Week 6 Recitation - Allograft Recognition Flashcards
Cellular Rejection
Th1 Mediated
Kidney is constantly producing FOREIGN AG’s
VVVV
Taken by DENDRITIC CELL (apc)
VVV
T-CELL ACTIVATION
CD4+ Th produces cytokines –> activate/proliferate other leukocytes
CD8+ Tc –> directly damage AG source
Cellular Rejection
Humoral Rejection
Th2-Cell
VVVV
B-CELL ACTIVATION
differentiate into AB producing Plasma cells
VVVV
ANTIBODIES + COMPLEMENT SYSTEM
Humoral Response
Direct & Indirect
Allo-Recognition
T-Cell Activation by the APC (dendritic cell)
is ESSENTIAL FIRST STEP
- *Direct**
- *APC = Donor Derived**
- *Indirect**
- *APC = Recipient Dirived**
Both ultimately do the same thing!
Indirect Allograft Rejection Pathway
CD8+ Tc Path
APC is RECIPIENT Derived
- Recipient APC recognizes Kidney Cells
- APC encounters CD8 T-Cytotoxic Cells –> ACTIVATED
- –> Proliferation of CD8 Tc
- –> Reach the RENAL BLOOD VESSEL (kidney)
- KILL / DESTROY cells that are carrying the ANTIGEN
Indirect Allograft Rejection Pathway
CD4+ Th Path
APC is RECIPIENT Derived
-
Recipient APC encounters CD4 Th Cells –> ACTIVE
- –> proliferation of CD4 Th
-
Th1 –> produces Cytokines IL-2 / INF-y
- IL-2 –> stimulates proliferation of all cells = CD8 + CD4
-
INF-y –> INCREASE MHC expression on endothelial cells + renal tubules
- –> more MHC to present AG for CD8
- also ACTIVATE MACROPHAGES –> assist Th cells
-
IF ENVIRONMENTAL FACTORS ARE CORRECT = Th1 –> Th2
-
Th2–> activatesB-cell
- –> bcomes a PLASMA CELL
- –> PRODUCE AB’s –> ENDOTHELIAL DMG to RENAL BLOOD VESSEL
- –> bcomes a PLASMA CELL
-
Th2–> activatesB-cell
Direct Allograft Rejection Pathway
APC is from DONOR
-
We dont just transplant the KIDNEY
- we also transplant OTHER CELLS like APC’s
-
DONOR APC –> migrates OUT OF THE KIDNEY –> LYMPHOIDS
- Encounters naive CD8 or CD4
- then body responds the same way as INDIRECT pathway
- occurs REGARDLESS if the APC is from donor or recipient
- Encounters naive CD8 or CD4
Three Signal Model of T-Cell Activation
Need the
Costimulatory Signal = #2
from
B7** (APC) & **CD28 (T-Cell)
in order for
Signal Transduction
Rejection Types & Timing
HYPERACUTE Rejection
Minutes
Failure to IDENTIFY Pre-Existing DONOR AB (DSA)
Below is a Failure of Immunosuppresive Therapy
Acute Rejection
Days-Weeks
Late-Acute Rejection
> 3 months
Chronic Rejection
What influences Rejection Risk for ORGAN TYPES?
Determining Rejection Risk
Organs that are:
Very rich in LYMPHOID TISSUE = HIGHER RISK of rejection
because a Higher Population of APC’s are transplanted w/ organ
LUNG / SMALL BOWEL
>
Heart
>
Kidney / Pancreas
>>
Liver (lowest risk)
Which Organ has the HIGHEST risk for REJECTION?
LUNG / SMALL BOWEL
Organs rich with lymphoid tissue = higher risk
due to APC’s transplanted w/ organ
Which ORGAN has the lowest risk for REJECTION?
LIVER
Less lymphoid tissue = lower risk for rejection
less APC’s are transplanted w/ organ
Rejection Risk
ABO BLOOD TYPES
Blood Group Mismatch for a DECEASED DONOR TRANSPLANT
is an ABSOLUTE CONTRAINDICATION
For living patient, due to organ shortage:
this can be overcome for LIVING KIDNEY DONOR but at HIGH RISK
AB = Universal RECIPIENT
O = Universal dOnor
A = Can only take A or O
B = Can only take B or O
What type of ORGAN DONOR can
OVERCOME ABO BLOOD TYPE MISMATCH?
