Transplant Immunology- A clinician's view Flashcards
What were the first immunosuppressive drugs (1959)?
- azathioprine
- steroids
The human leukocyte antigen system (HLA) codes for what molecules that are critical for discriminating self from non-self? What chromosome?
- MHC molecules
- chromosome 6
What cell type expresses class I versus class II MHC molecules?
I: nucleated cells
II: B cells, macrophages, APCs
What do the MHC molecules do?
present antigen to TCR
How are HLA alleles expressed?
Co-dominant
What does ‘HLA mismatch’ mean?
How many alleles are most critical wrt matching?
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).
Why might someone have anti-HLA Abs?
- pregnancy
- blood transfusion
- organ transplant
can also occur without foreign antigen exposure: viral infx
What test is carried out to detect HLA crossmatch?
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)
Hyperacute rejection is mediated by what mainly?
Antibodies
What is the most sensitive and specific method to test for crossmatch?
Flow cytometry
If CDC crossmatch is negative but flow cytometry crossmatch is positive what can happen to a graft?
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
Panel Reactive Antibody (PRA) tells us what?
What do we use these results for?
what percentage of relevant HLA class I and II molecules a person has antibodies against. (0-100%)
-used to perform a ‘virtual crossmatch’
What is direct Ag presentation versus indirect presentation in transplant?
direct: donor MHC presented intact to host T cell by donor APC
indirect: recipient APC presents processed donor MHC to recipient T cell
What are the three signals for T cell activation?
- Ag-specific : T cell receptor and MHC on APC
- Costimulatory signals (Ag nonspecific) –> signal 1+2= interleukin-2 production
- IL-2/CD25 –> activates mTOR–> CELL PROLIFERATION (T cell)
result: T cells proliferate and infiltrate graft…activate B cells as well which produce alloantibody
What is acute cellular rejection?
- 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)
List the immunosuppressive medications that 1. inhibit activation/proliferation and 2. deplete T cells:
(at the risk of infx/malignancy)
Inhibit activation/proliferation of T cells:
1. cyclosporin, tecrolimus : block cytokine production
- belatacept: block costimulation
- basiliximab: IL-2 mediated activation
- azathioprine, mycophenolic acid, sirolimus: lymphocyte proliferation
Deplete T cells:
1. thymoglobulin, alemtuzumab
What is the problem with T cell depletion?
- 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
What is acute humoral rejection?
- 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
Describe chronic cellular and humoral rejection:
- associated with fibrotic changes
- chronic humor rejection has characteristic changes that vary by organ
- no current effective treatments for chronic rejection
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
‘tolerance’
tolerance means: absent immune response to graft but normal immune response to third-party antigens.
What are characteristics of those who have spontaneous tolerance?
- younger donors w better graft quality
- less Ab produced with pre-tx transfusions
- normal response to vaccination
- may be more likely with liver
How does ‘mixed-chimerism’ work to produce tolerance?
- immunosuppress recipient before/at time of tx
- infuse donor bone marrow cells
- slowly remove immunosuppression post-tx
