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ACQUIRED IMMUNITY by alicejenny

VIEWS: 5 PAGES: 52

									Peter Medawar
     Immunologic Basis of Graft Rejection

     The Behavior and Fate of Skin Autografts and
             Skin Homografts in Rabbits
(A report to the War Wounds Committee of the Medical Research Council)
    By P.B. Medawar,*From the Department of Zoology and Comparative Anatomy
                               University of Oxford


                     •Inducibility
                     •Memory
                     •Specificity
First Set Rejection




            Rejection 7-8 Days
Second Set Rejection (Memory)


             First Graft




               Rejection 3-4 Days
Specificity




      “Third Party” Graft
                   Terminology

Autograft - One site to another on the
same individual



Isograft - between two
genetically identical
individuals
                 Terminology (cont.)
Allograft - between genetically
distinct individuals of the same
species



Xenograft - between different species
Beginning of Rejection
Rejected Mouse Skin Graft
Rejection is mediated by T cells
Role of CD4 and CD8 Cells
         Laws of Transplantation

   Tx between individuals of the same inbred
    strain will succeed.

   Tx between inbred strains are rejected.

   Tx parent to F1 will succeed, but the reverse
    will fail.
                 Parent to F2
    B           B                    A          B
A   AB        AB              A     AA    AB
         F1                            F2
A   AB        AB              B     BA    BB
         Survival Probability = 0.75
         For 2 Loci: (0.75) x (0.75)
    % Graft Survival (P to F2) = (0.75)n
         n= Number of histocompatibility loci
           The Human MHC


Class II     Class III      Class I




DP DQ DR    C4 C2 Bf     B C E A G F
Mixed Leukocyte Reaction


  Spleen



    2000 RADS              5 Days

                 Add 3H-Thymidine
                            18-24 Hours

 Spleen         Determine Incorporation
             Acute Rejection

 Primary Cellular
 Massive infiltration of macrophages and
  lymphocytes
 Decreased graft function
 Clinically appears at >10 days post-tx and can
  occur anytime thereafter.
Acute Rejection – Grade 1a
Acute Rejection - Grade 3a
           Chronic Rejection

 Slow steady decline of graft function and
  progressive occlusion of of
  vessels/passageways.
 Result of cellular and humoral mechanisms
Chronic Rejection
Hyperacute Rejection
Clinical Transplantation
   Objectives of Immunosuppression

Facilitate acceptance of the allograft
  Specific
  Low toxicity
    Basic Strategies of Immunosuppression

   High dose initial immunospression
     Facilitate
               graft acceptance
     Minimize early rejection
     Favor induction of tolerance

 Maintenance therapy for chronic acceptance
 Augmentation to reverse acute rejection.
    Major Immunosuppressants

 Cyclosporine A
 Tacrolimus (FK-506)
 Sirolimus (Rapamycin)
 Steroids
 Azathioprine
 Mycophenylate Mofetil
                  Medical Issues and
                 Immunosuppression

   Selected Side Effects of Cyclosporine
     Gingival    Hyperplasia
     Infection
     Nephrotoxicity
     Hypertension
     Tremors,    Nightmares, Insomnia
     Hirsutism
     Fibrous    Breast Tissue
                    Infections

   Prophylactic Antibiotics for procedures with
    potential to cause bacteremia.

   Metabolism of some drugs may be altered,
    especially for liver transplant patients (e.g.
    acetominophin, lidocain, procain ampicillin
    etc).
                Graft Rejection

   Highly dependent on T cell activation and
    proliferation.

   Signaling pathways and control points for
    entry into cell cycle are appropriate targets for
    immunsuppression.
      Broad Mechanisms of Immunosuppression


   Inhibition of T cell activation.
     Block  antigen binding.
     Block accessory molecules.
     Inhibition of IL-2 production.

 Inhibition of T cell proliferation.
 T cell depletion.
 Inhibition of B cell proliferation.
    Major Immunosuppressants

 Cyclosporine A
 Tacrolimus (FK-506)
 Sirolimus (Rapamycin)
 Steroids
 Azathioprine
 Mycophenylate Mofetil
Inhibitors of T cell Receptor Signaling


   Cyclosporine

   Tacrolimus
T cell Receptor Signaling Pathway


                               Zap-70
                     Fyn
                               PIP2
            PLC

                         IP3          DAG

            Ca2+
                  CaM
           Calcineurin
      T cell Signaling: Calcineurin
    Cyclosporine

                          CaM                 Calcineurin
                   Calcineurin


Cyclophilin

                                              P
                                     NF-ATP
                                                       NF-AT
                                 P
                                                             Transcription
                                                        Cytokine Gene
                                       NF-ATN

                                                   Nucleus
            Immunosuppressants

   Monoclonal/Polyclonal Antibodies
     Antithymocyte   Globulin
     CD3 (OKT3)
     CD25 (

   Inhibitors of Cytokine Transcription
     Corticosteroids
         Antiproliferative Agents

   Azathioprine

   Mycophenylate mofetil
Inhibition of Clonal Expansion
                Corticosteroids

   Mechanism
     Binds intracytoplasmic receptors
     Steroid/receptor complex migrates to nucleus
     Binds to gene promoters and NFAT



   Therefore impairs gene transcription of
    regulatory cytokines.
                     Summary

   Immunosuppressive properties related to
    effects on T cell activation and proliferation.

   Inhibition of T cell activation and proliferation
    are associated with the most successful
    immunosuppression.

								
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