Zoology

1. Relationship of donor and recipient, Immunological basis of graft
rejection, and the role of immunosuppressive drugs
Prof. R. MUTHUPPANDI
PG and Research Department of Zoology
Vivekananda College
Tiruvedakam west
Madurai – 625 234
India
Note: This material can be referred for M.Sc. Students

2. Relationship of donor and recipient:
• The MHC molecules (alloantigens) of the transplant (donor's tissue) is
considered by the MHC of the recipient as non – self, and production of
antibodies is triggered, as a consequence, the graft is rejected.
• So, in order to retain the graft the degree of similarities in HLA – class II alleles
between donor and recipient is termed as histocompatibility.
• Based on the histocompatibility, the graft is differentiated as follow:

3. Autograft:
Transplantation of cells (eg. hematopoietic stem cells) or tissues (eg. skin)
a within the body of same individual is called autograft.
Isograft:
Transplantation between identical twins is called Isograft.
Allograft:
The transplantation between the individuals belonging to the same species
is known as allograft.
Xenograft:
It is the transplantation between the individuals belonging to different
species.

4. Immunological basis of graft rejection
 The process of transferring cells, tissues, or organs (the graft or transplant) from
one region to the other of the same individual or from one individual – the donor
to another – the recipient is called Transplantation or grafting.
 The transplantation is a kind of treatment, involving replacement of the damaged
tissues or organs due to diseases or injury by healthy ones.
 Before transplantation, the donor and recipients are tested for crossmatching,
which involves the verification of whether the donor and recipient have same
HLA – A, HLA – B, and HLA – DR alleles or/and haplotypes (the genetic
determinants of matching) or not; i.e., histocompatibility.
 Unless the donor tissue is compatible to the recipient, the graft will summarily be
rejected called graft rejection. It is alloantigenic specific and has memory.

5.  There are mainly three types of graft rejection viz, i) Hyperacute rejection, ii) Acute
rejection, and iii) Chronic rejection.
i) Hyperacute rejection:
• It is the immediate response destroying the transplant within the time duration of few minutes to
few hours.
• It occurs due to the specific reaction between pre – existing antibodies in the recipient and
antigens in the donor.
• Ag – Ab – complement complexes induce the infiltration of neutrophils in the graft, to
inflammatory reaction, causing the massive thrombosis in capillaries preventing vascularization in
the graft and results its rejection.
ii)Acute rejection:
a. It occurs during six months to one year of transplantation.
b. This reaction is mediated by T cells.
c. The excessive infiltration of host macrophages and TH lymphocytes at the site of graft causes the
activation of TH cells to produce cytokines, IL - 2, IL - 4, IL – 5, IL – 6, IFN – γ, and IFN – β
which altogether involve in graft rejection.
d. Also, the DTH response, CD8 mediated cytotoxicity, Ab production, and ADCC by NK cells
involve in acute rejection,

6.  iii) Chronic rejection:
I. It is a late organ failure after more than six months and graft median survival is
up to 4.7 years of transplantation.
II. The mechanism cascade of chronic rejection begins with complement fixation
by the antibodies causes injury in the wall of the vessel called graft
vasculopathy or accelerated graft atherosclerosis..
III. It leads to ischemic damage (restriction in the blood supply to the tissues) in the
arteries of vascularized graft by the proliferation and acute rejection reactions
including generation of cytotoxic T lymphocytes (CTL) and induction of
delayed type hypersensitivity (DTH) like reactions of the host lymphocytes in
the graft vessels.
IV. The host alloreactive cells produce interferon – γ (IFN – γ), and TNF to
stimulate endothelial cells, muscle cells, and alloreactive cells to secrete growth
factors and chemokines causing accumulation of muscle cells at the graft
arterial intima finally graft is damaged and rejected.

7.  The usual methods of crossmatching are 1. Negative crossmatching test, and
2. Complement – dependent cytotoxicity (CDC) crossmatch.
 In crossmatching, WBCs of the donor and serum of the recipient are mixed, and
observed for the survival of donor’s blood cells.
If the donor’s cells alive, the result is negative crossmatching, favoring the
transplantation. It means that the recipient doesn’t have antibodies against the
donor’s HLA antigens; i.e., both have same HLA – A, B, and HLA – DR
haplotypes.
But, in positive crossmatching, both the donor and recipient have different alleles
of HLA -HLA – B, and HLA – DR, resulting in antigen – antibody reaction
indicating the destruction of grafted tissue, leading to graft rejection.
In CDC crossmatching, there is a specific reaction between the antibodies of
recipient and antigens of the donor mediated by some complement protein.
So, the crossmatching predicts the histocompatibility between the tissues of
donor and that of recipient.

8. Role of immunosuppressive drugs:
Although graft the graft rejection occurs even after the careful crossmatching tests,
the rejection can be minimized using following immunological drugs which control
alloimmune response:
1. Azathioprine:
• It is a purine analog, incorporated into cellular DNA and inhibits the biosynthesis
of purine and inhibits the biosynthesis of purine nucleotides in the graft and
thereby cell division is prevented.
2. Ciclosporin:
• It is a fungal metabolite, prevents the early acute rejection, and the key effect of
Ciclosporin is to inhibit the production of interleukin – 2 (IL – 2 – the activator of
T cell), in turn activation of T cell is prevented.

9. 3.Tacrolimus:
• Tacrolimus binds with another intracellular protein, FK- binding protein 12
(FKBP -12)
• The resulting complex inhibits calcineurin – the activator of T cells and
consequences of calcium dependent signaling.
4. Basiliximab:
• It binds to and inhibit interleukin – 2(IL – 2) receptors and thereby it prevents the
thymus dependent lymphocyte proliferation, in turn reduces the incidents of acute
immune response in renal transplants.
5. Cyclosporine:
• Is a potent immunosuppressant for treating graft rejection.
• It inhibits the production and release of IL – 2 (T cell growth factor).
• This inhibition reduces the proliferation of activated cytotoxic T cells, the most
responsible cells of graft rejection

10. 6. Prednisone:
• It is a synthetic corticosteroid acts as anti – inflammatory and non – specific
immunosuppressive agents.
• It reduces the activity and volume of lymphatic system (so called
lymphocytopenia).
• It reduces the concentration of immunoglobulins.
• Also, decreases the passage of immune complexes through basement membranes.
7. Sirolimus:
• Sirolimus blocks the response of T- and B-cell activation by cytokines.
• It prevents cell-cycle progression and proliferation.
• Also, it inhibits the production of cytokines.

11. 8. Mycophenolic Acids: Mycophenolate Mofetil and Mycophenolate Sodium:
• The mycophenolate is a semi – synthetic prodrug administered to the grafted
tissue where it is hydrolyzed rapidly to form active mycophenolic acid (MPA).
• These mycophenolic acids non-competitively, and reversibly inhibit inosine
monophosphate dehydrogenase.
• This inhibition blocks the purine guanosine synthesis.
• It selectively suppresses the proliferation of T- and B-lymphocytes.
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