Renal Transplant Immunobiology Flashcards
(31 cards)
Both cytotoxic T lymphocytes (CTLs) and Ab-producing B cells are important in mediating rejection.
That’s true. These both get activated by T helper cells.
Why is it significant that HLA genes are located very close to each other in the genome?
They’re inherited via haplotypes without crossing over between the HLA genes. Siblings have a 1/4 chance of having exactly matched HLA genotypes.
Which HLA loci are actually matched when matching solid organs?
HLA-A, HLA-B, and HLA-DR.
I’m not sure why… Probably just because DR is so close to DP and DQ that they’re very tightly linked?
Syngeneic, allogeneic, and xenogeneic?
Syngeneic - identical twins. (I don’t think this term applies if just the HLA genotype is the same… but not 100% sure)
Allogeneic - same species, different genes.
Xenogeneic - Different species.
The probability that T cells recognize a given peptide antigen is 1/100,000 to 1/1,000,000. What’s the probability that a given T cell will recognize an alloantigen?
1/20
(Which, you should recognize is astoundingly high. Maybe this is because of the way T cells develop - selected for loose affinity for self-MHC + self-peptide; if there’s slightly different donor-MHC or donor-peptide, they’re able to react? (I’m making this up… but it helps me make sense of this.)).
What is direct allorecognition?
A donor antigen-presenting cell (APC) presents donor-MHC + donor-peptide to a recipient T cell.
(the slide just says APC, but the way he talks about cells migrating out of the tissue, it sounds like he’s really talking about pAPCs like DCs and macrophages)
What is indirect allorecognition?
A recipient pAPC migrates into the graft, picks up some some donor antigen and present it on recipient-MHC to a recipient T cell.
(Non-self Ag on self-MHC to self-T cell)
Recall that this whole presentation to helper T cells business mainly happens in the lymph nodes.
OK
What is time frame over which direct vs. indirect alloresponses to a graft will happen?
(How does this correspond to the graft survival curves?)
Direct: Greatest immediately post-transplant, but then dwindles as the donor (p)APCs turn over and aren’t replaced with new ones from bone marrow.
Indirect: Starts low, but increases with time as more recipient pAPCs have had time to migrate into the graft tissue and present Ag to recipient T cells.
(explains the shape of the survival curves of transplanted grafts: higher rate of rejection early on, with slower rates of rejection as direct recognition as petered out.)
What mediates hyperacute rejection?
Time frame?
What can be done to prevent it?
Hyperacute rejection is from pre-formed Abs against MHC I molecules (from prior sensitization) or blood-group (ABO) antigens.
This happens in minutes - can see kidney turn black in the OR.
Prevention: Test for Abs, match blood type. If necessary, can try to desensitize the recipient.
Time frame for acute humoral and acute cellular rejection?
How are these prevented (broadly speaking)?
Time frame: Days to weeks.
Prevent/treatment: Immunosuppression.
What mediates “chronic rejection”?
It’s a mix of immune and non-immune causes.
Non-immune causes include…
-ischemic injury
-calcineurin inhibitors
What does H&E of a kidney that experienced hyperacute rejection look like?
Lots of necrosis. Some thrombus in the capillaries.
Not much cellular infiltrate- there wasn’t time for it.
What does H&E of a kidney with acute cellular rejection look like?
Mononuclear infiltrate
- tubulitis and interstitial infiltrate.
(as you’d expect, lots of lymphocytes)
What does H&E of a kidney with acute humoral rejection look like?
Vasculitis. I
Interstitial hemorrhage.
Capillary-endothelial swelling.
(there isn’t necessarily a lymphocytic infiltrate, but there can be)
What are 2 ways to more specifically distinguish between acute cellular and acute humoral rejection?
Acute humoral rejection will have:
- Circulating anti-donor Abs.
- C4d deposits in the tissue.
What’s specially about C4d?
It is deposited into the tissue where complement is activated. (in this case, the complement is activated via antibodies)
Typical histologic features of chronic rejection?
Fibrosis and neointimal thickening.
3 effects of immunosupression?
Which effect limits their usefulness?
Immunosuppression.
Immuno-deficient complications.
Non-immune toxicity (this tends to be the limiting factor).
Immuno review: 3 signals required for full activation of a T cell?
Signal 1: TCR binding MHC + Ag. (from APC)
Signal 2: CD28 binding B7. (from APC)
Signal 3: IL-2R binding IL-2. (autocrine/paracrine)
(I guess other cytokines could be considered part of Signal 3, as well.)
How can Signal 1 (TCR binding) be blocked from outside the cell? (2 ways)
Thymoglobulin - polyclonal anti-TCR Abs.
Monoclonal anti-CD3 (OKT3, or newer chimeric/humanized versions).
What second messenger is used to conduct TCR signaling?
What are the downstream effects of this?
Increased intracellular Ca++.
Ca++ binds calcineurin (important!).
Activated calcineurin allows NFAT (a transcription factor) to translocate into the nucleus (less important to know).
What are 2 drugs that inhibit intracellular TCR signaling? What are their molecular targets?
Cyclosporin binds cyclophilin.
Tacrolimus (FK506) binds FKBP12.
Each of these create a complex that inhibits calcineurin.
(tacrolimus is preferred, I believe)
What’s a drug that targets Signal 2?
Belatacept is CTLA-4-Ig, which binds B7.1 and B7.2, preventing them from binding CD28. (This is soluble CTLA-4. This is NOT an anti-CTLA-4 Ab.)
(recall that drugs that inhibit CTLA-4 have been used to try to “unleash” the immune system against things like melanoma)