LIVING KIDNEY DONOR
Due to severe organ shortage
but they are considered at VERY HIGH RISK for rejection
need STRONGEST Immunosuppression
HYPERACUTE Transplant REJECTION
Occurs in MINUTES = worst case scenario
ANTIBODY MEDIATED REJECTION
VVVV
COMPLEMENT ACTIVATION
AG-AB complexing
Rejection Risk
on PREVIOUS EXPOSURE to FOREIGN AG = HLA
Antibodies AGAINST HLA
Since RBC’s are NOT nucleated –> do NOT communicate with cell markers
but All other cells present HLA’s
Only These HLA-Types are VERY IMMUNOGENIC
HLA - A
HLA - B
HLA - DR (MHC2)
ABSOLUTE CONTRAINDICATION for
DECEASED Donor Transplants
May be overcome for Living RENAL Donor
3 THINGS THAT RESULT IN DSA (HLA Antibody) PRODUCTION
- Ab’s** to HLA are *NOT naturally occuring
- unlike blood group AB’s*
BLOOD TRANSFUSION
PREGNANCIES
HLA from the FATHER
Previous ORGAN/TISSUE TRANSPLANTS
Which HLA-Types are important for TRANSPLANTS
These are all very IMMUNOGENIC
HLA - A
HLA - B
HLA - DR
MHC2
What do you call it when there is
2 HLA Matches?
Ex.
Both patients have:
HLA - B27 & HLA - DR36
2/6 in the HLA MATCH
OR
4/6 in the HLA-MISMATCH
What type of ORGAN DONOR can OVERCOME
DSA MISMATCH
DSA = Donor-Specific HLA Antibody
LIVING RENAL = KIDNEY DONOR
Due to organ shortage, we can do this
ABSOLUTE CONTRAINDICATION
for deceased donor transplants for:
Kidney / heart / lung / livers
How to we PREDICT REJECTION RISK?
Based on DSA, before finding a donor.
PRA = Panel Reactive Antibody
Estimates BOTH:
Rejection RISK & WAIT TIME
evaluated every 1-3 months
Measures the:
- *# of Pre-Formed DSA** in
- *Potential Recipient vs RANDOM POOL of HLA from GEN-POP**
- *High PRA = >30%**
- *SENSITIZED = High Risk for Rejection**
PRA
What does it measure?
And against what?
- *Panel Reactive Antibody**
- *Test to PREDICT REJECTION RISK**
Measures:
Amount of Pre-Formed HLA AB (DSA)
in Potential Recipient
vs
Random pool of HLA from GENERAL POPULATION
Higher PRA –> Greater Waiting Time
>30 = sensitized & @high risk
What test do we use to PREDICT REJECTION RISK
AFTER we find a UNIQUE DONOR?
CROSSMATCH = XM
Determines the immunologic compatibility between:
- *Donor & Recipient**
- *before EVERY TRANSPLANT**
Measures:
the immune response (HLA Ab) that the RECIPIENT has
to his/her UNIQUE DONOR (HLA Ag)
NONE/NEGATIVE is what we want
not specific to WHICH ab is present
- *Crossmatch = XM**
- *TEST**
Negative** or **NONE
is the result we want
Measures the:
Immune Response Recipient = HLA Antibody
has to
His/Her Unique Donor = HLA Antigen
Test is NOT specific for WHICH AB is present
not DSA specific
What does it mean to have a
POSITIVE CROSSMATCH RESULT?
Positive = BAD –> Poor Outcome
If Deceased Donor Transplant –> CANCELLED
organ moves to next person on list
Due to severe organ shortage,
May be OVERCOME in case of
Living Kidney Donor and Rarely in Heart transplant
HIGH RISK
Is there a DSA Specific test?
YES
Crossmatch is NOT SPECIFIC
But it is EXPENSIVE & OPTIONAL
Used AFTER TRANSPLANT to monitor for appearance of
de-novo DSA
What type of ORGAN DONOR can OVERCOME
a POSITIVE CROSSMATCH RESULT?
LIVING KIDNEY DONOR
and
in some cases Heart Transplants
Due to severe organ shortage
Positive = Recipient has Pre-formed DSA
HIGH RISK or rejection
