INTRODUCTION — Graft-versus-host disease (GVHD) is the major cause of morbidity and non-relapse mortality in patients after allogeneic hematopoietic cell transplantation (HCT). GVHD refers to multi-organ syndromes of tissue inflammation and/or fibrosis that primarily affect skin, gastrointestinal tract, liver, lungs, and mucosal surfaces. Clinically, GVHD comprises three syndromes, acute GVHD (aGVHD), chronic GVHD (cGVHD), and GVHD overlap syndrome. The various GVHD syndromes are defined by clinical manifestations according to National Institutes of Health consensus criteria [1], rather than the time of onset (ie, before or after day 100 of transplantation, as was used previously). Greater understanding of the underlying pathophysiology is important for more effectively controlling GVHD and improving clinical outcomes with HCT.
This topic will discuss the pathogenesis of aGVHD and cGVHD.
Clinical manifestations, diagnosis, grading, treatment, and prevention of aGVHD and cGVHD are discussed separately. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease" and "Prevention of graft-versus-host disease" and "Treatment of chronic graft-versus-host disease".)
Innate immunity, transplantation immunobiology, and normal B and T lymphocyte development are discussed separately. (See "An overview of the innate immune system" and "Transplantation immunobiology" and "Normal B and T lymphocyte development".)
OVERVIEW OF GVHD — GVHD refers to multi-organ syndromes that can develop after allogeneic hematopoietic cell transplantation (HCT). GVHD arises from one of the principal functions of the immune system: distinguishing between self and non-self. GVHD occurs when immune cells transplanted from a non-identical donor (graft) into the recipient (host) recognize the host cells as "foreign," thereby initiating a graft-versus-host reaction [2,3]. Successful transplantation requires that the donor immune system develop tolerance to these alloantigens, while maintaining the ability to recognize and respond to foreign antigens, such as microorganisms or tumor cells.
GVHD is manifest clinically as three syndromes with different clinical manifestations and temporal courses:
●Acute GVHD (aGVHD) – Characterized by a rapid onset and acute disease course
●Chronic GVHD (cGVHD) – Characterized by a chronic disease course that can involve virtually all organs with variable manifestations, including sclerosis
●GVHD overlap syndrome – Defined by simultaneous features of both cGVHD and aGVHD
Both aGVHD and cGVHD are consequences of the interplay between cellular/immune mediators from the immunological graft with host tissues. Although the two syndromes share some features, they differ with regard to aspects of the underlying pathophysiology, pathology, clinical manifestations, and management. Whereas aGVHD is typically manifest as an inflammatory immune cell infiltrate, including T cells, neutrophils, and monocytes, with tissue destruction, the tissue response in cGVHD is relatively acellular and reveals fibroproliferative findings. Acute GVHD is primarily driven by activation of donor T lymphocytes and release of pro-inflammatory cytokines; by contrast, cGVHD is a more complex and less well-understood syndrome that involves interactions of the innate immune system (macrophages, neutrophils, dendritic cells) with alloreactive and dysregulated B and T cells and non-hematopoietic cells, such as fibroblasts. Further details of the pathophysiologic mechanisms that underlie aGVHD and cGVHD are provided in the sections below. (See 'Acute GVHD' below and 'Chronic GVHD' below.)
It is unclear if the GVHD effect can be separated from the graft-versus-tumor effect.
PATHOPHYSIOLOGY — Greater understanding of the pathophysiology is important for development of new and more effective treatments for GVHD.
Acute GVHD — Acute GVHD (aGVHD) is primarily manifest as a maculopapular rash, weight loss, diarrhea, and/or hepatitis that typically occurs within the first 100 days after transplantation. Clinical manifestations of aGVHD are discussed separately. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Clinical and histological manifestations'.)
