Graft-versus-host disease
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Publication
Journal: Seminars in Hematology
May/15/2006
Abstract
Complications of allogeneic hematopoietic stem cell transplantation (HSCT) remain barriers to its wider application for a variety of diseases. Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality following allogeneic HSCT. GVHD can be considered an exaggerated, undesirable manifestation of a normal inflammatory mechanism, in which donor lymphocytes encounter foreign antigens in a milieu that fosters inflammation. Recent advances in the study of cytokine networks, chemokine gradients, and the direct mediators of cellular cytotoxicity have led to improved understanding of this complex syndrome. The pathophysiology of acute GVHD can be considered as a three-step process in which the innate and adaptive immune systems interact: (1) tissue damage to the recipient by the radiation/chemotherapy pretransplant conditioning regimen; (2) donor T-cell activation and clonal expansion; and (3) cellular and inflammatory factors. Here we review the immunologic interactions that cause clinical GVHD and discuss the risk factors and prophylactic strategies for acute GVHD according to this model.
Publication
Journal: Blood Reviews
July/8/2004
Abstract
Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). The immunobiology of acute GVHD is complex and can be conceptualized to be a three-step process. In step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to the damage and activation of host tissues and induces the secretion of inflammatory cytokines TNF-alpha and IL-1. As a consequence expression of MHC antigens and adhesion molecules is increased, thus enhancing the recognition of host alloantigens by donor T cells. Donor T-cell activation in step 2 is characterized by donor T-cell interaction with host APCs and subsequent proliferation, differentiation, and secretion of cytokines. Cytokines such as IL-2 and IFN-gamma enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses, and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. These inflammatory cytokines in turn stimulate production of inflammatory chemokines, thus recruiting effector cells into target organs. In step 3, effector functions of mononuclear phagocytes are triggered via a secondary signal provided by lipopolysaccharide (LPS) that leaks through the intestinal mucosa damaged during step 1. This mechanism may result in the amplification of local tissue injury and further promotion of an inflammatory response, which, together with the CTL and NK components, leads to target tissue destruction in the transplant host.
Publication
Journal: Hematological Oncology
February/23/2004
Abstract
Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). The pathophysiology of acute GVHD is complex and can be conceptualized to be a three-step process based on murine studies. In step 1, the conditioning regimen leads to the damage and activation of host tissues and induces the secretion of inflammatory cytokines. As a consequence, the expression of MHC antigens and adhesion molecules is increased enhancing the recognition of host alloantigens by donor T cells. Donor T-cell activation in step 2 is characterized by donor T cell interaction with host APCs and subsequent proliferation, differentiation and secretion of cytokines. Cytokines such as IL-2 and IFN-gamma enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. These inflammatory cytokines in turn stimulate production of inflammatory chemokines, thus recruiting effector cells into target organs. In step 3, effector functions of mononuclear phagocytes are triggered via a secondary signal provided by lipopolysaccharide (LPS) that leaks through the intestinal mucosa damaged during step 1. This mechanism may result in the amplification of local tissue injury and further promotion of an inflammatory response, which, together with the CTL and NK components, leads to target tissue destruction in the transplant host. The following review discusses the three-step process of the pathophysiology of experimental acute GVHD.
Publication
Journal: Annual Review of Medicine
June/2/2003
Abstract
Stem cell transplantation is being used to treat a number of hematologic malignancies as well as hematologic and immune deficiency states. The ages of patients being offered this therapy and the donor marrow sources have been expanded. One persistent problem has been graft-versus-host disease (GVHD). This article reviews the basic biology of GVHD, clinical manifestations of acute and chronic GVHD, prophylaxis and treatment of acute GVHD, and treatment of chronic GVHD.
