue damage and the release of a storm of proinflammatory cytokines that promote the activation and maturation of antigen-presenting cells (APCs) and the rapid amplification of donor T cells. [8][9][10] Step 2: T-cell activation and costimulation. Activation occurs as the result of the recognition and interaction of the T-cell receptor (TCR) and costimulatory molecules with their cognate ligands expressed on the surface of the APC.Step 3: alloreactive T-cell expansion and differentiation.Step 4: activated T-cell trafficking. Activated T-cell migration to GVHD target tissues (gut, liver, skin, and lung) is followed by the recruitment of other effector leukocytes. 11 Step 5: destruction of the target tissues by effector T cells. Destruction occurs via exposure to cell surface and release of soluble immune effector molecules. Tissue damage then leads to increased inflammatory signals, perpetuating and augmenting the disease process by contributing to the cytokine storm that fuels GVHD. Previous reviews 1,2,7,8,11,12 have detailed these phases of GVHD initiation and tissue destruction. We will focus on recent advances in GVHD pathophysiology and their translation into clinical knowledge or therapies. In each section, we briefly summarize key experimental data and then provide a persp...

Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia

“…19 The fact that severe aGVHD induced larger numbers of apoptotic epithelial cells in the skin and gut of FA patients compared with acquired AA patients could be linked to a greater sensitivity of FA epithelial cells to the alloimmune reaction. Studies in Fanc À / À mice 20 and in FA children 21 have shown the sensitivity of hematopoietic progenitor cells to IFN-g and TNF-a, two cytokines involved in aGVHD 22 and able to induce apoptosis by priming the Fas pathway. 21 Apoptosis through Fas engagement has also been observed in the skin and gut epithelial cells in an experimental model of acute alloimmune reaction.…”

State-of-the-art acute and chronic GVHD treatment

“…According to Billingham et al [7], for the patient to develop GVHD, the graft should include immunologically competent cells, the host must have antigens that the donor cells would recognize as foreign leading to their activation and finally the host must be incapable to mount a response against graft cells allowing them sufficient time to attack the host tissues. Our understanding of GVHD comes mainly from animal models [17,18]. On the basis of these models and other experiments a three-step pathogenesis of GVHD is described.…”

Numerical impairment of nestin+ bone marrow niches in acute GvHD after allogeneic hematopoietic stem cell transplantation for AML

“…1,2 The success rate of HSCT is severely limited by acute GvHD (aGvHD), which is mediated by host-reactive, donor-derived T cells. 3 The primary target tissues of these T cells are host epithelia in the skin, liver and intestine. 3,4 There is increasing evidence that the bone marrow (BM) stem cell niche and endothelial cells are also targets of GvHD.…”

“…3 The primary target tissues of these T cells are host epithelia in the skin, liver and intestine. 3,4 There is increasing evidence that the bone marrow (BM) stem cell niche and endothelial cells are also targets of GvHD. [5][6][7][8][9][10] Moreover, hematopoietic dysfunction, especially thrombocytopenia, is associated with GvHD.…”