Pathologically, aGVHD is apparent as an inflammatory immune cell infiltrate involving T cells, macrophages, monocytes and neutrophil granulocytes with associated tissue destruction and apoptosis. The transplantation conditioning regimen, innate immune system, and gastrointestinal (GI) microbiome all contribute to the pathophysiology of aGVHD [4,5]:
●Conditioning regimen – The transplantation conditioning regimen damages the GI epithelium and leads to translocation of bacteria, fungi, and viruses that initiate inflammation mediated by the innate immune system in cooperation with T and B lymphocytes of the adaptive immune system [6,7]. Macrophages, neutrophils, and dendritic cells mediate this response through Toll-like receptors (TLR) and through nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), which are involved in pathogen recognition via patterns of nucleic acids or sugars [8-11]. Non-pathogen associated molecules such as uric acid, adenosine triphosphate, or IL-33 (so-called damage associated molecular patterns [DAMPs]) also promote aGVHD [12,13]. Cellular components of the innate immune system and TLRs are discussed separately. (See "An overview of the innate immune system" and "Toll-like receptors: Roles in disease and therapy".)
●Inflammatory milieu – A pro-inflammatory milieu activates antigen presenting cells (APC) that prime naïve T cells to Th1 and Th17 differentiation, expand T effector cells, and target host tissues. Scavenger macrophages, plasmacytoid and myeloid dendritic cells, B cells, and neutrophils produce cytokines that enhance antigen presentation and drive differentiation to the Th1 and Th17 effector lineages [6]. Signaling through Janus kinase (JAK)1 and JAK2 and signal transducers and activators of transcription (STAT) contributes to inflammation and tissue damage by neutrophils, dendritic cells, and inflammatory cytokines [14-18]. TLR pathway activation induces transcriptional activation of interferon (IFN) alpha (IFNa) through IFN response factors (IRF 3, IRF 7) and induces tumor necrosis factor (TNF) and interleukin (IL)-6 through nuclear factor kappa B (NFkB) [19-21]. IFNa can drive Th1 commitment and result in IFN gamma (IFNg) production and, together, IFNa and IFNg induce chemokines (eg, CXCL9, CXCL10, CXCL11) that recruit Th1 cells to sites of inflammation and enhance processing and presentation of host antigens [6,22]. Inflammasome complexes catalyze production of IL-1b and IL-18 which, together with IL-6, induce differentiation of Th17 cells, regulate antigen presentation and migration of dendritic cells and lymphocytes, and result in loss of myeloid-derived suppressor cell function [23,24]. Human beta-defensin 2 (hBD-2), an endogenous epithelial cell-derived host-defense peptide, was shown to reduce inflammation in mice developing aGVHD [25].
●Tissue regeneration – Acute GVHD also affects enterocytes, intestinal stem cells (ISC), and Paneth cells and dysregulates tissue-regenerative mechanisms such as intestinal stem cell (ISC) and Paneth cell repair; these effects may enable therapeutic strategies to enhance intestinal cell repair (eg, treatment with IL-22, R-spondin, keratinocyte growth factor, and Glucagon-like peptide 2) [26-29].
Experimental models and clinical experience confirm the importance of innate immunity and TLRs in aGVHD. Deletion or inhibition of TLR or NOD-like receptor pathways significantly reduce aGVHD [30-33]. Furthermore, polymorphisms of proteins that mediate innate immunity are associated with clinical outcomes in HCT [34]. As an example, NOD2/CARD15 is an intracellular sensor of muramyl dipeptide (a component of the bacterial cell wall) that is expressed by intestinal epithelial cells and cells of monocyte/macrophage lineage and mediates activation of NFkB. In a study of 169 consecutive patients receiving transplants from related or unrelated donors, polymorphisms of NOD2/CARD15 were found in 21 percent of recipients and 14 percent of donors [34]. The cumulative incidence of one-year transplant-related mortality rose from 20 percent in donor/recipient pairs without single nucleotide polymorphisms, to 49 percent in pairs with recipient mutations, 59 percent in pairs with donor mutations, and 83 percent in 12 pairs with mutated alleles in both donor and recipient.
Observational studies suggest that the diversity and composition of the GI microbiome (ie, intestinal bacteria) plays a role in the development of GVHD involving the lower GI tract, as discussed in more detail separately.
Chronic GVHD — Chronic GVHD (cGVHD) is manifest as fibrosis and chronic inflammation of skin, lungs, GI tract, and soft tissues that generally presents ≥100 days after transplantation. Clinical aspects of cGVHD are discussed separately. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Clinical manifestations'.)
