Biology Reference
In-Depth Information
CTLs from mHag-vaccinated donors. Although both options are extremely
difficult to explore in the human setting, these murine studies are challenging
and demonstrate new possibilities for improving mHag-specific therapies.
Immunobiology and biochemical identity of mHags
The first illustrative example of a long list of in vitro experimental studies with
human mHag-specific T cells is the detailed functional characterization of
mHag-specific CTLs isolated from a female patient who rejected the trans-
plant from an HLA-identical brother [10] . This study demonstrated for the
first time the existence of male-specific (HY) mHags in humans and suggested
their involvement in graft rejection. Subsequently, CTLs directed against an
autosomal mHag were successfully isolated from a male patient who devel-
oped GVHD after receiving a graft from an HLA identical sister [18] . This was
the first study demonstrating the possibility of isolating mHag-specific CTLs
by propagating the post-SCT PBMC with patient's pretransplant lymphocytes.
Using similar techniques several investigators also succeeded in isolating
mHag-specific T cells from allo-SCT recipients [19-26] . These T cells were used
as cellular tools to demonstrate the existence of many other Y-gene-linked, or
autosomal, mHags. In all cases, mHags appeared to be immunogenic only in
the context of a certain HLA molecule, displayed low-polymorphism, were
inherited in a Mendelian trait but independent of the HLA alleles [10,18-26] .
41
Together with the growing body of evidence indicating the importance
of mHags in allo-SCT (see below), unraveling the biochemical nature of
mHags became a major goal. Through molecular sequencing of mitochon-
drial genes from mHag-disparate mouse strains, Lindahl et al. were the
first to uncover the molecular identity of the murine mitochondrial mHag
MTF [27] . This was rapidly followed by Rammensee et al., who uncovered
the molecular identity of three other murine mHags through biochemical
fractionation and analysis of enzymatic cleavage products of mHag-posi-
tive cell lysates or of peptides eluted from MHC molecules [28,29] . Subse-
quently, the peptide elution technology from surface MHC molecules has
been employed for the identification of the first series of human mHags [30-
32] . These pioneering studies have revealed that both murine and human
mHags are MHC-bound polymorphic peptides present in the recipient but
not in the donor and are thus recognized as foreign antigens by donor T
cells. The mHag peptides are derived from intercellular proteins that dis-
play sequence differences between related and unrelated individuals due
to (low) genetic polymorphism in the encoding genes. This fundamental
feature has been subsequently confirmed by the molecular identification of
several other mHags recognized by CD4 + and CD8 + T cells [15,33-51] .
Mechanisms of generation of mHags
The molecular identification of mHags also revealed the essential rules for
the generation of mHags: for all autosomal mHags identified so far, the
immunogenic mHag peptide and its non-immunogenic counterpart dis-
play a single amino acid (aa) difference, due to a non-synonymous single
nucleotide polymorphism (nsSNP) in the genome. The single aa difference
gives rise to mHag disparities through various mechanisms. For a number
 
Search WWH ::




Custom Search