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HIS > HIS14 Transplantation Immunology > Flashcards

HIS14 Transplantation Immunology Flashcards

1
Q

Transplantation

A
  • Taking of cells, tissues, organs (graft) from one to another
  • Donor vs Recipient
  • Orthotopic: transplanted into normal anatomical location (e.g. liver transplant)
  • Heterotopic: grafted into a different anatomical location (e.g. kidney transplant in iliac fossa)
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2
Q

Transplantation immunology

A
  1. Tolerance to foreign antigens (in transplantation in end stage organ failure)
  2. Attack tumour antigens (tumour biology)
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3
Q

Autograft, Isograft, Allograft, Xenograft

A

Autograft: Graft from one part of body to another (same body)

Isograft: Graft between genetically identical individuals (monozygotic twins)

Allograft: Graft between different members of same species

Xenograft: Graft between members of different species (monkey to man)

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4
Q

2nd set response - 1st input in transplantation

A

1st time: skin B on mouse A —> rejected between days 10-15

2nd time: skin B on mouse A —> rejected in days 5-8 (accelerated fashion)
1st time: skin C on mouse A —> rejected between days 10-15

Conclusion: something in mouse recognise specific strain of skin from different mouse

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5
Q

Human leukocyte antigens (HLA)

A

Chromosome 6

HLA-A, HLA-B, HLA-C region genes: MHC class I molecules —> ALL nucleated cells

HLA-D (DP, DQ, DR) region genes: MHC class II molecules —> APC

Well matched HLA predicts better transplant survival (less important in liver)

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6
Q

Specific immune response

A

Dendritic cells / Macrophage (MHC class II)
—> CD4 Helper T cell
—> **IFNγ + **IL-2

—> B cell —> Ab
AND
—> CD8 Cytotoxic T cell
AND
—> Macrophage (although belong to innate)
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7
Q

Allograft rejection

A
  1. Cell-mediated immunity (T cells)
  2. Humoral immunity (B cells)
  3. NK cells
    —> Hard to target a specific type of cell and induce tolerance to Allograft
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8
Q

T cell selection —> Discriminate between Self and Non-self

A

HSC in BM
—> ***Thymocytes in BM
—> Maturation in Thymus
—> Positive selection (T cells able to bind self MHC molecules)
—> Negative selection (T cells not reactive but recognise self-MHC/antigen)
—> Mature T cell (CD4+ / CD8+, able to recognise foreign antigens/self-MHC complex)

System NOT absolutely perfect —> some Self-reacting T cells remain

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9
Q

MHC class II-Peptide TCR interaction

A

Signal 1:

  • TCR: recognise foreign peptide + α1, β1 subunit of MHC
  • CD4 co-receptor: recognise β2 subunit of MHC

Different foreign peptide —> Requires different TCR shape

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10
Q

Dendritic cells

A

Most potent APC
—> Immature DC circulating in bloodstream
—> Antigen capture
—> Mature DC migrate into Secondary lymphoid organ (e.g. LN)
—> Present Ag to T cell in Secondary lymphoid organ

Immature DC:

  • High intracellular MHC-II
  • High endocytosis/phagocytosis
  • Low CD40, CD80, CD86
  • Highly mobile

Mature DC:

  • ***High surface MHC-II
  • Low endocytosis/phagocytosis
  • ***High CD40, CD80, CD86
  • Stationary in LN
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11
Q

Antigen recognition by T cell

A

MHC restricted!!!
—> TCR “A” can only recognise MHC “A”
—> TCR “A” cannot recognise MHC “B”

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12
Q

2 signals of T cell activation (safety mechanism)

A

Signal 1: MHC / Peptide complex
Signal 2: Co-stimulatory signal (recognised by Co-receptor on T cell)

T cells cannot be activated with Signal 1 alone, Signal 2 also required

Signal 1 only: Anergy / cell death
Signal 2 only: No effects
Signal 1 + 2: Activation of T cells

Co-stimulatory pathways:

  1. B7 (on APC) - CD28/CTLA4 (on T cells)
  2. CD40-CD40L
  3. ICOS-B7RP1
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13
Q

B7 - CD28/CTLA4 pathway

A

Without B7 co-stimulation:

  • Limited expansion
  • Minimal cytokines
  • Requires high concentration of Ag to activate T cell
  • Non-sustained responses
  • Anergy / apoptosis

Together with B7 co-stimulation:

  • Robust expansion
  • Maximal cytokines
  • Responds to low Ag concentration
  • Sustained responses
  • T cells primed for re-challenge (i.e. Memory T cells)

Negative feedback loop of CTLA4 signaling:
—> B7 / CD28 stimulatory signaling
—> induce gene transcription of CTLA4 in T cell at the same time
—> B7 / CTLA4 bind together (CTLA4 compete with CD28)
—> Negative feedback
1. Blockage of IL-2R expression on T cell
2. Suppression of IL-2 production on T cell
3. Cell cycle arrest
4. Dominant inhibition of both CD28 and TCR mediated pathway
5. Induction of anergy / apoptosis
—> T cell response ***dampen down
—> Ensure no sustained T cell response (prevent severe inflammatory reaction)

