GN 204- Final Exam Guide - Comprehensive Notes for the exam ( 95 pages long!)

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29 Mar 2018
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GN 204
Final EXAM
STUDY GUIDE
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ADVANCED IMMUNOLOGY LECTURE NOTES
TOPIC 1: MAJOR HISTOCOMPATABILITY COMPLEX (MHC)
Introduction
Grafting of tissues or organs between genetically unrelated individuals is inevitably followed by
rejection of the grafted tissue or organ. On the other hand, if tissues or organs are transplanted
between genetically identical individuals, rejection does not take place. The understanding of the
factors controlling rejection became possible after inbred strains of mice became available.
Inbred strains are obtained after 20 or more generations of brother/sister mating and for all
purposes are constituted by genetically identical animals.
The use of these animals made it possible to prove that graft rejection is under genetic control,
and that is subject to general immunological rules, i.e., specificity and memory. The genetic
control of graft rejection became obvious in experiments in which skin was transplanted among
laboratory animals of the same or different inbred strains. When skin was grafted among animals
of the same inbred strain, no rejection was observed. When grafting involved mice of different
strains, the recipient animals rejected the graft, but the speed and intensity of the rejection
reaction were clearly dependent on the degree of genetic relatedness between the strains used in
the experiment.
Further understanding of the genetic regulation of graft rejection was obtained in studies
involving first-generation hybrids (F1 hybrids) produced by mating animals of two genetically
different strains. Such hybrids did not reject tissue from either parent, while the parents reject
skin from the hybrids. The acceptance of tissues from both parental strains
by F1 hybrids of two inbred strains was explained by the development of tolerance to all paternal
and maternal specificities expressed by the hybrids during embryonic differentiation. On the
other hand, animals of the parental strains rejected tissues from the hybrids because those tissues
express histocompatibility determinants of the other nonidentical strain to which they were not
tolerant. Another important conclusion from these experiments was that the histocompatibility
determinants are co-dominantly expressed. Further studies, diagrammatically summarized in
Figure 1, showed that graft rejection shares two important characteristics with the classical
immune responses: specificity and memory.
Animals repeatedly grafted with skin from a donor of one given strain show accelerated
rejection, but if they receive a skin graft from an unrelated strain, the rejection time is as long as
that observed in a first graft. With time, it also became clear that the antigens responsible for
graft rejection are expressed in most cells and tissues. Laboratory animals receiving skin grafts
from animals of the same species but of a different strain developed antibodies that reacted
specifically with skin and peripheral blood lymphocytes of the donor strain. These findings
pointed to the sharing of antigens by different tissues of the donor animal. This possibility was
confirmed through reverse immunizations in which mice pre-injected with lymphocytes obtained
from a different strain would show accelerated rejection of a skin graft taken from the animals of
the same strain from which the lymphocytes were obtained. It is now well established that most
nucleated cells of the organism express the antigens responsible for rejection, which are
designated as histocompatibility antigens.
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After many years of this detailed genetic analysis, it became clear that the system that determines
the outcome of a transplant is complex and highly polymorphic. It was also determined that
this system contained antigens of variable strength. The major antigens are responsible for most
graft rejection responses and trigger a stronger immune response than others, which are
designated as minor. The aggregate of major histocompatibility antigens is known as the major
histocompatibility complex (MHC). All mammalian species express MHC antigens on their
nucleated cells.
Historically, the human histocompatibility antigens were defined after investigators observed
that the serum of multiparous women contained antibodies agglutinating their husbands’
lymphocytes. These leukoagglutinins were also found in the serum of multitransfused
individuals, even when the donors were compatible with the transfused individual for
all the known blood groups. The antigens responsible for the appearance of these antibodies
were thus present on leukocytes and received the designation of human leukocyte antigens
(HLA).
Fig. 1 Diagrammatic representation of an experiment designed to demonstrate the memory and
specificity of graft rejection. Memory is demonstrated by the progressive shortening of the time
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