Lecture 9

Question 1

What are the two types of allorecognition?

Answer 1

1. Direct alloantigen recognition

2. Indirect alloantigen recognition

Question 2

Direct alloantigen recognition

Answer 2

T-cell recognises unprocessed allogeneic MHC molecule on graft APC = ACUTE REJECTION

Question 3

Indirect alloantigen recognition

Answer 3

Presentation of processed peptide of allogeneic MHC molecule bound to self MHC molecule = CHRONIC REJECTION

Question 4

Define Immunotolerance

Answer 4

= the lack of immune response to antigen on re-exposure

• tolerance to self antigens = auto immunity
• tolerance to environmental antigens
  o Dietary = coeliac disease
  o Air-bourne = Allergies
• tolerance to non-self (allo) antigens = graft rejection

Question 5

Tolerance

Answer 5

= Regulatory mechanisms to prevent aberrant activation of self-reactive lymphocytes

• active process
• antigen-dependent
• involves both B & T cells

Question 6

Define central tolerance

Answer 6

Operates during lymphocyte ontogeny

Question 7

Define peripheral tolerance

Answer 7

Operates in peripheral lymphoid tissue

–> deletion, anergy or regulation of lymphocytes that can recognise self-antigens in the peripheral tissue

Question 8

Transplant tolerance - central tolerance

Answer 8

• Inducing mixed chimerism
• Donor & recipient haemapoitetic cells co-exist
• Deletion of allo-reactive clones

Question 9

Transplant tolerance - peripheral tolerance

Answer 9

• Not all antigens expressed in thymus - evade central tol.
• Tolerance to antigens achieved by
  o Deletion of activate T-cells
  o T cell anergy
  o Activation regulation

Question 10

What are the two signals for T cell activation?

Answer 10

Signal 1: TCR binds to HLA-peptide complex

Signal 2: Co-stimulation
CD28 on T-cells binds to co-stim
molecules B7-1 (CD80) and B7-2 (CD86)
on activated APCs

Question 11

Induction of Anergy

Answer 11

Functional responsiveness on antigen recognition (self-reactive T-cells unresponsive to self-antigens)

Question 12

Inhibitory receptors - function and types

Answer 12

= engagement of inhib. receptors on recognition of self antigen

--> CD28 family known to have role in tolerance
o CTLA-4 competes w CD28 for binding to 
CD80/86
o PD-1 binding to ligand affects CD28 
mediated activation

Question 13

Belatacept

Answer 13

Drugs that blocks CD28 interaction with ligands

• inc. graft survival
• Phase II clinical trials

Question 14

Regulatory T cells

• types
• role

Answer 14

• Suppress Immune Responses
• Need TGF-B & IL-2 to survive

o Natural (nTregs) & Peripheral (pTregs)

–> Generated in thymus & auto-reactive (nTregs)

–> Generated outside thymus from naive CD4+ T cells after antigen exposure and in presence of TGF-B (pTregs)

Question 15

Mesenchymal Stromal Stem Cell

Answer 15

• Derived from bone marrow
• Precursors to bone, fat and other CT
• migrate to site of inflam.
• Induction/Diff. of suppressive pop.s
• Inhibits allo-antibody production

Question 16

Dendritic Cells

Answer 16

• Immature DCs express low MHC II & co-stim molecules
• Constantly present self antigen without maturation
• Induce T-cell tolerance
  o Autoreactive T cells
  o Promote Treg generation

Question 17

Lymphocyte depletion

Answer 17

• Depletion of allo-specific T & B cells

Question 18

B Cell Tolerance

Answer 18

• Tolergenic B cells less well understood

- Bregs : immunosuppressive effects through IL-10 production