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Deptt. Of Zoology
Deptt.
R.T.M. Nagpur University, Nagpur
 ¢ 
h untroduction

h u unology of Transplant Rejection

h Tissue and Organ Transplantation

h u unosuppressive Agents

h u unosuppressive Therapy

h Conclusion
h References
 
h Transplantation i unology - sequence of events that
occurs after an allograft or xenograft is re oved fro
donor and then transplanted into a recipient.

h A ajor li itation to the success of transplantation is

the i une response of the recipient to the donor
tissue.
 
 


u is self-tissue transferred fro one body site to

another in the sa e individual.

u  is tissue transferred between genetically identical

individuals.

u is tissue transferred between genetically different

e bers of the sa e species.

uº  is tissue transferred between different species





 
¢

   

   
  
Ñ Antigen presenting cells ²
h Dendritic cells

h Macrophages

h Activated B Cells

2 B cells and antibodies ²

h Prefor ed antibodies

h Natural antibodies

h Prefor ed antibodies fro prior sensatization

h unduced antibodies

3 T cells
4 Other cells ²
h Natural killer cells

h T cells that express NK cell ² associated Markers

h Monocytes/Macrophages
  

  



h Recognition of transplanted cells that are self or

foreign is deter ined by poly orphic genes
(MHC that are inherited fro both parents and
are expressed co-
co-do inantly.

h Alloantigens elicit both cell-

cell- ediated and
hu oral i une responses.
   
h !  
h Recognition of an intact MHC olecule displayed by donor APC in the
graft
h Basically, self MHC olecule recognizes the structure of an intact
allogeneic MHC olecule
h unvolves both CD8+ and CD4+ T cells.
w undirect Presentation
w Donor MHC is processed and presented by recipient APC
w Basically, donor MHC olecule is handled like any other foreign
antigen
w unvolve only CD4+ T cells.
w Antigen presentation by class uu MHC olecules.
    

 

h Donor APCs igrate to regional ly ph nodes
and are recognized by the recipient·s TH cells.
h Alloreactive TH cells in the recipient induce
generation of TDTH cell and CTLs then igrate
into the graft and cause graft rejection.
Activation of Alloreactive T cells and
Rejection of Allografts

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h CD4+ differentiate into cytokine producing
effector cells
h Da age graft by reactions si ilar to DTH
h CD8+ cells activated by direct pathway kill
nucleated cells in the graft
h CD8+ cells activated by the indirect pathway are
self MHC-
MHC-restricted
  ¢% &
 
h '( ), u
N ² ü , and TN
-
are i portant ediators of graft
'(
rejection.
h '(( * pro otes T-
' T-cell proliferation and generation of T ²
Ly phocytes.
h +,-- is central to the develop ent of DTH response.
+,
h ,+--
has direct cytotoxic effect on the cells of graft.
,+
h A nu ber of cytokines pro ote graft rejection by inducing
expression of class ² u or class ² uu MHC olecule on graft cell.
h The interferon (ơ,
and , TN
² ơ and TN
-
all increases
class ² u MHC expression, and u
N - increases class ² uu MHC
expression as well.
r   

 

h Hyperacute Rejection
h Acute Rejection
h Chronic Rejection
 
  
h Characterized by thro botic occlusion of the
graft
h Begins within inutes or hours after
anasta osis
h Pre--existing antibodies in the host circulation
Pre
bind to donor endothelial antigens
h Activates Co ple ent Cascade
h Xenograft Response
 
  

Ñ. Prefor ed Ab, 2. co ple ent activation,

3. neutrophil argination, 4. infla ation,
5. Thro bosis for ation
   
h ascular and parenchy al injury ediated by T
cells and antibodies that usually begin after the
first week of transplantation if there is no
i unosuppressant therapy
h uncidence is high (30% for the first 90 days
   

Ñ. T-cell, acrophage and Ab ediated,

2. yocyte and endothelial da age,
3. unfla ation
 ¢ 
h Occurs in ost solid organ transplants
h Heart
h Kidney

h Lung

h Liver

h Characterized by fibrosis and vascular

abnor alities with loss of graft function over a
prolonged period.
 ¢ 

Ñ. Macrophage ² T cell ediated

2. Concentric edial hyperplasia
3. Chronic DTH reaction
   


h Today it is possible to transplant any different organs
and tissues including.
u Most co on transplantation is blood transfusion.
u Bone Marrow transplantation

u Organs : Heart, kidneys, pancrease,

pancrease, lungs, liver and
intestines.
u Tissues : include bones, corneas, skin, heart values,
veins, cartilage and other connective tissues.
 ¢



-  
  --

÷
 Not transfused

  .

