By Heather M. Gilbert, MD and Josef T. Prchal, MD
2009-01-01
Drs. Gilbert and Prchal indicated no relevant conflicts of interest.
Spaapen RM, Lokhorst HM, van den Oudenalder K, et al. Toward
targeting B-cell cancers with CD4+ CTLs: identification of a
CD19-encoded minor histocompatibility antigen using a novel genome-wide
analysis. J Exp Med. 2008;205:2863-72.
Minor histocompatibility antigens (mHAgs) are formed by polymorphic
peptides located in the helical grooves of the major histocompatibility
complex (MHC) molecules. These mHAgs are recognized by T-lymphocyte
clones and provoke T-cell immune responses, thus playing an important
clinical role in mediating both the graft-versus-host disease and
graft-versus-leukemia effects of allogeneic hematopoietic stem cell
transplantation. Although they can be expressed ubiquitously on tissues
throughout the body, several recently discovered mHAgs are expressed
selectively on hematopoietic cells. Until now, all of these
hematopoietic-specific mHAgs have been identified on MHC class I
molecules, with recognition by CD8+ T cells. However, Spaapen and
colleagues have discovered the first hematopoietic-restricted mHAg on
an MHC class II molecule, with recognition by CD4+ T cells, a discovery
that offers tremendous opportunity for developing selective cytotoxic
responses in cancer immunotherapy.
The identification of mHAg peptides and the genes encoding them is
an important step in deciphering the role of individual mHAgs and their
specific T-cell clones. However, discovering these genes has
traditionally been a laborious and time-consuming process. Spaapen, et
al. have not only identified an important minor H antigen, but they
have also discovered a powerful new genetic tool for identifying genes
encoding mHAgs. The authors first isolated a specific mHAg clone from a
multiple myeloma patient and performed a genome-wide, two-point linkage
analysis to identify a large region of interest on chromosome 16. Then,
using a novel genetic strategy termed “zygosity-genotype correlation
analysis,” they were able to correlate the zygosity of a given
individual with previously identified SNP genotypes on chromosome 16,
which allowed them to precisely map the genetic locus of this antigen
to a single nucleotide substitution within the third exon of CD19.
Further testing, including reactivity with CD19-specific T-cell clones,
confirmed that this class II mHAg is encoded by the CD19 allele.
CD19 is a cell surface receptor that is expressed on normal
lymphocytes from the earliest stages of pre-B-cell development through
terminal differentiation into plasma cells, as well as on B-cell
malignancies. Because this class II mHAg is not present on myeloid
lineage cells or pluripotent stem cells, it presents an attractive
potential target for directing an mHAg-specific T-cell clone against
B-cell malignancies. And functional testing did reveal that these
mHAg-specific CD4+ T cells demonstrated anti-tumor effects by directly
lysing CD19-positive tumor cells in vitro.
Minor histocompatibility antigens are important
potential targets for future immunotherapeutic treatments, and the
identification of the polymorphic genes encoding mHAgs is an important
step in directing the anti-tumor activity of mHAg-specific T-cell
clones. Applying their zygosity-genotype correlation analysis using the
complete genome-wide set of HapMap SNPs, the authors were able to
precisely map the genetic locus of a wide range of previously
identified mHAg clones using the data from only 23 individuals, showing
the broad clinical applicability of this novel genetic strategy. The
discovery of hematopoietic lineage-restricted responses within the
T-cell receptor and the ability to precisely and easily locate the
genetic locus of these mHAgs should provide new opportunities to
manipulate these responses in a wide range of hematologic diseases.
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