Download Transplantation: The replacement of diseased organs by a

Transplantation:
The replacement of diseased organs by a
transplant of healthy tissue has long been an
objective in medicine but has been frustrated
to no mean degree by the uncooperative
attempts by the body to reject grafts from
other individuals.
Graft rejection is an immunologic reaction
• It shows specificity, the second set response is
brisk, it is mediated by lymphocytes, and
antibodies specific for the graft are formed.
Consequences of major histocompatibility
complex (MHC) incompatibility
• Class II MHC molecules provoke a mixed
lymphocyte reaction (MLR) of proliferation and
blast transformation when genetically dissimilar
lymphocytes interact.
• Class II differences are largely responsible for
the reaction of tolerated grafted lymphocytes
against host antigen (graft-vs-host (g.v.h.)
reaction).
Mechanisms of graft rejection
• CD8 lymphocytes play a major role in the acute
early rejection of first set responses.
• The strength of allograft rejection is due to the
surprisingly large number of allospecific
precursor cells. These derive mainly from the
variety of T-cells which recognize allo-MHC
plus self peptides plus a small number which
directly recognize the allo-MHC molecule itself;
later rejection increasingly involves allogeneic
peptides presented by self MHC.
Different forms of graft rejection exist
• Preformed antibodies cause hyperacute
rejection within minutes.
• Acute graft rejection is mediated mainly by
cytotoxic Tcells.
• Chronic or late rejection is due to release of
proinflammatory cytokines by macrophages in
the vessel wall. This arteriosclerosis may also be
due to antibody directed against the donor or to
immune complex deposition.
Prevention of graft rejection
• Rejection can be minimized by cross-matching
donor and graft for ABO and MHC tissue types.
• Rejection can be blocked by agents producing
general immunosuppression such as antimitotic
drugs like azathioprine, or anti-inflammatory
steroids. Cyclosporin and FK506 prevent
interleukin-2 (IL-2) production, and rapamycin
blocks signal transduction triggered by activation
of the IL-2 receptor.
• Anumber of T-cell specific monoclonal
antibodies, such as anti-CD3 and anti-IL-2R, are
useful in controlling graft rejection.
Xenografting
• The major hurdle to the use of animal organs is
hyperacute rejection due to the presence of
xenoreactive crossreacting antibodies in the host.
Clinical experience in grafting
• Cornea and cartilage grafts are avascular and
comparatively well tolerated.
• Kidney grafting gives excellent results,
although immunosuppression must normally be
continuous.
• High success rates are also being achieved with
heart, liver and, to a lesser extent, lung
transplants.
• Bone marrow grafts for immunodeficiency and
aplastic anemia are accepted from matched
siblings but it is difficult to avoid g.v.h. disease
with allogeneic marrow. Stem cells may be
obtained from umbilical cord blood or from
peripheral blood, especially after administration
of granulocyte colony-stimulating factor (GCSF).
• There are two forms of g.v.h disease, an acute
form with severe skin, liver and bowel
involvement and a chronic form which resembles
scleroderma.
Association of HLA type with disease
• HLA specificities are often associated with
particular diseases, e.g. HLA-B27 with
ankylosing spondylitis, DR4 with rheumatoid
arthritis and DQ2 and DQ8 with type 1 insulindependent diabetes. The reason for these disease
associations is not known.
The fetus as an allograft
• Differences between MHC of mother and fetus
may be beneficial to the fetus but as a potential
graft it must be protected against transplantation
attack by the mother.
• Amajor defense mechanism is the lack of
classical class I and II MHC antigens on
syncytiotrophoblast and cytotrophoblast which
form the outer layers of the placenta.
• The extravillous cytotrophoblast expresses a
nonclassical nonpolymorphic MHC class I
protein, HLA-G, which inhibits cytotoxicity by
maternal natural killer (NK) cells.
• The placenta produces inhibitory cytokines and
other factors that protect against maternal Tcells.