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Immunology > Transplant Immunology- A clinician's view > Flashcards

Transplant Immunology- A clinician's view Flashcards

1
Q

What were the first immunosuppressive drugs (1959)?

A
  • azathioprine

- steroids

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2
Q

The human leukocyte antigen system (HLA) codes for what molecules that are critical for discriminating self from non-self? What chromosome?

A
  • MHC molecules

- chromosome 6

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3
Q

What cell type expresses class I versus class II MHC molecules?

A

I: nucleated cells
II: B cells, macrophages, APCs

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4
Q

What do the MHC molecules do?

A

present antigen to TCR

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5
Q

How are HLA alleles expressed?

A

Co-dominant

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6
Q

What does ‘HLA mismatch’ mean?

How many alleles are most critical wrt matching?

A

the number of donor alleles that are foreign to the recipient

16 alleles (2 x 8 loci: A, B, C, DR, DQ, DQa, DP, DPa).

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7
Q

Why might someone have anti-HLA Abs?

A
  • pregnancy
  • blood transfusion
  • organ transplant

can also occur without foreign antigen exposure: viral infx

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8
Q

What test is carried out to detect HLA crossmatch?

A

Compliment-Dependent Cytotoxicity Crossmatch Test= (CDC) Crossmatch Test

(Ab binds MHC on donor T cell and triggers compliment–> MAC punches hole in T cell and dye enters= + crossmatch…not good bc risk of hyperacute rejection)

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9
Q

Hyperacute rejection is mediated by what mainly?

A

Antibodies

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10
Q

What is the most sensitive and specific method to test for crossmatch?

A

Flow cytometry

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11
Q

If CDC crossmatch is negative but flow cytometry crossmatch is positive what can happen to a graft?

A

acute antibody-mediated rejection

  • can occur ~7 days post transplant
  • memory cells produce high levels of anti-HLA Abs
  • compliment activated–> deposits C4d in organ
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12
Q

Panel Reactive Antibody (PRA) tells us what?

What do we use these results for?

A

what percentage of relevant HLA class I and II molecules a person has antibodies against. (0-100%)

-used to perform a ‘virtual crossmatch’

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13
Q

What is direct Ag presentation versus indirect presentation in transplant?

A

direct: donor MHC presented intact to host T cell by donor APC
indirect: recipient APC presents processed donor MHC to recipient T cell

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14
Q

What are the three signals for T cell activation?

A
  1. Ag-specific : T cell receptor and MHC on APC
  2. Costimulatory signals (Ag nonspecific) –> signal 1+2= interleukin-2 production
  3. IL-2/CD25 –> activates mTOR–> CELL PROLIFERATION (T cell)
    result: T cells proliferate and infiltrate graft…activate B cells as well which produce alloantibody
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15
Q

What is acute cellular rejection?

A
  • activated T cells enter into a graft and release inflammatory cytokines
  • kills cells expressing foreign HLA Ag
  • metaplasia (to mesenchymal cells)–> fibrosis
  • occurs within days of transplant (if no immunosuppression given)
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16
Q

List the immunosuppressive medications that 1. inhibit activation/proliferation and 2. deplete T cells:
(at the risk of infx/malignancy)

A

Inhibit activation/proliferation of T cells:
1. cyclosporin, tecrolimus : block cytokine production

  1. belatacept: block costimulation
  2. basiliximab: IL-2 mediated activation
  3. azathioprine, mycophenolic acid, sirolimus: lymphocyte proliferation

Deplete T cells:
1. thymoglobulin, alemtuzumab

17
Q

What is the problem with T cell depletion?

A
  • T cell depletion is transient (lymphocyte population reconstitutes over time)
  • does not prevent humoral (Ab-mediated) rejection –> mostly for cell mediated rejection
  • inc in risk of infx and malignancy when immunosuppressed
18
Q

What is acute humoral rejection?

A
  • activation of B cells with specificity against donor HLA
  • new DSA made against donor HLA (** if Ab was present before tx: hyperacute rejection, if Ab develops after tx: acute and/or chronic humoral rejection)
  • see compliment deposition in graft
19
Q

Describe chronic cellular and humoral rejection:

A
  • associated with fibrotic changes
  • chronic humor rejection has characteristic changes that vary by organ
  • no current effective treatments for chronic rejection
20
Q

What is the word for: a durable state of Ag- specific unresponsiveness in presence of Ag in a patient that is immunologically competent 9not immunosuppressed or immunodeficient)

-no DSA, no T cell response to graft

A

‘tolerance’

tolerance means: absent immune response to graft but normal immune response to third-party antigens.

21
Q

What are characteristics of those who have spontaneous tolerance?

A
  • younger donors w better graft quality
  • less Ab produced with pre-tx transfusions
  • normal response to vaccination
  • may be more likely with liver
22
Q

How does ‘mixed-chimerism’ work to produce tolerance?

A
  • immunosuppress recipient before/at time of tx
  • infuse donor bone marrow cells
  • slowly remove immunosuppression post-tx

Immunology (32 decks)

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