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14
Q

***Direct + Indirect pathways in Ag presentation in organ transplantation

A

Indirect pathway (Non-self Peptide + Self MHC) (Predominant):
Donor Ag
—> picked up by Recipient APC
—> presented on Recipient MHC
—> recognised and activation of Recipient T cells

Direct pathway (Non-self Peptide + Non-self MHC) (Relatively minor):
Donor APC
—> present Donor MHC
—> recognised and activation of Recipient T cells

BOTH pathways need to be suppressed to ensure no rejection

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15
Q

***Tempo of rejection after organ transplantation

A
  1. Hyperacute rejection (用Ab)
    - **Pre-existing Recipient Ab to Donor tissue (7 mins) (Rarely seen) (e.g. ABO blood group incompatibility)
    - Rapid **    thrombotic occlusion of graft vessels within minutes after vascular anastomosis
    - Pre-existing Ab bind to graft endothelium —> activate ***Complement (Classical pathway)
  2. Acute rejection (用Cellular immunity)
    - **CD4 controlled CD8 mediated (8-11 days) (Mostly seen)
    - CD4 + CD8 activation
    - Acute cellular rejection
    —> **    Cytotoxic T cell-mediated lysis, Macrophage-meditated lysis, NK-mediated lysis
    —> Necrosis of parenchymal cells, lymphocyte, macrophage infiltration
  3. Chronic rejection
    - ***Mixed CD4 and Ab (3 months - 10 years) (even patients are on immunosuppressants)
    —> Perivascular inflammation, Fibrosis, Arteriosclerosis, Macrophages + Smooth muscle cells predominant
  4. Xenograft rejection (Hyperacute)
    - Pre-existing Ab to Donor tissue (7 mins)
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16
Q

***Immunological components of rejection

A

APC
—> CD4 Th cell

  1. IL-2, IFNγ —> ***CD8 (activated by graft cells directly as well, ∵ recognise foreign MHC) —> Cell mediated cytotoxicity
  2. IL-2, IL-4, IL-5 —> ***B cells —> Ab —> ADCC by NK cells, Complement activation, Lytic damage vascular occlusion
  3. Lymphotoxin, IFNγ —> ***Macrophage —> Inflammatory mediators

另外:
***Complement —> Lytic damage vascular occlusion, Inflammatory mediators

17
Q

***Preventing rejection

A
  1. Pre-transplant - Laboratory tissue matching
    - ABO antigens testing
    - Lymphocytotoxicity
    - Molecular HLA typing
  2. Non-specific immunosuppression
    - Cyclosporin A
    - Tacrolimus
    - Monoclonal Ab targeting CD / other lymphocyte surface molecules (more specific)
18
Q

Prevent rejection —> 1. Pre-transplant - Laboratory tissue matching

A
  1. ABO antigens testing
    - ABO antigens present on vascular endothelium of graft apart from RBC
    - Prevent Hyperacute rejection
  2. Lymphocytotoxicity
    - **Serological detection of MHC-I and MHC-II by using Ab for **both Recipient and Donor
    —> 用Ab去睇下Recipient / Donor既cell上面有咩類型的MHC
    —> match MHC between them
    —> better graft survival
    - Mixing patient’s lymphocyte with Ab (specific for a particular MHC) —> incubate —> add Complement and Trypan blue after
    - Performed while Donor organ is preserved on ice
  3. Molecular HLA-typing
    - PCR-based
    - Detection of genomic HLA in donor + recipient using sequence-specific primers
    - Very useful esp. in ***Bone marrow transplantation (HLA details are needed)
    - Not routinely done in organ transplantation
    - Good HLA matching —> Better graft survival
    - ABO antigen mismatch not accepted
    - HLA mismatch not accepted in BM transplantation
    - HLA mismatch may be accepted in solid organ transplantation
19
Q

***Prevent rejection —> 2. Non-specific immunosuppression

A

Non-specific immunosuppression abolish activity of immune system regardless of the antigen
—> leave graft recipient susceptible to infections

  1. Cyclosporin A
    - **IL-2 transcription inhibitor
    - natural metabolite in fungus
    - common for current use
    - **    Narrow therapeutic window
    - **Renal damage
    MOA:
    Binds to and inhibit **    Calcineurin
    —> inhibit NFAT
    —> inhibit transcription of IL-2 (important for T cell expansion)
  2. Tacrolimus (FK506)
    - fungal metabolite, novel macrolide, structurally unrelated to Cyclosporin A
    - **100x potent than Cyclosporin A
    - **    Less Renal damage
    - Commonly used
    MOA:
    Binds to FKBP
    —> inhibit ***Calcineurin
    —> inhibit NFAT
    —> inhibit transcription of IL-2 (important for T cell expansion)
  3. New non-specific but more selective agents
    MOA:
    - Monoclonal Ab against lymphocyte surface molecules (esp. CD3, CD4, CD8, IL2R (Anti-CD25))
    —> Eliminate cells / Block their function
    - Rescue therapy in patients refractory to steroid therapy after acute rejection
  4. Experimental: CTLA4-Ig (compete with CD28 on T cell for co-stimulatory signal —> block co-stimulatory signal to T cell), Anti-CD40
20
Q

