Immunobiology of acute graft-versus-host disease

doi:10.1016/S0268-960X(03)00009-2

Blood Reviews

Volume 17, Issue 4, December 2003, Pages 187-194

https://doi.org/10.1016/S0268-960X(03)00009-2 Get rights and content

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-α 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-γ enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses, and prime additional mononuclear phagocytes to produce TNF-α 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.

Introduction

Allogeneic bone marrow transplantation (BMT) is an important curative therapy for a number of hematologic diseases. Unfortunately its utility is limited by acute graft-versus-host disease (GVHD), the most major complication of allogeneic BMT.¹ Acute GVHD occurs when donor T cells react to host antigens on antigen-presenting cells (APCs) with sequential activation of donor T cells and monocytes/macrophages causing target organ damage that we recognize as clinical acute GVHD. This report will focus on the complex immunobiology of T cells, antigen presenting cells, NK cells, and cytokines as they relate to the pathophysiology of acute GVHD. Acute GVHD pathophysiology can be conceptualized in three sequential phases: (1) effects of conditioning, (2) donor T-cell activation that constitute the afferent phase, and (3) efferent effector phase.[2], [3]

Section snippets

Phase 1: Effects of conditioning

The first step involves the transplant conditioning regimen, which includes total body irradiation (TBI) and/or chemotherapy. Donor T cells are infused into a host that has been profoundly damaged by underlying disease, infection, and conditioning, all of which result in activation of host cells with secretion of proinflammatory cytokines, such as TNF-α and IL-1.⁴ The presence of inflammatory cytokines during this phase may increase expression of adhesion molecules, costimulatory molecules, and

Phase 2: T-cell activation

GVHD fundamentally depends on donor T cells interaction with host antigen-presenting-cells and their subsequent activation, proliferation, and differentiation. This process occurs during the second step of the afferent phase of acute GVHD. The central role of host APC has recently been established by elegant murine studies which demonstrated those hosts APCs alone are sufficient to activate donor T cells.¹² Although alloantigen can be presented directly by host-derived and indirectly by

Phase 3: Cellular and inflammatory effector phase

The efferent phase of acute GVHD is a complex cascade of multiple effectors mediated by cellular effectors such as CTLs and NK cells, and inflammatory effectors such as TNF-α, IL-1 and NO.³³

Research agenda

•
The relative contribution of host professional (dendritic cells) and semiprofessional (monocyte/macrophages and B cells) APCs in the induction of acute GVHD and GVL.
•
The relevance of the timing, induction and the impact of conditioning on Th1/Th2 secretion by donor T cells on the outcome of acute GVHD.
•
The mechanisms of regulatory T cells in the separation of GVHD from GVL responses.
•
The role of resident APCs and chemokines in defining the target organ distribution of acute GVHD.
•
The role of

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Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vascular endothelial cells are entirely exposed and damaged during the pathogenesis of acute GVHD (aGVHD). Defibrotide (DF) is a mixture of single-stranded oligonucleotides that has several pharmacologic effects that contribute to its endothelial protective properties. B10.BR mice were conditioned, followed by the infusion of donor C57BL/6J T cell-depleted bone marrow cells with or without splenocytes. The mice were either treated with DF or appropriate controls daily for the first week and then 3 times per week thereafter. Allogeneic DF-treated recipients demonstrated significantly better survival with reduced clinical GVHD. Significantly reduced organ pathology in the gut was associated with significantly decreased T cell infiltration in the ileum and colon on day +28. Serum cytokine analysis revealed significantly reduced levels of TNF and IL-6 at day +7 and of TNF at day +28 in allogeneic DF-treated recipients. Significantly reduced levels of ICAM-1 and angiopoietin-2 in serum and reduced VCAM-1 and HCAM levels in the ileum and colon of allogeneic DF-treated recipients were observed. Improved survival was seen in the graft-versus-leukemia (GVL) model (C3H.SW into C57BL/6J mice with C1498-luc). Through its anti-inflammatory and endothelial protective effects, DF treatment reduces the severity of aGVHD while not impairing GVL activity.
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic modality commonly used to treat hematological and immunological disorders. Among the main complications of allo-HSCT is the acute graft-versus-host disease (a-GVHD), a condition which accounts for a high incidence of mortality. Several genes encoding inflammatory mediators may present polymorphisms, which have been implicated in the risk of developing a-GVHD. In our study, we investigated the association between genotypes of cytokine-encoding genes and the incidence and severity of a-GVHD and survival of HSCT recipients. No statistically significant association was found between IL and 6-174 G/C, INF-γ + 874 T/A, TNF-α -238 A/G, -308 A/G and IL-10-819C/T, -592 A/C polymorphisms and the presence or severity of a-GVHD. A higher risk of a-GVHD was associated with the IL-10-1082 GG genotype compared to the AA + AG genotypes of recipients and donors. The IL-10-1082 genotype can be used as a prognostic determinant to predict which HSCT recipient will be more responsive to the transplant. Thus, cytokine gene assays may be useful in the individualization of prophylactic regimens and for an appropriate selection of immunosuppressants based on the HSCT recipient’s responsiveness.
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Immunobiology of acute graft-versus-host disease

Abstract

Introduction

Section snippets

Phase 1: Effects of conditioning

Phase 2: T-cell activation

Phase 3: Cellular and inflammatory effector phase

Research agenda

Exp. Hematol.

Blood

Blood

Semin. Hematol.

Curr. Opin. Immunol.

Cell

Curr. Opin. Cell. Biol.

Blood

Blood

Blood

Blood

Blood

Blood

Transpl. Proc.

Blood

Blood

Immunity

Immunity

Immunity

Blood

Biol. Blood Marrow Transpl.

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Graft versus host disease

N. Engl. J. Med.

Effects of interferon-γ and tumor necrosis factor-α on the expression of an Ia antigen on a murine macrophage cell line

J. Immunol.

Can graft endothelial cells initiate a host anit-graft immune response

Transplantation

The danger model: a renewed sense of self

Science

Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: randomized trial of two irradiation regimens

Blood

Viral infections and graft-vs.-host disease

Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice

Science

Acute graft-versus-host disease does not require alloantigen expression on host epithelium

Nat. Med.

Prevention of graft versus host disease by inactivation of host antigen-presenting cells

Science

The instructive role of dendritic cells on T-cell responses

Arthritis Res.

The immunological synapse

Annu. Rev. Immunol.

Role of adhesion molecules in activation signaling in T lymphocytes

J. Clin. Immunol.

Pathophysiology of human GVHD

T cell subsets in graft-vs.-host disease

Cytokine dysregulation in acute graft-versus-host disease

Hematology

Critical role of interleukin-2 in the development of acute graft-versus-host disease

Int. Immunol.

Lethal murine graft-versus-host disease in the absence of detectable cytotoxic T lymphocytes

Transplantation

Host-specific interleukin-2-secreting donor T-cell precursors as predictors of acute graft-versus-host disease in bone marrow transplantation between HLA-identical siblings

N. Engl. J. Med.