Overview of the immune biology of allogeneic hematopoietic stem cell transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 5

partially based on genetic features of the underlying disease will likely come
of age (reviewed in reference [8] ).

GVHD pathophysiology

GVHD is a complex disease resulting from donor T-cell recognition of a
genetically disparate recipient that is unable to reject donor cells follow-
ing allogeneic HSCT. The classical scheme of GVHD [2,6,9] development
includes five basic steps:

Step 1: Priming of the immune response. Cytoreductive conditioning
induces tissue damage and the release of a storm of proinflammatory
cytokines that promote the activation and maturation of antigen-pre-
senting cells (APCs) and the rapid amplification of donor T cells [10-12] .
Step 2: T-cell activation and costimulation. Activation occurs as the re-
sult of the recognition and interaction of the TCR and costimulatory mol-
ecules with their cognate ligands expressed on the surface of the APC.
Step 3: Alloreactive T-cell expansion and differentiation.
Step 4: Activated T-cell trafficking. Activated T-cell migration to GVHD
target tissues (gut, liver, skin and lung) is followed by the recruitment of
other effector leukocytes [13] .
Step 5: Destruction of the target tissues by effector T cells. Destruction
occurs via exposure to cell surface and release of soluble immune effec-
tor molecules. Tissue damage then leads to increased inflammatory sig-
nals, perpetuating and augmenting the disease process by contributing
to the cytokine storm that fuels GVHD.

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Previous reviews [2,6,9,10,13-15] and chapters in this topic have detailed
these phases of GVHD initiation and tissue destruction.

Priming of the immune response

The earliest phase of acute GVHD is set into motion by the damage caused
by the underlying disease and exacerbated by conditioning regimens
(reviewed in chapter 8). Damaged host tissues secrete proinflammatory
cytokines, such as TNF-α and IL-1, which contribute to the “cytokine
storm” increasing the expression of adhesion molecules, costimula-
tory molecules, MHC antigens and chemokine gradients that alert the
residual host and the infused donor immune cells. These “danger sig-
nals” activate host tissue cells including APCs. Damage to the GI tract
from the conditioning is particularly important in this process, because
it allows for systemic translocation of lipopolysaccharide that further
enhances host APC activation [9,16] . This scenario is in accord with the
increased GVHD risk associated with intensive conditioning regimens in
some human randomized trials [17-19] . However, preclinical studies in
dogs [1,3,20-22] and clinical studies have indicated that reduced inten-
sity conditioning is associated with less morbidity and less early acute
GVHD [23] .

It is noticeable that IL-1 blockade [24] or protection of epithelial tissue dam-
age by infusion of keratinocyte growth factor, although partially efficacious
in some experimental GVHD models [25,26] , thus far have proved ineffec-
tive in preventing acute GVHD in randomized human trials performed in