Publication
Journal: Orphanet Journal of Rare Diseases
November/27/2007
Abstract
Acute graft-versus-host disease (GVHD) occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues. Activated donor T cells damage host epithelial cells after an inflammatory cascade that begins with the preparative regimen. About 35%-50% of hematopoietic stem cell transplant (HSCT) recipients will develop acute GVHD. The exact risk is dependent on the stem cell source, age of the patient, conditioning, and GVHD prophylaxis used. Given the number of transplants performed, we can expect about 5500 patients/year to develop acute GVHD. Patients can have involvement of three organs: skin (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea). One or more organs may be involved. GVHD is a clinical diagnosis that may be supported with appropriate biopsies. The reason to pursue a tissue biopsy is to help differentiate from other diagnoses which may mimic GVHD, such as viral infection (hepatitis, colitis) or drug reaction (causing skin rash). Acute GVHD is staged and graded (grade 0-IV) by the number and extent of organ involvement. Patients with grade III/IV acute GVHD tend to have a poor outcome. Generally the patient is treated by optimizing their immunosuppression and adding methylprednisolone. About 50% of patients will have a solid response to methylprednisolone. If patients progress after 3 days or are not improved after 7 days, they will get salvage (second-line) immunosuppressive therapy for which there is currently no standard-of-care. Well-organized clinical trials are imperative to better define second-line therapies for this disease. Additional management issues are attention to wound infections in skin GVHD and fluid/nutrition management in gastrointestinal GVHD. About 50% of patients with acute GVHD will eventually have manifestations of chronic GVHD.
Publication
Journal: Cancer
November/15/2004
Abstract
Hematopoietic stem cell transplantation has evolved as a central treatment modality in the management of different hematologic malignancies. Despite adequate posttransplantation immunosuppressive therapy, acute graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in the hematopoietic stem cell transplantation setting, even in patients who receive human leukemic antigen (HLA) identical sibling grafts. Up to 30% of the recipients of stem cells or bone marrow transplantation from HLA-identical related donors and most patients who receive cells from other sources (matched-unrelated, non-HLA-identical siblings, cord blood) will develop>> Grade 2 acute GVHD despite immunosuppressive prophylaxis. Thus, GVHD continues to be a major limitation to successful hematopoietic stem cell transplantation. In this review, the authors summarize the most current knowledge on the pathophysiology, clinical manifestations, and management of this potentially life-threatening transplantation complication.
Publication
Journal: Philosophical Transactions of the Royal Society B: Biological Sciences
February/5/2006
Abstract
Haematopoietic stem cell transplantation (HSCT) offers promise for the treatment of haematological and immune disorders, solid tumours, and as a tolerance inducing regimen for organ transplantation. Allogeneic HSCTs engraftment requires immunosuppression and the anti-tumour effects are dependent upon the immune effector cells that are contained within or generated from the donor graft. However, significant toxicities currently limit its efficacy. These problems include: (i) graft-versus-host disease (GVHD) in which donor T cells attack the recipient resulting in multi-organ attack and morbidity, (ii) a profound period of immune deficiency following HSCT, and (iii) donor graft rejection. Currently available methods to prevent or treat GVHD with systemic immunosuppression can lead to impaired immune recovery, increased opportunistic infections, and higher relapse rates. This review will provide an overview of GVHD pathophysiology and discuss the roles of various cells, pathways, and factors in the GVHD generation process and in the preservation of graft-versus-tumour effects. Variables that need to be taken into consideration in attempting to extrapolate preclinical results to the clinical paradigm will be highlighted.
Publication
Journal: Translational Research
December/5/2007
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for many malignant and nonmalignant hematologic diseases. Donor T cells from the allografts are critical for the success of this effective therapy. Unfortunately these T cells not only recognize and attack the disease cells/tissues but also the other normal tissues of the recipient as "foreign" or "nonself" and cause severe, immune-mediated toxicity, graft-versus-host disease (GVHD). Several insights into the complex pathophysiology of GVHD have been gained from recent experimental observations, which show that acute GVHD is a consequence of interactions between both the donor and the host innate and adaptive immune systems. These insights have identified a role for a variety of cytokines, chemokines, novel T-cell subsets (naĩve, memory, regulatory, and NKT cells) and for non-T cells of both the donor and the host (antigen presenting cells, delta T cells, B cells, and NK cells) in modulating the induction, severity, and maintenance of acute GVHD. This review will focus on the immunobiology of experimental acute GVHD with an emphasis on the recent observations.
Publication
Journal: Scandinavian Journal of Immunology
June/5/2005
Abstract
Despite improvements in allogeneic stem cell transplantation, acute graft-versus-host disease (GVHD) remains a significant problem after transplantation, and it is still a major cause of post-transplant mortality. Disease progression is characterized by the differentiation of alloreactive T cells to effector cells leading to tissue damage, recruitment of additional inflammatory cell populations and further cytokine dysregulation. To make the complex process of acute GVHD more explicit, the pathophysiology of acute GVHD is often divided into three different phases. This review summarizes the mechanisms involved in the three phases of acute GVHD.