Pathologically, tissues affected by cGVHD are relatively acellular and fibroproliferative. Development of cGVHD is a complex, multi-phase process that involves various cell lineages and types of injury [6,19,35]. In cGVHD, early inflammation results from the conditioning regimen and activation of donor T cells. Injury of vascular endothelial cells (EC) facilitates migration of donor immune cells into target organs. Donor-derived effector T lymphocytes, B lymphocytes, and APCs mount an immune response against host tissues. Immune tolerance is affected by depletion of regulatory T cells (Treg) and their functional suppression by calcineurin inhibitors [36], along with thymic injury/dysfunction [37]. Aberrant repair mechanisms foster activation of fibroblasts, collagen deposition, and fibrosis that lead to irreversible end-organ injury and dysfunction.
Experimental studies support a three-phase model of cGVHD [6]:
●Early inflammation and tissue injury – Early inflammation and tissue injury in cGVHD is initiated and sustained by the innate immune system. The cellular components (ie, macrophages, neutrophils, dendritic cells, and B cells), signaling mechanisms (eg, TLR and NOD-like pathways), and mediators (eg, cytokines) of cGVHD resemble the mechanisms that underlie aGVHD [6], as described above. (See 'Acute GVHD' above.)
Activation and injury of ECs contribute to early inflammation in cGVHD [6]. ECs function as a barrier between donor and recipient tissues and they are the first host cells encountered by the transplanted donor immune system. EC injury and early inflammation may be caused by irradiation, lipopolysaccharide, TNFa, and cytotoxic lymphocytes.
Mature donor T cells infused with the transplanted host graft also contribute to inflammation. Depletion of T cells in vivo or short courses of cyclophosphamide reduce the incidence and severity of cGVHD, which supports this observation [6]. Activation and clonal expansion of donor T cells into Th2 and Th17 functional subsets produces inflammatory cytokines and cytolytic enzymes that contribute to the early inflammation of cGVHD. Mobilization of peripheral blood stem cells with granulocyte colony-stimulating factor (G-CSF) also promotes Th17 differentiation [38].
●Chronic inflammation and tissue injury – Donor- and/or host-derived immune regulatory responses are not sufficient to control the early inflammation, which results in chronic inflammation and dysregulated immunity [6]. Tregs are important for immune homeostasis and immune tolerance, and dysregulated Tregs contribute to sustained inflammation in cGVHD, although the underlying mechanisms are poorly defined [6,39,40]. Effects of early inflammation on the thymus may also contribute to a lack of immune tolerance and sustained inflammation in cGVHD [41]. Disordered immune suppression by type 1 regulatory T cells (Tr1), myeloid-derived suppressor cells, and other cell types also contribute to persistent inflammation [42-44].
Diminished immune regulatory functions of B cells and natural killer (NK) cells also contribute to chronic inflammation. Detection of autoantibodies against minor histocompatibility antigens, antinuclear antibodies (ANA), anti-double-stranded DNA indicate a loss of B cell tolerance [45]. NK cells are cytotoxic lymphocytes that express killer-cell immunoglobulin-like receptors (KIR), which can detect major histocompatibility complex (MHC) on the cell surface, trigger cytokine release, and cause lysis or apoptosis of target cells. KIR haplotypes can be activating or inhibitory. (See "An overview of the innate immune system", section on 'Natural killer cells'.)
●Aberrant tissue repair and fibrosis – Dysregulated immunity and aberrant tissue repair contribute to scarring and fibrosis in cGVHD [6]. Early EC damage activates coagulation pathways that release chemotactic factors, and macrophages are a source of transforming growth factor (TGF) beta (TGFb), TNFa, IL-1b, platelet-derived growth factor (PDGF), and matric metalloproteinases, with an ensuing cascade of fibrosis [46]. IL-22 may also contribute to cutaneous manifestations of cGVHD [47]. Fibroblasts contribute to extracellular matrix production and collagen deposition.
