Transplantation

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					    Major Histocompatibility Complex
           and Transplantation
• Major histocompatibility complex (MHC) proteins were
   discovered for the first time with the beginning of tissue
   transplantation
• The success of tissue and organ transplantation depends
   upon the donor’s and recipient’s “human leukocyte
   antigens” (HLA) encoded by HLA genes
• These proteins ( MHC ) are allo-antigens which means :
 the same gene locus ( site ) in different individuals of the
   same species will express different antigens ( proteins ) ,
   so when one antigen of one individual is transported to
   another who doesn’t have it , it will induce immune
   response against it ] like blood groups [
    Major Histocompatibility Complex
           and Transplantation

• Genes for HLA proteins are
  clustered in the MHC complex
  region located on the short arm
  of chromosome 6
• Three genes HLA-A, HLA-B and
  HLA-C code for Class I MHC
  proteins
• HLA-D loci encode for Class II
  MHC proteins ie, DP, DQ and
  DR
    Major Histocompatibility Complex
           and Transplantation
• Each individual has two “haplotypes” ie, ( two sets of
  these genes one paternal and one maternal )
• These genes are very diverse “polymorphic”

   – There is about 47 HLA-A genes
   – There is about 88 HLA-B genes
   - There is about 29 HLA-C genes
   – There is about More than 300 HLA-D genes

   So the child will have a different combination of genes different
     from his parents and from any other person ( except for
     identical twins )
    Major Histocompatibility Complex
           and Transplantation

• Minor HLA genes – are unknown
• They mount a weak immune response
• Play role in chronic rejection of a graft
• There are no laboratory tests to detect minor
  antigens
• Class III MHC locus found between MHC I & II
  regions
• Encode for TNF, lymphotoxin, complement
  proteins ( C2 and C4 )
MHC Class I, II & III Genes
             MHC Class I Proteins
• They are glycoproteins found on surface of virtually all the
  nucleated cells
• The A locus which have HLA-A genes encode 20 different
  proteins , B locus having HLA-B genes will encode 40
  different proteins and C locus will encode 8 different
  proteins
• So the different proteins will make the individuals differ from
  each other
• all class I proteins are composed of a heavy chain (α1 + α2 +
  α3 ) bound to a 2-microglobulin molecule
• The heavy chain is highly polymorphic and has a
  hypervariable region at N-terminal

   – Polymorphism – self and non-self recognition
   – Constant regions react with CD8 protein of   Tcytotoxic
                         MHC Class I Protein



The polymorphism happen
in the α chain ( heavy
chain )
And the α chain (
specially α3 domain ) has
transmembrane part which
contact with the
intracellular part of α chain
          Class II MHC Proteins
• They are glycoproteins normally found on the surface
  of antigen presenting cells such as ( marophages, B
  cells, dendritic cells of spleen and Langerhans cells of
  skin
• They are highly polymorphic
• Composed of two polypeptide chains bound non-
  covalently
• They have hypervariable regions leading to
  Polymorphism
                           MHC Class II Protein




Here the polymorphism
found in both α and β
chains
And both α and β chains
have a transmembrane part
to contact it’s intracellular
part
 Major Histocompatibility Complex
        and Transplantation
• Both chains of Class II MHC proteins are
  encoded by the MHC locus

• Constant regions of both the peptides
  interact with CD4 proteins of helper T cells
  Biologic Importance of MHC
• Tc kills virus infected cells in association
  with class I MHC proteins
• Helper T cell recognize antigen in
  association with class II MHC proteins
• This is called MHC restriction
• Success of organ transplant is determined
  by compatibility of the MHC genes between
  the donor and the recipient
                 Transplantation antigens




Compatible ,                                Non –
so there is no                              compatible
immune                                      , so there is
response                                    immune
against the                                 response
graft                                       against the
                                            graft
Transplantation
        Transplantation
• Types of transplants:
  – Autografts or ( Autologous grafts )
     • Donor and recipient are the same person
     • Common in skin grafting; bone marrow
  – Syngeneic grafts or ( isograft )
     • Donor and recipient are genetically
       identical
     • Animal models; identical twins
           Transplantation
• Types of transplants:
  – Allogeneic grafts ( allograft ) very imp
     • Donor and recipient are in the same species,
       but genetically unrelated
     • Common : heart, lung, kidney, liver graft
  – Xenogeneic grafts ( xenograft )
     • Donor and recipient are different species
     • Like graft from Animal to humans
  – Artificial grafts
       Like artificial joints and skin
          Transplantation
• Major Barrier to transplantation is the immune
  response
  – T cells play primary ( main ) role in graft rejection
  – B cells can/do play a role
  – Classic adaptive/acquired immune response
     • Memory
     • Specificity
1st set versus 2nd set reactions
              Transplantation
                   In the previous picture :-

1- in column ( a ) there is in autograft of epidermis from the same
person , so there will be no immune response against it and no
rejection
2- in column ( b ) there is allograft from human to another human ,
there will be a rejection if they don’t match , but it will take long time
( up to 14 days ) because he exposed to it for the first time ( hens
called first- set rejection )
3 – in column ( c ) we repeat the step 2 but the rejection happen faster
because there is memory cell which directly get activated ( called
second-set rejection ) it is always faster ( up to 6 days )
1st set versus 2nd set reactions
        Role of cell mediated responses




                           Unprimed syngeneic
                           recipient
               Transplantation
                       In the previous slide

