Cytokine cascades in acute graft-versus-host disease1
W Krenger, GR Hill, JLM Ferrara - Transplantation, 1997 - journals.lww.com
W Krenger, GR Hill, JLM Ferrara
Transplantation, 1997•journals.lww.comBone marrow transplantation (BMT*) is currently indicated in the treatment of a number of
malignant and non-malignant diseases, including acute and chronic leukemias, myelomas,
lymphomas, aplastic anemia, solid tumors, and severe immunodeficiencies. Allogeneic
BMT, ie, transplantation between two genetically nonidentical individuals, is associated with
serious side effects; its most common complication is graft-versus-host disease (GVHD).
Recently, the use of unrelated donors and HLA-nonidentical family members has resulted in …
malignant and non-malignant diseases, including acute and chronic leukemias, myelomas,
lymphomas, aplastic anemia, solid tumors, and severe immunodeficiencies. Allogeneic
BMT, ie, transplantation between two genetically nonidentical individuals, is associated with
serious side effects; its most common complication is graft-versus-host disease (GVHD).
Recently, the use of unrelated donors and HLA-nonidentical family members has resulted in …
Bone marrow transplantation (BMT*) is currently indicated in the treatment of a number of malignant and non-malignant diseases, including acute and chronic leukemias, myelomas, lymphomas, aplastic anemia, solid tumors, and severe immunodeficiencies. Allogeneic BMT, ie, transplantation between two genetically nonidentical individuals, is associated with serious side effects; its most common complication is graft-versus-host disease (GVHD). Recently, the use of unrelated donors and HLA-nonidentical family members has resulted in increased frequencies of severe GVHD (1). The development of acute and chronic GVHD and the immunosuppression used for GVHD prophylaxis represent significant risk factors for bacterial, fungal, and viral infections (2). Studies of experimental and clinical allogeneic BMT have shown that immunologically competent T cells must be present in the transplanted graft for GVHD to occur (3). Depletion of T cells or T-cell subsets prevents GVHD and eliminates the need for further immunosuppression but is associated with a higher rate of graft failure and increased incidence of leukemic relapse, resulting in equivalent disease-free survival for patients who receive conventional prophylaxis (4). GVHD thus remains a major barrier to allogeneic BMT for a variety of diseases, and further elucidation of the pathophysiological mechanisms involved is critical to its wider application.
Advances in basic immunology during the last decade have demonstrated how interactions between immunologically competent cells are governed by cytokines, and much recent research has focused on the roles of these mediators in the pathogenesis of acute GVHD. In this Overview, we examine current evidence that dysregulated cytokine production occurs as a cascade during sequential monocyte and T-cell activation and is responsible for many of the manifestations of acute GVHD. Cytokine dysregulation can be conceptualized as three sequential phases (Fig. 1). Phase 1 is initiated by the conditioning of the host, which induces inflammatory processes in recipient tissues. Donor T-cell activation by host alloantigens and subsequent cytokine secretion in phase 2 are facilitated by the events of phase 1. The T cell-derived cytokines of phase 2 activate distal inflammatory mediators which, in synergy with T and natural killer (NK) cell-mediated cytotoxicity, produce the systemic morbidity of GVHD-associated immunosuppression (phase 3). Each of these three phases is considered in detail below. It should be noted that these mechanisms have been most clearly delineated in mouse BMT models. Although there is preliminary work to suggest that these cascades are important in clinical GVHD (5), detailed analysis of human tissue is required.
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