Adaptive immunity also contributes to tissue injury and scarring. Activated Th2 and Th17 T cells promote fibrosis by secretion of IL-13 and IL-17, respectively [6]. B cell activation contributes auto- and allo-antibody production which, in concert with colony-stimulating factor 1 (CSF-1), further activate monocytes and macrophages to release TGFb, which activates myofibroblasts and collagen production leading to further tissue scarring and fibrosis [48].
CONTRIBUTING FACTORS
Histocompatibility — GVHD arises when immune cells transplanted from a non-identical graft recognize cells in the host as foreign. The major histocompatibility complex (MHC) provides the crucial surface upon which foreign antigens are displayed for immune recognition by T lymphocytes. Minor antigens also contribute to tissue histocompatibility. The MHC and mechanisms of allorecognition are discussed separately. (See "Transplantation immunobiology".)
MHC/HLA antigens — In humans, MHC molecules are called human leukocyte antigens (HLA). HLA is highly polymorphic from individual to individual and segregates in families in a Mendelian codominant fashion. (See "Transplantation immunobiology", section on 'Major histocompatibility complex structure and function'.)
In allogeneic hematopoietic cell transplantation (HCT), the principal antigenic targets of the T cells of the graft are host MHC molecules. The genes of the HLA locus encode two distinct classes of cell surface molecules, class I and class II. There are three different class I (HLA-A, -B, -C) and class II (HLA-DQ, -DR, -DP) antigens. HLA-A, -B and -DR antigens appear to be the most important loci for determining whether transplanted cells initiate a graft-versus-host reaction [49]. Class I molecules are expressed on the surfaces of virtually all nucleated cells at varying densities, while class II molecules are more restricted to cells of the immune system, primarily B lymphocytes and monocytes. However, cytokines secreted by lymphocytes and monocytes during immune activation may cause dramatic increases in class II HLA antigen expression, even on cell types that normally have little or no surface expression. (See "Human leukocyte antigens (HLA): A roadmap".)
Antigen-presenting cells, such as macrophages, present a complex of an MHC molecule bearing a small peptide fragment to a lymphocyte, which expresses a single T cell receptor (TCR). Class II molecules display antigenic peptide fragments to CD4-positive inducer (helper) T cells. Class I molecules function at the effector phase of immunity by presenting antigens to CD8-positive T cells, which generally have cytotoxic/suppressor function. (See "Transplantation immunobiology".)
The role of MHC/HLA in selection of a donor for HCT is discussed separately. (See "Donor selection for hematopoietic cell transplantation".)
Minor histocompatibility antigens — GVHD can develop even with grafts that are fully matched at the MHC/HLA loci due to mismatching of other antigens, termed minor histocompatibility antigens (miH).
Minor antigens (miH) are presented in the context of MHC. Because the manner in which a particular protein is processed is dependent upon genes outside of the MHC, two siblings, despite having identical MHC molecules, will have different peptides in the MHC groove [50,51]. MHC class I-related chain A (MICA) and killer-cell immunoglobulin-like receptor (KIR) are examples of miH that can cause rejection. Other specific proteins that account for miH in humans are poorly defined. (See "Transplantation immunobiology", section on 'Minor transplantation antigens'.)
Histocompatibility antigen matching — HLA can be matched serologically or using genetic-based testing, as discussed separately. (See "Human leukocyte antigens (HLA): A roadmap".)
Tissue microenvironment — Cells, cytokines, and signaling pathways of the tissue microenvironment contribute to GVHD and the graft-versus-leukemia (GVL) effect.
As an example, Notch signaling, which orchestrates cell fate and differentiation, is critical in both acute and chronic GVHD. Notch inhibition results in blockade of multiple cytokines, expansion of T regs and decrease in pathogenic T cells without decreasing GVL [52]. Similarly, T follicular helper cells in germinal centers of secondary lymphoid organs contribute to development of GVHD [53].
Clinical factors — A number of clinical variables are associated with the development of GVHD and may influence the underlying pathophysiology [6]. Factors that relate to clinical features of the recipient and the donor are discussed separately. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Risk factors' and "Donor selection for hematopoietic cell transplantation".)