There is 2 syngeneic mice ( like identical twins ) , the first one get skin
graft that doesn,t match , so after 14 days the grafted skin get rejected
by the first-set rejection
Now the T cells have memory cells , if we transplant another skin graft
to the same mouse the rejection will happen in 6 days due to the
memory cells
If we transport the T memory cells to the other mouse who didn’t have
skin graft , and then give him a skin graft it will reject it in 6 days due
to the presence of T memory cells
And that tells that T cells have a main role in graft rejection
Role of CD4+ versus CD8 T+ cells




      Injecting recip. mice with mab to
     deplete one or both types of T cell
              Transplantation
                     ] In the previous slide [
This slid will tell you which type of T cell is dominant or have the
main function in graft rejection :
1- when we transplant a graft that doesn’t match and give the recipient
an ( anti CD8 ) the graft will stay intact for about 15 days before it get
rejected
2 – when we transplant a graft that doesn’t match and give the
recipient an ( anti CD4 ) the graft will stay intact for about 30 days
before it get rejected
That tells you that the CD4 cell have the main function in graft
rejection
And if we block both CD4 and CD8 the grafr will persist for 60 days
           Transplantation
• T cells play primary role in 1st and 2nd set
  rejection reactions
  – Nude mice ( don’t have T cells ) accept allografts
  – B cell deficient mice reject allografts , because they still
    have T cells



                                                      A Nude
                                                      mouse has
                                                      a transplant
                                                      of rabbit
                                                      skin
Mechanisms involved in Graft Rejection
   Sensitization stage = = = = Effector stage
Rejection Response
      Clinical manifestations of graft rejection
I.    Hyperacute rejection: very quick ( within minutes )




II.   Acute rejection: about 10 days (cell mediated)
III. Chronic rejection: months-years (both) by minor HLA gene
       Clinical manifestations of graft rejection


Hyperacute rejection ( mediated by humoral immunity ) :
In this condition , the recipient already have antibodies against the graft
even before the transplant , so when we transplant the organ the pre-
existing antibodies will attach to the organ and activate the complement
system to destroy the organ within minutes
Acute rejection ( cell mediated ) :
In this condition , the graft persist for about 10 days ( in contrast to
hyperacute which is in minutes ) and that due to the action of T cells
this reaction is cell mediated so take longer time to multiply and arrive
to the site of graft
           Chronic Rejection
( cell mediated and humoral immunity )
– This occurs months to years after engraftment
– Main pathologic finding in chronic rejection is
  atherosclerosis of the vascular endothelium
– Main cause of chronic rejection is not known
   • Minor histocompatibility antigen miss match
   • Side effects of immunosuppressive drugs
    Graft-versus-Host (GVH) Reaction

• Some times the patient need a transplanted bone marrow or
  thymus which are have a large number of lymphocytes from
  the donor
• So when the graft is allograft ( from the same species but not
  identical ) the transplanted lymphocyte ( specially T cells ) will
  lock around in the recipient body if it didn,t find a match in the
  MHC it will attack the recipient body because it look foreign
  bodies for it
• so in this case instead of making the patient healthier , he will
  become worse
      Graft-versus-Host (GVH) Reaction

The donor’s cytotoxic T cell will play a
major role in destroying the recipient’s
cells

Symptoms are: maculopapular rash,
jaundice, hepatosplenomegaly and
diarrhea
GVH reactions usually end in infections
and death
So in brief the transplanted organ will
work against or versus the host
                                           Maculopapular rash
   HLA Typing in the Laboratory
• Prior to transplantation , laboratory test commonly
  called as HLA typing or tissue typing is performed
  to determine the closest MHC match between the
  donor and recipient is performed
• Methods applied in this test is :
   –   DNA sequencing by Polymerase Chain Reaction (PCR)
   –   Serologic Assays
   –   Mixed Lymphocyte Reaction (MLR)
   –   Crossmatching – (D) lys + (R) serum + complement ( very
       important )
                       Tissue Matching
   Effect of HLA class I & II matching on survival of kidney grafts



Zero = means no difference
So the MHC match




Notice that class II is more
important than class I
So when it is zero or close
to zero the survival rate
increase
                   Tissue Matching
                          Serological Method

In this test you take the recipient’s
serum which contain antibodies
and then add to it the donor’s
HLA antigens
Then add complement to them , if
the antibodies bind to the HLA
antigens the complement will be
activated and will attack the
donor’s cells and then add a dye
to confirm the lysis
If the dye radiate ( visible ) that
mean the recipient will reject the
graft , if not he will except it
                        Tissue Matching
                  Mixed Leukocyte Reaction (MLR)




In this test we will take leukocytes from the recipient and the donor and but them in
tube , if the MHC in the different leukocytes don’t match they will be activated
against each other and proliferate , then we add a radioactive material ( thymidine )
which will be incorporated into the DNA and it will radiate ( become visible ) , if the
MHC match ther will be no proliferation and the thymidine will not be taken by the
cell’s DNA
Tissue Matching




 Very important
General Immunosuppression Therapy


          After the transplantation

 1) Mitotic inhibitor : azathioprine ( pre & post )
 2) Corticosteroids: (+ 1)
 3) Cyclosporin A, FK506: IL-2 and IL-2R
 4) Total lymphoid irradiation
Immunosuppresive Therapy
Immunosuppresive Therapy




       Cyclosporin
       FK506
Immunosuppresive Therapy

                    Here you see the
                    survival of the graft
                    with and without the
                    immunosuppresive
                    therapy



                     The blue = with



                   The black = without
   Specific Immunosuppression
              Therapy
a) Mabs (Monoclonal antibody ) to T cell components or
   cytokines
b) Agents that blocking co-stimulatory signal
       Immunosuppresive
           Therapy
• Downsides
  – Must be maintained for life
  – Toxicity
  – Susceptibility to infections
  – Susceptibility to tumors ( due to inactivation of CD8 )

				
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