h Used for Leuke ia, Ane ia and i unodeficiency, especially
severe co bined i unodeficiency (SCuD .
h About Ñ09 cells per kilogra of host body weight, is injected
intravenously into the recipients.
h Recipient of a bone arrow transplant is i unologically
suppressed before grafting.
h Eg.. Leuke ia patients are often treated with cyclo-
Eg cyclo-phospha ide
and total body irradiation to kill all cancerous cells.
h Because the donor bone arrow contains i unoco petent
cells, the graft ay reject the host, causing graft versus host
disease (GHD .
 &  ! 
h Caused by the reaction of grafted ature T-
T-cells
in the arrow inoculu with alloantigens of the
host
h Acute GHD
h Characterized by epithelial cell death in the skin, Gu
tract, and liver
h Chronic GHD
h Characterized by atrophy and fibrosis of one or
ore of these sa e target organs as well as the lungs
 

h
irst heart transplant in South Africa by Dr. Christian Barnard in Ñ964.
h One year survival rate is >80%.
h HLA atching is desirable but not often possible, because of the li ited
supply of heart and the urgency of the procedure.

'

h
irst atte pt in Ñ963 by Hardy and Co - workers.
h
irst successful transplantation by Toronto group in Ñ983.
h un conjunction with heart transplantation, to treat diseases such as cystic
fibrosis and e physe a or acute da age to lungs.
h
irst year survival rate is about 60%.
‰ 

h Diseases like diabetes and various type of nephritis can be
elleviated by kidney transplantation.
h Survival rate after one year transplantation is >90%.

h 25,000 candidates are waiting for kidney transplantation.

' 

h ut treat congenital defects and da age fro viral (hepatitis
or che ical agents. (Chronic alcoholis .
h Liver one year survival exceeds 75% and five year is 70%.
  

h Offers a cure for diabetes ellitus.

h Graft survival is 72% at one year.

h
urther i proved if a kidney is transplanted si ultaneously.

h Overall goal - to prevent the typical diabetic secondary

co plications.

|%
h ut is used to treat burn victi s.

h un severe burn, grafts of foreign skin ay be used and rejection

ust be prevented by the use of i unosuppressive therapy.
 º    


h A ajor barrier to xenogeneic transplantation is

the presence of natural antibodies that cause
hyperacute rejection.


 

   
u unosuppression can be brought about by 3
different ways :-
:-

h Surgicalablation
h Total Ly phoid urradiation

hu unosuppressive drugs


 

  !

Three ain i unosuppressant drugs

h ¢
 act by inhibiting T- T-cell activation, thus
preventing T-T-cells fro attacking the transplanted organ.
h /
 disrupt the synthesis of DNA and RNA and
cell division.
h ¢   such as prednisolone suppress the
infla ation associated with transplant rejection.


 

   0   

 




h  1
0 in co bination with cyclosporin and

corticosteroids, in kidney transplants.
h !/
0 in co bination with cyclosporin and
corticosteroids, in kidney transplants.
h

0 CD3 (Orthoclone
(Orthoclone OKT3 along with
cyclosporin,, in kidney, liver and heart transplants.
cyclosporin
h 
 is used in liver transplants and is under study for
kidney, bone arrow, heart, pancreas, pancreatic island cell,
and s all bowel transplantation.
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h /
 in treat ent of rheu atoid arthritis , chronic ulcerative
colitis but li ited value.
h ¢
 is used in heart, liver, kidney, pancreas, bone arrow and
heart/lung transplantation. Also used to treat psoriasis and rheu atoid
arthritis, ultiple sclerosis, diabetes and yesthenia gravis.
h &
   is used in treat ent of relapsing-
relapsing-re itting ultiple
sclerosis.
h 
  is used along with cyclosporin in kidney, liver and heart
transplants. Also used to prevent the kidney proble s associated with
lupus erythe atosus.
atosus.
h |
 in co bination with cyclosporin and corticosteroids, in kidney
transplants. The drug is also used for the treat ent of psoriasis.


 

   

Monoclonal antibodies
h To suppress the activity of subpopulation of T- T-cells.
h To block co-
co-sti ulatory signals.
h Ab to the CD3 olecule of TCR (T cell receptor co plex results in a rapid
depletion of ature T T--cells fro the circulation.
h Ab specific for the high
high--affinity uL
uL--2 receptor is expressed only on activated
T-cell, blocks proliferation of T-
T-cells activated in response to the alloantigens
of the graft.
h To treat donor·s bone arrow before it is transplanted.

h Molecules present on particular T- T-cells subpopulation ay also be targeted

for i unosuppressive therapy.
h Antibody to CD4 shown to prolong graft survival.

h Ab specific for i plicated cytokine can prolong the survival of graft.

 ¢ 
h More than 50,000 people, waiting for co patible donor.
or
ethical an practical reasons, species closely related to hu an such
as Chi panzee have not been widely used.
h Xenogeneic transplantation ay be ajor issue of research
xenograft technology including genetically odified ani al ay
beco e a new source of organ supply.
h Side effects of i unosuppressive agent use for graft need a
change of specificity in action and avoiding general i une
suppression.
h Techniques such as transgenic ani al production and wide range
of research in this field hope to result in opening a new window
for the process of transplantation i unology.
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