12/10/2020 Pathogenesis of graft-versus-host disease (GVHD) - UpToDate

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Pathogenesis of graft-versus-host disease (GVHD)

Author: Nelson J Chao, MD
Section Editor: Robert S Negrin, MD
Deputy Editor: Alan G Rosmarin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2020. | This topic last updated: Apr 23, 2020.

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 is described as
acute GVHD (aGVHD) within 100 days after HCT or chronic GVHD (cGVHD) after 100 days, but
these syndromes may overlap in time.

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, diagnosis, and grading of chronic graft-
versus-host disease" and "Prevention of acute graft-versus-host disease" and "Treatment of
chronic graft-versus-host disease".)

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 [1]. Successful
transplantation requires that the donor immune system develop tolerance to these
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alloantigens, while maintaining the ability to recognize and respond to foreign antigens,
such as microorganisms or tumor cells.

GVHD is manifest clinically as two syndromes that are generally defined temporally:

● Acute GVHD (aGVHD) – Clinical findings develop ≤100 days after HCT

● Chronic GVHD (cGVHD) – Clinical findings develop >100 days after HCT

Both aGVHD and cGVHD are consequences of the interplay between cellular/immune
mediators from the 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. As an example, aGVHD is typically manifest as an
inflammatory T cell infiltrate with tissue destruction. In contrast, the tissue response in
cGVHD is relatively acellular with fibroproliferative findings. Whereas aGVHD is primarily
driven by activation of donor T lymphocytes and release of pro-inflammatory cytokines,
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. Details of the pathophysiologic mechanisms that underlie aGVHD
and cGVHD are provided in the sections below. It remains unclear if the GVHD effect can be
separated from the graft-versus-tumor effect. (See "Biology of the graft-versus-tumor effect
following hematopoietic cell transplantation", section on 'Possible separation of GVT from
GVHD'.)

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".)

Clinical manifestations, pathology, grading of severity, and management of aGVHD and

cGVHD are discussed separately. (See "Clinical manifestations, diagnosis, and grading of
acute graft-versus-host disease" and "Clinical manifestations, diagnosis, and grading of
chronic graft-versus-host disease" and "Treatment of acute graft-versus-host disease" and
"Treatment of chronic graft-versus-host disease".)

PATHOPHYSIOLOGY

Greater understanding of the pathophysiology of GVHD is important for development of new

and more effective treatments.

Acute GVHD — Acute GVHD (aGVHD) is primarily manifest as a maculopapular rash, weight

loss, diarrhea, and/or hepatitis within 100 days of 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'.)
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Pathologically, aGVHD is apparent as an inflammatory T cell infiltrate with associated tissue

destruction and apoptosis. The transplantation conditioning regimen, innate immune
system, and gastrointestinal (GI) microbiome all contribute to the pathophysiology of aGVHD
[2,3]. The conditioning regimen damages the GI epithelium and leads to translocation of
bacteria, which initiates inflammation mediated by the innate immune system in cooperation
with T and B lymphocytes of the adaptive immune system [4]. Macrophages, neutrophils, and
dendritic cells mediate this response through Toll-like receptors (TLR), which are involved in
pathogen recognition via patterns of nucleic acids or sugars [5-8]. 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".)

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 [4]. 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 [9-13]. 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) [14-16]. 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 [4,17]. 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 [18].

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
reduces aGVHD [19-22]. The clinical relevance of TLRs to GVHD pathophysiology is reinforced
by the observation that clinical outcomes in HCT are affected by polymorphisms of proteins
that mediate innate immunity [23]. 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, which 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 [23]. 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.
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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. (See "Prevention of acute graft-versus-host disease",
section on 'Antibiotics'.)

Chronic GVHD — Chronic GVHD (cGVHD) is manifest as fibrosis of skin, lungs, GI tract, and
soft tissues that generally presents at least 100 days after transplantation. Clinical aspects of
cGVHD are discussed separately. (See "Clinical manifestations, diagnosis, and grading of
chronic graft-versus-host disease", section on 'Clinical and histologic features'.)

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 [4,14,24]. The immune response in cGVHD is more complex than the
mechanisms that underlie aGVHD. 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, along with thymic injury/dysfunction. 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 [4]:

● 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 [4], as described above. (See 'Acute GVHD' above.)

Activation and injury of ECs contribute to early inflammation in cGVHD [4]. 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 [4]. 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

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of cGVHD. Mobilization of peripheral blood stem cells with granulocyte colony-

stimulating factor (G-CSF) also promotes Th17 differentiation [25].

● 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 [4]. 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
[4,26,27]. Effects of early inflammation on the thymus may also contribute to a lack of
immune tolerance and sustained inflammation in cGVHD [28]. Disordered immune
suppression by type 1 regulatory T cells (Tr1), myeloid-derived suppressor cells, and
other cell types also contribute to persistent inflammation [29-31].

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 [32]. 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 (NK) cells'.)

● Aberrant tissue repair and fibrosis – Dysregulated immunity and aberrant tissue repair
contribute to scarring and fibrosis in cGVHD [4]. 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 [33]. IL-22
may also contribute to cutaneous manifestations of cGVHD [34]. 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 [4]. 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 [35].

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)

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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 [36]. 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
[37,38]. 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

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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".)

Clinical factors — A number of clinical variables are associated with the development of
GVHD and may influence the underlying pathophysiology [4]. 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 [39-42]. 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
[43]. The study profiled 8767 fecal samples from 1362 patients at four institutions and used
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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 [44-46].

SUMMARY

● 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.

● 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 two syndromes that are generally defined
temporally (see 'Overview of GVHD' above):

• Acute GVHD (aGVHD) – Clinical findings develop ≤100 days after HCT

• Chronic GVHD (cGVHD) – Clinical findings develop >100 days after HCT

● Pathologically, aGVHD is manifest as an inflammatory T cell infiltrate with associated

tissue destruction and apoptosis. The transplantation conditioning regimen, innate
immune system, and gastrointestinal microbiome all contribute to the pathophysiology
of aGVHD. (See 'Acute GVHD' above.)

Cells of the innate immune system (eg, macrophages, dendritic cells, neutrophils, natural
killer [NK] cells) produce inflammatory cytokines that enhance antigen presentation and
promote differentiation of T and B lymphocytes.  

● 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.)  

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● 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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