This document discusses various methods for preventing graft rejection in transplantation. It describes familial grafting which reduces HLA mismatches, tissue typing to determine allele matches between donor and recipient, and cross-matching to check for preexisting antibodies. It also discusses immunosuppression drugs like corticosteroids and cyclosporine A that are used when some mismatches are present. A special case of fetal transplantation is mentioned where the fetus carries HLA alleles from both parents.

1. Course-Immunochemistry.
TOPIC: PREVENTION OF GRAFT REJECTION
3/14/2018 Dept. 0f Plant Biotechnology 1

2. PREVENTION OF GRAFT REJECTION
• Familial grafting
• Tissue typing
• Cross-matching
• Immunosuppression
• The special case of the ‘fetal transplant’

3. Familial Grafting
• Transplantation within families significantly reduces allele mismatches because of
the inheritance patterns of HLA (Fig. 1).
• In general, there is little crossover within the locus and the whole locus is usually
inherited en bloc.
• Thus, if you need a transplant, make sure you come from a family with lots of
brothers and sisters!

4. • Other tissue antigens that trigger far less vigorous rejection responses (minor
histocompatibility antigens) are encoded outside the MHC locus and include
male specific antigens.
• In fact, mismatches of minor transplantation antigens can be important in
determining the fate of grafts between HLA matched donor and recipient,
especially as it relates to chronic rejection over a longer period of time.

6. Tissue typing
• If a familial donor is not available, then the extent of the mismatches between
alleles must be determined by tissue typing, in order to best match donor and
recipient.
• One of the most useful assays involves cytotoxic antibodies to individual HLAs.
• The principal of the antibody method depends on the surface expression of the
HLA.

7. • Donor and recipient blood for typing are enriched for B cells and specific
cytotoxic antibodies are added.
• Binding of the antibody to a surface HLA in the presence of complement
results in the direct killing of the B cells.
• These can be microscopically scored. Using a panel of antibodies, it is
possible to HLA type for the majority of alleles.

9. Cross-matching
• It is used to check that there are no
preformed antibodies to donor HLA in the
recipient.
• Blood lymphocytes from the donor are
mixed with serum from the recipient.
• Anti-donor antibodies are detected by lysis
of the cells (mediated by complement) or by
using fluorescent staining and flow
cytometry.
• The presence of such antibodies is contra
indicatory to the use of the tissues from that
donor.
• Cross matching for blood groups is also
important for renal transplants

10. Immunosuppression
• There will be some allelic mismatches and some donor minor histocompatibility
antigens, therefore the immune system of the recipient has to be suppressed to avoid
rejection.
• The mainstay drug treatment is a mixture of corticosteroids, synthetic cytotoxic drugs
and cyclosporin A (a fungal nonapeptide).
• The mechanisms of immunosuppression by these and other drugs used are shown below.

11. • Not surprisingly, a major problem with these drugs is that by inhibiting the immune
response against the graft they can also lead to increased susceptibility to infections.
• In fact, infection and rejection are the main reasons for the failure of kidney grafts to be
maintained.
• Other drugs, e.g. anti-lymphocyte antibodies, which kill the recipient’s lymphocytes, are
also used by some transplant teams.

12. The special case of the ‘fetal transplant
• The fetus is a chimera carrying HLA alleles from both parents.
• It is therefore effectively an allograft in close apposition to maternal tissues.
• The main potential mechanisms for prevention of rejection are shown below for a
recently implanted embryo (day 14), but also play an important role throughout
gestation.