This section is intended to provide a brief overview of some clinical issues that exemplify the basic aspects of immune system functioning discussed previously.
SOME CLINICAL PERSPECTIVES OF IMMUNE SYSTEM
This section is intended to provide a
brief overview of some clinical issues that exemplify the basic aspects of
immune system functioning discussed previously.
Transplantation is the process of
transferring cells, tissues or organs—termed a graft—from one location to
another. An autologous graft is a transplant between two sites within the same
individual, e.g. skin graft from the thigh to the hand. An allogeneic graft is
a transplant between two genetically different individuals of the same species,
e.g. kidney transplant from a donor to a
recipient individual. A xenogenic graft is a transplant across different
species, e.g. pig to human.
The tempo of clinical rejection—in kidney
transplantation, for example—is often categorized by the following stages.
• Hyperacute
rejection occurs within minutes to hours following revascularization of a
graft. The cause is due to the presence of preformed circulating antibody (IgG)
that reacts with the blood cell antigens (the ABO system), or MHC I molecules
or other poorly defined antigens. This should now be a rare event clinically as
recipients are tested (cross-matched) before transplantation for the presence
of antibodies reactive with cells of the donor.
• Acute
rejection occurs within weeks to months following transplantation and involves
humoral (antibody) and cell-mediated induced cytotoxicity. Damage may be
reversed with early diagnosis and more aggressive immunosuppressive therapy.
• Chronic
rejection occurs many months or even years following transplantation. The
pathology is characterized by fibrosis and may require differential diagnosis
to distinguish between a chronic rejection event and the recurrence of the
original disease that necessitated transplantation in the first place.
The major alloantigens (i.e. antigens
responsible for rejection of allogeneic grafts) are the MHC proteins. Although
there are two distinct classes of MHC protein (described in section 4.1), the
MHC molecules actually have a number of subclasses which vary further in the
general nature of peptides that they will accept within their binding clefts.
The MHC I molecules are composed of three subclasses, MHC IA, MHC IB and MHC
IC, on each nucleated cell of the body; all three subclasses are simultaneously
expressed. The MHC II molecules are also made up of three subclasses, MHC II
DR, MHC II DP and MHC II DQ, and again on each APC all three subclasses of MHC
II molecule are simultaneously expressed. APCs, like other cells in the body,
will also express MHC I molecules on their surface in addition to MHC II.
As indicated previously, the major cause
of allogeneic tissue transplantation rejection is the polymorphic nature of the
MHC phenotype between individuals. Polymorphism in MHC arises within the
population because the genes for each of the MHC subclasses can exist in
multiple different forms or alleles. For example, in humans there are at least
52 different forms of the MHC IB gene and at least 24 different forms of the
MHC IA gene. It follows that individuals in a population can possess any one of
the 52 different forms of MHC IB gene and any one of the 24 different forms of
MHC IA gene, so the number of different combinations for the six classes of MHC
proteins is many millions. The situation is further complicated by the fact
that each individual inherits and co-expresses a set of MHC I and II genes from
each parent. This means that on each nucleated cell of the body there will be
co-expressed paternally derived and maternally derived versions of the MHC IA,
MHC IB and MHC IC molecules. The same principle will apply for co-expression on
APCs of paternal and maternal MHC II protein subclasses.
This tremendous polymorphism is important
in immune defence because it allows the broadest possible scope of peptide
antigen presentation, and thus the best chance of survival of a population as a
whole, but it also confers the very high probability of MHC mismatch during
allogeneic transplantation. As a result of the mode of MHC inheritance, the
highest probability of a MHC tissue match between individuals who are not
genetically identical twins will be that obtained between siblings, where there
is a 1 in 4 chance of a sibling possessing an exact match for all the MHC I and
MHC II subclasses. The MHC proteins are also termed human leucocyte antigens (HLA),
and HLA tissue typing is undertaken routinely before transplantation to gain
improved matches between donor and recipient. In kidney transplantation it has
been found that matching the MHC IA, IB and IIDR genes in particular appears to
improve shortand long-term graft survival.
The main target for the modern
immunosuppressants such as ciclosporin and tacrolimus is inhibition of cytokine
gene transcription in a highly selective manner in the helper T-lymphocyte
populations. The consequence of this is to inhibit helper T-cell autoactivation
and helper T-cell coactivation of cytotoxic T-lymphocytes and of B-lymphocytes,
and thus considerably ‘damp down’ cell-mediated and humoral immune responses to
the graft.
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