The impact of minor histocompatibility antigens in allogeneic stem cell transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 45

conditions [45] . Recently, the first hematopoietic mHag presented by HLA
class II molecules has also been identified as a polymorphic peptide on the
B-cell lineage-specific molecule CD19 [46] . This was followed by the identi-
fication of HLA DRB13 restricted LB-LY75-1K [49] .

Besides these genuine hematopoietic mHags, a number of mHags encoded
by broadly expressed genes (ADIR, ECGF-1, CTSH, P14K2B) seems to have
a preferential functional expression in activated hematopoietic cells and
malignant cells, since T cells directed against these mHags do not recog-
nize resting hematopoietic cells and non-hematopoietic cells in in vitro
assays [84-87] . The therapeutic value of such mHags is, however, disputed
and awaits further confirmation. It may be appropriate to be reticent on
this issue because in the first mHag-based clinical trial, adoptive transfer of
mHag-specific CTLs selected on the basis of recognition of recipient hema-
topoietic cells, but not skin fibroblasts, was still associated with lung toxici-
ties and GVHD in a number of patients [88] .

Immunotherapeutic targeting of hematopoietic
mHags
mHags versus tumor-associated antigens

46

From the point of view of specific immunotherapy, targeting donor T cells
toward tumor-associated antigens (TAAs) seems, at first thought, a more
straightforward approach than targeting hematopoietic mHags. However, the
advantageous power of mHags in the GVT response resides in the fact that they
are allo-, thus foreign, antigens for the donor immune system, while many
TAAs are over-expressed self-antigens [89] . Consequently, while TAA-specific
T-cell responses are subjected to regulation by self-tolerance mechanisms,
the mHag-specific T-cell responses are not. Therefore, mHags are expected
to induce more potent responses as compared to TAAs. Another reason for
the relatively potent immunogenicity of mHags is their mode of presenta-
tion: mHags are usually expressed by professional host dendritic cells (DCs)
that can readily prime mHag-specific CTLs without the need for trafficking
into the tumor site. In contrast, priming of TAA-specific CTLs usually requires
cross-presentation by DCs that need to sample and present tumor antigens in
the relatively immunosuppressive microenvironment of tumors [90,91] .

mHag-based immunotherapy strategies

Although the concept of mHag-based immunotherapy was put forward in the
early 1990s [78] , the development and clinical implementation of mHag-based
immunotherapy started several years later, on the heels of the availability of
the necessary tools, i.e. mHag peptides, mHag genes and mHag-specific TCRs.

Currently, there are two distinct strategies to exploit mHags in the therapeu-
tical setting ( Box 3.1 ):
1. Adoptive immunotherapy with ex vivo generated mHag-specific CTLs, and
2. Therapeutical mHag vaccination of recipients, either in a preemptive
setting or simultaneously with a donor lymphocyte infusion in non-
responder patients. Below, the main advantages and drawbacks of both
strategies will be outlined briefly.