Acquired Immunity

1
(No Transcript)
2
Peter Medawar
3
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

4
(No Transcript)
5
First Set Rejection
Rejection 7-8 Days
6
(No Transcript)
7
Second Set Rejection (Memory)
First Graft
Rejection 3-4 Days
8
(No Transcript)
9
Specificity
Rejection 3-4 Days
Rejection 7-8 Days
Third Party Graft
10
Terminology
Autograft - One site to another on the same
individual
Isograft - between two genetically identical
individuals
11
Terminology (cont.)
Allograft - between genetically distinct
individuals of the same species
Xenograft - between different species
12
Beginning of Rejection
13
Rejected Mouse Skin Graft
14
Rejection is mediated by T cells
15
Role of CD4 and CD8 Cells
16
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.

17
(No Transcript)
18
Parent to F2
B
B
A
B
A
A
AA
AB
AB
AB
F2
F1
A
B
AB
AB
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
19
The Human MHC
Class I
Class III
Class II
DP
DQ
DR
C4
C2
Bf
B
C
E
A
G
F
20
(No Transcript)
21
(No Transcript)
22
Mixed Leukocyte Reaction
Spleen
5 Days
2000 RADS
Add 3H-Thymidine
18-24 Hours
Spleen
Determine Incorporation
23
Acute Rejection

• Primary Cellular
• Massive infiltration of macrophages and
  lymphocytes
• Decreased graft function
• Clinically appears at gt10 days post-tx and can
  occur anytime thereafter.

24
Acute Rejection Grade 1a
25
Acute Rejection - Grade 3a
26
Chronic Rejection

• Slow steady decline of graft function and
  progressive occlusion of of vessels/passageways.
• Result of cellular and humoral mechanisms

27
Chronic Rejection
28
Hyperacute Rejection
29
(No Transcript)
30
(No Transcript)
31
Clinical Transplantation
32
(No Transcript)
33
(No Transcript)
34
(No Transcript)
35
(No Transcript)
36
Objectives of Immunosuppression

• Facilitate acceptance of the allograft
• Specific
• Low toxicity

37
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.

38
Major Immunosuppressants

• Cyclosporine A
• Tacrolimus (FK-506)
• Sirolimus (Rapamycin)
• Steroids
• Azathioprine
• Mycophenylate Mofetil

39
Medical Issues and Immunosuppression

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

40
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).

41
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.

42
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.

43
Major Immunosuppressants

• Cyclosporine A
• Tacrolimus (FK-506)
• Sirolimus (Rapamycin)
• Steroids
• Azathioprine
• Mycophenylate Mofetil

44
Inhibitors of T cell Receptor Signaling

• Cyclosporine
• Tacrolimus

45
T cell Receptor Signaling Pathway
46
T cell Signaling Calcineurin
Calcineurin
47
Immunosuppressants

• Monoclonal/Polyclonal Antibodies
• Antithymocyte Globulin
• CD3 (OKT3)
• CD25 (
• Inhibitors of Cytokine Transcription
• Corticosteroids

48
(No Transcript)
49
Antiproliferative Agents

• Azathioprine
• Mycophenylate mofetil

50
Inhibition of Clonal Expansion
51
Corticosteroids

• Mechanism
• Binds intracytoplasmic receptors
• Steroid/receptor complex migrates to nucleus
• Binds to gene promoters and NFAT
• Therefore impairs gene transcription of
  regulatory cytokines.

52
(No Transcript)
53
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.