Fetal & Transplantation

Question 1

List the 4 types of transplants.

Answer 1

• autograft (self)
• isograft (identical twin)
• allograft (same species)
• xenograft (different species)

Question 2

What is the main barrier to transplant?

Answer 2

MHC recognizes graft as non-self/foreign and activates an immune response

Question 3

Which MHC genes are looked at for transplantation tolerance predictability?

Answer 3

MHC Class II DR genes are predictive of graft tolerance

Question 4

List methods of MHC matching.

Answer 4

• ELISA - test for host antibodies against donor MHC
• flow cytometry - test for host antibodies, determine compatibility
• DNA sequencing - determine compatibility between host and donor MHC genes

Question 5

Describe the basis of a Mixed Lymphocytic Culture (MLC) assay.

Answer 5

• essentially, a transplant in vitro
• primary concept: donor cells will cause the culture cells to mount an immune response by activating T cells to proliferate and divide
• assay: add irradiated stimulator T cells into culture and measure the amount of T cell division through DNA synthesis

Question 6

Recall T cell maturation in the thymus.

Answer 6

• positive selection: T cell must have weak or intermediate interaction with self MHC and self peptide expressed on TECs and DCs
• negative selection: T cells with strong interaction to self peptide secreted by AIRE and presented on DCs are deleted

Question 7

Why is immune reaction to non-self MHC peculiar?

Answer 7

During thymic maturation, T cells are exposed to self MHC. Only those T cells that can bind to and recognize self-MHC are allowed to progress. Thus, all T cells in the body can bind to self-MHC with weak/intermediate affinity.

Why do T cells recognize another MHC as non-self? T cells that do not bind to self-MHC (presumably, those that are possible to bind to non-self) are deleted. How can they even interact with non-self MHC?

Question 8

Describe the concept of accidental resemblance.

Answer 8

Typically, you have self-MHC presenting foreign antigen => robust immune response. However, when you have foreign-MHC presenting self peptide it looks structurally similar to self-MHC+foreign Ag.

Therefore, when you have an organ transplant, the organ is expressing donor-MHC. However, physiological peptide presentation is the same as self (ex: insulin for pancreatic islet cell transplantation). Thus, this combination of allo-MHC and self-peptide resembles self-MHC+foreign Ag.

Question 9

Describe the direct method of transplantation rejection

Answer 9

donor cell is presenting endogenous donor peptide on donor-MHC => T cells mount an immune response against donor-MHC and donor peptide
- recall: accidental resemblance

Question 10

Describe the indirect method of transplantation rejection.

Answer 10

• indirect = host immune system responds to foreign antigen presented on Class II self-MHC (present to CD4 T Cells)
  ==> donor MHC are treated as foreign antigen and phagocytosed => processed => donor MHC peptide presented on self-MHC

Question 11

Define hyperacute rejection.

Answer 11

• occurs within 24 hours of transplantation
• mediated by antibodies
  1. healthy graft transplanted into organ recipient
  2. recipient has antibodies against donor that were present before transplantation (or antibodies against donor MHC)
  3. host antibodies attack graft endothelium and initiate inflammation
  4. causes hemorrhage and graft failure

Question 12

Define acute rejection.

Answer 12

• occurs 10-90 days after transplantation
• sudden appearance of immune cells in graft
• intensity of response depends on amount of HLA DR mismatch, gender, intensity of immunosuppressive drug therapy post-transplant

Question 13

Define chronic rejection.

Answer 13

• usually due to widespread arteriolar narrowing due to smooth muscle cell proliferation and collagen production
• aka graft arteriosclerosis
• results in fibrosis => ischemia => death
• major problem of modern solid organ transplantation
• leading cause of re-transplantation

Question 14

Give an example of a hyperacute rejection.

Answer 14

• mismatched blood type
• if an O individual receives an A/B/AB organ, their circulating anti-A or anti-B antibodies will react immediately to the organ

Question 15

Describe the mechanism of pathology of a hyperacute rejection.

Answer 15

1. alloantibodies bind to donor antigens on graft endothelium => initiates platelet aggregation at site
2. platelets activate coagulation and fibrin deposition => graft ischemia
3. neutrophils are recruited to site and degranulation causes destruction of vascular barriers and necrosis
4. complement activation leads to more vascular clotting
5. ultimately, graft is ischemic, edematous, and necrotic

Question 16

Describe the mechanism of pathology of an acute rejection.

