Overview of the immune biology of allogeneic hematopoietic stem cell transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 6

matched sibling donors [27] (including both randomized IL-1 and KGF tri-
als). Because the mechanisms associated with acute (late onset) GVHD after
reduced (eventually minimal) conditioning have not been well elucidated,
additional studies are warranted that go back to the bench to develop the
so-called “mini transplant” in the mouse setting that may complement the
aforementioned canine investigations.

T-cell activation and costimulation

The core of the graft-versus-host immune reaction lies within the second
step, in which donor T cells proliferate and differentiate in response to host
APCs [28,29] (reviewed in chapter 9). Recent advances have indicated the
presence of a subset of post-mitotic, self-renewing CD44 (lo)/CD62L (hi)/
CD8 + T cells that can generate and sustain all allogeneic T-cell subsets in
GVHD reactions, including central memory, effector memory and effector
CD8 + T cells [30] . The danger signals generated in the first phase augment
this activation, at least in part, by increasing expression of costimulatory
molecules. In mouse models, in which genetic differences between donor
and recipient strains can be tightly controlled, CD4 + T cells induce acute
GVHD to MHC class II differences and CD8 + T cells induce acute disease to
MHC class I differences [29,31-38] . Under typical bone marrow transplan-
tation (BMT) conditions, murine studies with MiHA-disparate models
have demonstrated that GVHD initiation requires donor T-cell recognition
of host antigen in the context of host APCs [29,31-38] . Donor-derived APCs
are then able to augment CD8 + T-cell-mediated GVHD by acquiring and
presenting host antigens [34] .

6

In humans, the incidence of acute GVHD is directly related to the degree
of mismatch between HLA determinants [39] , mapped by high-resolution
DNA typing of HLA genes with PCR-based techniques, largely replacing
earlier cellular methods (reviewed in chapter 2). However, recipients of
HLA-identical grafts can still develop systemic acute GVHD due to genetic
differences that lie outside the MHC loci and that encode proteins referred
to as MiHAs (reviewed in chapter 3). Thus, there is strong evidence for
MiHA-mismatch mediated GVHD in humans [40-42] . Although individ-
ual human MiHA antigens associated with GVHD have been identified,
the relative contribution of diverse MiHA and the existence (if any) of
single, dominant MiHAs in humans (such as B6dom and H60 that have
been well characterized in rodents [43,44] ) is unknown. With respect to
the donor-versus-host origin of APCs initiating GVHD in humans, little
data are available. However, recent studies on the fate of human Lang-
erhans cells, dermal dendritic cell and macrophages in patients suggest
that host-derived APCs at least participate to the early stage of the disease
[45-47] . Donor and recipient polymorphisms of cytokine genes ascribed
to the cytokine storm in rodents and humans have also been implicated
as risk factors for the disorder. For example, TNF-α, IL-10 and INF-γ vari-
ants have correlated with GVHD in some, but not all, studies (reviewed in
reference [48] and in chapter 16). Genetic polymorphisms of proteins con-
nected with innate immunity, such as NOD2, have been associated with
acute GVHD in patients [49] . Lastly, in some experimental models, poly-
morphisms in members of the Toll-like receptor family have been linked
to GVHD risk [50] .