Transposition WORLD OF MICROBIOLOGY AND IMMUNOLOGY554•
are genetically alike, as in identical twins. An allograft is a
graft between members of the same species but who are not
genetically alike. A xenograft is one between members of dif-
ferent species. The allograft we are most familiar with is that
of a blood transfusion. Nonetheless, the replacement of dis-
eased organs by transplantation of healthy tissues has frus-
trated medical science because the immune systemof the
recipient recognizes that the donor organ is not “self” and
rejects the new organ.
The ability to discriminate between self and nonself is
vital to the functioning of the immune system so it can protect
the body from disease and invading microorganisms.
However, the same immune response that serves well against
foreign proteins prevents the use of organs needed for life sav-
ing operations. Virtually every cell in the body carries distinc-
tive proteins found on the outside of the cell that identify it as
self. Central to this ability is a group of genes that are called
the (MHC), or major histocompatibility complex. The genes
that code for those proteins in humans are called the HLAor
Human Leukocyte Antigen. These are broken down to class I
(HLA-A, B, and Cw), class II (HLA-DR, DQ, and DP) and
class III (no HLA genes).
The MHC was discovered during tumor transplantation
studies in mice by Peter Gorer in 1937 at the Lister Institute,
and was so named because “histo” stands for tissue in medical
terminology. The genes that compose the MHC are unique in
that they rarely undergo recombinationand so are inherited as
a haplotype, one from each parent. They are also highly poly-
morphic. This means that the genes and the molecules they
code for vary widely in their structure from one individual to
another and so transplants are likely to be identified as foreign
and rejected by the body. Scientists have also noted that this
area of the genome undergoes more mutational events then
other regions, which probably accounts for some of its high
degree of polymorphism. As previously mentioned, there are
several classes of the MHC. The role of the MHC Class I is to
make those proteins that identify the cells of the body as
“self,” and they are found on nearly every cell in the body that
has nucleus. Nonself proteins are called antigens and the body
first learns to identify self from nonself just before birth, in a
selectionprocess that weeds out all the immature T-cells that
lack self-tolerance. Normally, this process continues through-
out the lifespan of the organism. A breakdown in this process
leads to allergiesand at the extreme, results in such autoim-
mune diseases as multiple sclerosis, rheumatoid arthritis, and
systemic lupus erythematosus. The job of the Class I proteins
is to alert killer T cellsthat certain cells in the body have
somehow been transformed, either by a viral infection or can-
cer, and they need to be eliminated. Killer T-cells will only
attack cells that have the same Class I glycoproteins that they
carry themselves. The Class II MHC molecules are found on
another immunocompetant cell called the B-cells. These cells
mature into the cells that make antibodies against foreign pro-
teins. The class II molecules are also found on macrophages
and other cells that present foreign antigens to T-helper cells.
The Class II antigens combine with the foreign antigenand
form a complex with the antibody, which is subsequently rec-
ognized and then eliminated by the body.The ability of killer T-cells to respond only to those
transformed cells that carry Class I antigen, and the ability of
helper T-cells to respond to foreign antigens that carry Class II
antigen, is called MHC restriction. This is what is tested for
when tissues are typed for transplantation. Most transplantation
occurs with allogeneic organs, which by definition are those
that do not share the same MHC locus. The most sensitive type
of transplantation with respect to this are those involving the
bone marrow (Haematopoietic Stem Cell Transplantation)
HLA matching is an absolute requirement so its use is limited
to HLA-matched donors, usually a brother or sister. The major
complications include graft-versus-host disease (GvHD is an
attack of immunocompetant donor cells to immunosuppressed
recipient cells) and rejection, which is the reverse of GvHD.
The least sensitive are corneal lens transplantation, probably
because of lack of vascularisation in the cornea and its relative
immunological privilege. Drugs like cyclosporin A have made
transplant surgery much easier, although the long term conse-
quences of suppressing immune function are not yet clear. This
antirejection drug is widely used in transplant surgery and to
prevent and treat rejection and graft-versus-host disease in
bone marrow transplant patients by suppressing their normal
immune system. Newer strategies, including genetherapy, are
being developed to prevent the acute and chronic rejection of
transplanted tissues by introducing new genes that are impor-
tant in preventing rejection. One promising aspect is the deliv-
ery of genes that encode foreign donor antigens (alloantigens).
This might be an effective means of inducing immunological
tolerance in the recipient and eliminate the need for whole-
body immunosuppression.See also Antibody and antigen; Immunogenetics;
Immunologic therapies; Immunosuppressant drugs; Major his-
tocompatibility complex (MHC)TTranspositionRANSPOSITION
A transposition is a physical movement of genetic material
(i.e., DNA) within a genome or the movement of DNA across
genomes (i.e., from one genome to another). Because these
segments of genetic material contain genes, transpositions
resulting in changes of the loci (location) or arrangements of
genes are mutations. Transposition mutations occur in a wide
range of organisms. Transposonsoccur in bacteria, and trans-
posable elements have been demonstrated to operate in higher
eukaryotic organisms, including mammalian systems.
Transposition mutations may only occur if the DNA
being moved, termed the transposon, contains intact inverted
repeats at its ends (terminus). In addition, functional tran-
posase enzymesmust be present.
There are two types or mechanisms of transposition.
Replicative transpositions involve the copying of the segment
of section DNA to be moved (transposable element) before the
segment is actually moved. Accordingly, with replicative
transposition, the original section of DNA remains at its orig-
inal location and only the copy is moved and inserted into its
new position. In contrast, with conservative transpositions, thewomi_T 5/7/03 11:02 AM Page 554