***Problems with long term immunosuppression

A
  1. Opportunistic infections
    - by low virulent bacteria / fungi
  2. Risk of malignancy
    - lymphoma, post-transplant lymphoproliferative disease (PTLD)
  3. Pharmacological SE
    - hypertension, hirsutism, renal damage
21
Q

EBV reactivation in immunosuppressed individuals

A

EBV reactivation
—> Transform B cells in vitro / in vivo
—> induce expression of **LMP-1 on B cell surface
—> **mimics CD40 in B cells (involved in ***B cell activation pathway)
—> monoclonal band of B cells (B cells express limited viral + cellular protein)
—> PTLD (cancer)

EBV viral load ↑ in PTLD
—> ∴ used to monitor transplant patients
—> initiate preemptive therapy

22
Q

***Treatment of EBV PTLD

A

Against EBV:

  1. Reduce immunosuppression (to fight against EBV) (early, polymorphic lesions often responsive)
  2. IFNα
  3. Autologous OR HLA-matched, EBV-specific, ***CD8 T cell infusion (for solid organ transplant recipients)

Against B cells:
4. Anti-CD20 monoclonal Ab (Rituximab) —> may also be used for RA, SLE (Lecture 9)

23
Q

Calcineurin inhibitors (Cyclosporin, Tacrolimus) and PTLD

A

Original intention:
- Inhibit generation of T cell cytotoxic activity

However:

  • Induce expression of **IL-6 and **TGF-β that supports B cell activation and proliferation
  • Enhance survival of EBV-transformed cells in vitro by ***protecting from Fas-mediated apoptosis

Therefore:
- Lower doses of Cyclosporin allow T cell responses to EBV (in vitro)
—> associated with lower rates of Lymphoma than higher doses
- In children Tacrolimus is associated with higher risk of PTLD than Cyclosporin in some studies

24
Q

Holy Grail

A

Donor specific tolerance (can still recognise other foreign antigens) without need of immunosuppression

25
Q

***4 Immunological mechanisms of tolerance

A

Central tolerance
1. Clonal Deletion - essential in central tolerance (i.e. tolerance to self)

Peripheral tolerance
1. Clonal Anergy - co-stimulatory blockage (remove signal 2 e.g. CTLA4-Ig)

  1. Activation-induced cell death
    - negative feedback to T cells after a while of activation (e.g. CTLA4 signaling)
    —> apoptosis
  2. Sequestrated antigens / Ignorance
    - immunologically privileged sites (e.g. anatomically isolated: Testis, Eye not attacked by WBC)
    - precluded from contact with lymphocytes
    - lack of Ag presentation
  3. Treg cells (special Th cells): CD4+, CD25+
    - production of suppressive cytokines TGFβ and IL-10
    —> actively suppressing autoreactive T cells
26
Q

Evidence of regulatory cells

A
  1. ***Infectious tolerance (CD4+ Treg cells將tolerance傳比其他T cells instead of suppressing donor T cells because once recipient Treg cells removed, recipient T cells can still tolerate skin graft)
  2. ***Linked suppression (將tolerated同intolerated skin crossover —> 溫水煮蛙, 慢慢接受graft)

Regulatory T cells (Treg) facts:

  • CD4+, CD25+, FoXP3+ cells
  • Expression of CTLA4 (negative regulator of other T cells)
  • Existence of indigenous (native) regulatory cells to suppress “escaped” T cells against self Ag (e.g. deletion of CD25+ cells causes inflammatory bowel disease in mouse model)

Questions:

  • Can we “induce” regulatory cells for transplantation tolerance?
  • Presence of CD8+ T reg?
27
Q

Unresolved clinical problem - Chronic rejection

A

Significant problem long-term

  • **Histological hallmarks:
    1. Perivascular inflammation
    2. Fibrosis
    3. Arteriosclerosis
    4. Macrophages + Smooth muscle cells predominant
  • Antigen dependent and independent mechanisms
28
Q

Possibilities of xenotransplantation?

A
  • Lack of organs for transplantation
  • Pig-human xenotransplantation:
  1. Hyperacute Xenograft rejection
    —> Pre-existing human Ab against animals proteins
    —> Construct transgenic pigs expressing human proteins that inhibit complement activation
  2. Delayed Xenograft rejection
    —> Acute vascular rejection (incompletely understood)
  3. T cell-mediated Xenograft rejection

Concerns:

  • Barrier
  • ***Viruses?
29
Q

Future directions in solid organ transplantation immunology

A
  • Study into donor specific tolerance —> no need generalised immunosuppression
  • Characterisation of regulatory cells (T-reg)
  • Solution to chronic rejection
  • Xenotransplantation

HIS (30 decks)

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