Answer 16

1. CD4+ T cells react with alloantigen (directly or indirectly) => TMMI => Th1 => activate macrophages => IL-1, -6, -8, TNF-a => inflammation
2. CD8+ T cells attack graft
3. Th17 T cells promote inflammation via neutrophil recruitment, promotes pro-inflammatory cytokine production
4. alloantigen-specific B cells enter the graft and make alloantigen antibodies

Question 17

List some anti-rejection strategies.

Answer 17

• achieve optimal MHC matching
• immunosuppression to stop alloantigen immune response
• inhibitory molecules to override Th1 and CD8 activation (ex: CTLA4, IL-10, TGF-b)
• induce specific tolerance in recipient (mediated by CD4, CD25, and FOXP3 regulatory cells)

Question 18

Hyperacute, acute, and chronic rejection are examples of…?

Answer 18

Host vs Graft Disease

Question 19

Define Graft vs. Host Disease.

Answer 19

• unique to bone marrow transplants or infusion of immune cells into an immunodeficient host
• donor immune cells attack the host…host has no immune cells and cannot fight them off

Question 20

Describe an MLC assay for a bone marrow transplant.

Answer 20

• irradiated donor cells + culture cells
• culture cells act as stimulator => proliferation of the donor cells
• this is the opposite of MLC for solid organ where donor cells are the stimulator and culture cells proliferate

Question 21

What is the drawback of miniature pig transplants?

Answer 21

• non-primates express a-gal
• primates (and humans) have a-gal antibodies
• use a-gal knockout pigs to abate hyperacute reaction

Question 22

Summarize the local immune strategies during pregnancy.

Answer 22

trophoblastic tissue

• does not express MHC Class I or II => only HLA-G
• HLA-G inhibits maternal NK cells
• secretes IL-10 and TGF-b
• any infiltrating maternal T cells are converted to Tregs
• fetal trophoblastic tissue upregulates a gene complex that inhibits complement

pregnant maternal NK cells

• do not express antibody directed cytotoxicity receptors (inhibited by HLA-G) => regulatory and tolerogenic effects
• maternal NK cells also promote angiogenesis for a successful pregnancy
• maternal gd T cells and Tregs (specific for paternal antigens) secrete immunosuppressive cytokines (IL-10, TGF-b)

===> very tolerant environment

Question 23

Summarize systemic immune strategies during pregnancy.

Answer 23

Progesterone

• suppress local and systemic Th1 responses => mother has downregulated Th1 and normal Th2
• increased IL-10 => immunosuppression
• stimulates uterine lining to display Decay Accelerating Factor (DAF) => inhibits complement

Tregs

• increased Tregs against paternal antigens
• decrease postpartum but remain as memory T cells
• assist in immune tolerance for subsequent pregnancy by same father

Question 24

What situations might lead to an unsuccessful pregnancy?

Answer 24

• inability to produce Tregs for paternal antigens

- inability to shut down Th1 responses

Question 25

What are some clinical implications for a pregnant mother?

Answer 25

• suppressed Th1 responses => can’t fight off infections that rely on Th1, such as influenza, TB, leprosy, toxoplasmosis
• subsequent pregnancies by different fathers may be associated with adverse effects b/c existing Tregs are for another father.

Question 26

What are clinical immunological implications for a fetus?

Answer 26

• infection during development can lead to tolerance

- as a child or an adult, that person will not be able to respond to that same infection

Question 27

List the TORCH infections.

Answer 27

These are perinatal/vertically transmitted infections that a fetus can develop tolerance to

• toxoplasmosis
• rubella
• CMV
• syphilis
• zika

Question 28

Describe the mechanistic pathway that occurs after allogeneic activation.

Answer 28

• IL12 => CD4+ Th1 cells => macrophage activation
• CD8+ T cells that are alloantigen specific (driven by Th1 and IL21) => graft cytolysis
• Th17 and IL23 => inflammation => graft destruction
• Th2 cells express IL4 and IL21 => alloantigen specific B cells => complement, antibody-driven graft cell death
• balance with Tregs