Clinical factors that contribute to GVHD include:
●Donor type (ie, matched related, matched unrelated, haploidentical)
●Source (peripheral blood, bone marrow, umbilical cord)
●Sex-mismatch
●Age of donor and recipient
●Conditioning regimen intensity
●Underlying malignancy (eg, myelodysplastic syndrome, acute or chronic myeloid or lymphoid leukemia)
●T cell depletion in vivo (eg, anti-thymocyte globulins, alemtuzumab)
●Post-transplantation cyclophosphamide
●Infection history (eg, CMV, EBV)
The roles of these factors in selection of a HCT donor are discussed separately. (See "Donor selection for hematopoietic cell transplantation", section on 'Effect of donor characteristics'.)
Microbiome — The composition of gastrointestinal microbiota has been associated with outcomes in patients who undergo allogeneic HCT. However, it is not clear that this is a causal relationship or if it is possible to manipulate the intestinal microbiome to influence outcomes.
An increase of potentially pathogenic bacteria and loss of diversity in the number of bacterial taxa is commonly found in patients undergoing allogeneic HCT [54-57]. A large international study reported that higher diversity of intestinal microbiota was associated with lower mortality, lower rates of transplant-related death, and fewer deaths attributable to GVHD [58]. The study profiled 8767 fecal samples from 1362 patients at four institutions and used 16S ribosomal RNA sequence to stratify patients into higher-diversity (HD) and lower-diversity (LD) groups. In a preliminary study at one of the institutions, compared with LD patients, patients with HD had a hazard ratio (HR) for death of 0.71 (95% CI 0.55-0.92); analysis from three other institutions reported the HR for death was 0.49 (95% CI 0.27-0.90). Samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was also associated with poor survival. Single-institution studies have reported similar associations between diversity of intestinal microbiota and transplantation outcomes [59-61].
SUMMARY
●Description – Graft-versus-host disease (GVHD) is the major source of non-relapse morbidity and mortality in patients who undergo allogeneic hematopoietic cell transplantation (HCT). GVHD refers to multi-organ syndromes of tissue inflammation and/or fibrosis that primarily affect skin, gastrointestinal tract, liver, lungs, and mucosal surfaces. Greater understanding of the pathophysiology of GVHD is important for development of new and more effective treatments.
●Overview – GVHD arises when immune cells transplanted from a non-identical donor (graft) into the recipient (host) recognize the host cells as "foreign," thereby initiating a graft-versus-host reaction. GVHD is manifest clinically as three syndromes that are generally defined by their clinical manifestation (see 'Overview of GVHD' above):
GVHD comprises three syndromes:
•Acute GVHD (aGVHD) – Characterized by a rapid onset and acute disease course
•Chronic GVHD (cGVHD) – Characterized by a chronic disease course that can involve virtually all organs with variable manifestations, including sclerosis
•GVHD overlap syndrome – Defined by simultaneous features of both cGVHD and aGVHD
●Acute GVHD – Pathologically, aGVHD is manifest as an inflammatory immune cell infiltrate involving T cells, macrophages, monocytes and neutrophil granulocytes with associated tissue destruction and apoptosis. The transplantation conditioning regimen, innate immune system, impaired tissue repair mechanisms, and gastrointestinal microbiome all contribute to the pathophysiology of aGVHD. (See 'Acute GVHD' above.)
●Chronic GVHD – Tissues affected by cGVHD are relatively acellular and fibroproliferative. The pathogenesis of cGVHD is a complex process that involves early inflammation and tissue injury, chronic inflammation and dysregulated immunity, and aberrant tissue repair and fibrosis. Description of the cellular components and signaling pathways the mediate cGVHD are discussed above. (See 'Chronic GVHD' above.)
●Histocompatibility antigens – Proteins of the major histocompatibility complex (MHC) are the principal antigenic determinants of graft rejection; in humans, MHC proteins are called human leukocyte antigens (HLA). Genes of the HLA locus encode two distinct classes of cell surface molecules, class I and class II, which are expressed by different cell types, are highly polymorphic from individual to individual, and provide the surface upon which foreign antigens are displayed for immune recognition by T lymphocytes. (See 'MHC/HLA antigens' above.)
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