Fetal/transplant immunology

Question 1

allogenic

Answer 1

transplant between members of the same species who differ genetically

Question 2

Allograft

Answer 2

tissue transplant between allogeneic individuals - variable degrees of rejection

Question 3

Xenograft

Answer 3

transplants of organs between members of different species - strong rejection

Question 4

Isograft

Answer 4

identical twin to twin - accepted

Question 5

reason for rejection of transplants

Answer 5

MHC(allow discrimination between self and non-self)

Question 6

Mixed Lymphocyte Culture

Answer 6

measures transplant compatibility. take cells from the recipient and put them into culture with paralyzed cells from the donor (which display their MHC but cannot proliferate) If the recipient cells proliferate it indicates a bad match

Question 7

predictors of graft survival

Answer 7

the more matched MHC loci the better, especially MHC type II matches are the most predictive of graft survival

Question 8

Mechanisms of Rejection

Answer 8

Both donor and host DC get involved
Almost all, if not all, immune effector cells will get involved
The intensity of the rejection will depend on multiple factors, including MHC disparity, host immune response genes, physician interventions

Question 9

Complement-Dependent cytotoxic assay

Answer 9

1. incubate their serum with a panel of lymphocytes of known HLA specificity (if there are HLA antibodies they will bind)
2. add complement to all the wells- lymphocytes with bound antibodies are lysed

Question 10

2 ways that alloantigens activate the immune response

Answer 10

1. direct - activation of the immune system by the foreign MHC marker (whole)
2. Indirect- alloantigens are phagocytize, processed and represented in the context of MHC class II antigens by APC(recognizes pieces)

Question 11

Immunologic Hersey

Answer 11

the direct mechanism of alloantigen recognition conflicts with the MHC restriction concept of antigen presentation in the context of ones own MHC

Question 12

effects of graft rejection

Answer 12

1. activated macrophage mediated graft destruction, 2) CD8 antigen specific graft cytolysis, 3) Th17medicated inflammation and $) antibody mediated graft destruction either by complement and/or Fc receptor activation of cell death mechanisms

Question 13

which if dominant produces a more destructive response, Th1, Th2, Th17?

Answer 13

Th17 - more neutrophils

Question 14

Clinical classifications of rejection

Answer 14

hyperacute, acute, chronic

Question 15

Hyperacute rejection

Answer 15

within 48 hours after transplantation, usually an immediate response, recipient alloantibody directed against donor antigens that were present prior to transplantation. Can also occur if there is a mismatch across the RBC type (ABO). Widespread vascular injury results from alloantibody mediated endothelial damage. Blood supply to the graft is cut off.

Question 16

Acute rejection

Answer 16

sudden (10 to 90 days) appearance of anti-donor organ immune effector cells. Due to CD4 T-cells reacting with alloantigens and initiating a TMMI response. Also have CD8 cells attacking the graft and Th17 cells initiating inflammation.

Vigor depends upon Dr(MHC II) mismatch, gender, intensity of immunosuppression. Easier to diagnosis with new array technology and manage with immunosuppressive agents

Question 17

Chronic Rejection

Answer 17

slow process of graft attriction. diffuse, widespread arteriolar narrowing caused by intimal thickening of the vessel (slowly chokes the graft of its blood supply). Mechanism is probably different from acute rejection. Main issue with solid organ transplants today.

Question 18

strategies to prevent rejection

Answer 18

1. Optimal MHC especially MHC II matching
2. immunosuppression to block t-cell responses to alloantigens
3. Provide inhibitory second signals(CTLA-4), T regulatory cells (CD4,25) or cytokines (Il-21, IL-23, IL-10 & TGF-β to override Th1, Th17 and CD8 responses
4. Induce specific tolerance to the organ- may be possible by manipulating T-regs, (CD4, 25, FoxP3)

Question 19

Graft vs. Host Disease (GvF)

Answer 19

can happen with bone marrow transplants and inadvertent transfusion of immunocompetent cells into an immunodeficient host (immunodeficient person who receives a blood transfusion w/ lymphocytes). T cells in the transplant attack the recipient.

Question 20

xenotransplantation

Answer 20

Higher primates deleted an α-1,3 GT gene to gain a survival advantage
These primates now produce anti-α-1,3GT in response to gut bacteria
xenotransplants undergo hyperacute rejection
If they survive hyperacute rejection, they then are subject to standard acute and chronic rejection
xenovirus transmission also a potential problem

Question 21

Fetus survival in utero

Answer 21

both the mother and the fetus evoke transient but specific tolerance mechanism that are both systemic and local at the feto-maternal interface

Question 22

trophoblastic (fetal tissue) at the maternal-fetal interface display?

Answer 22

a “public” MHC (HLA-G) no MHC class i or II. this has an inhbitory motif for maternal NK cells

Question 23

How are pregnant uterine NK cells different

Answer 23

They is inhibited by HLA-G, they do NOT express the FcR and promote regulatory effects by producing TGF-β & IL-10 (Fetal trophoblastic tissue does the same!)
They produce angiogenic factors to support the placenta
HLA-G & TGF-β in turn promote differentiation of T regulatory cells that suppress regional immune responses

Question 24

Maternal γδ T cells

Answer 24

home to the uterus (uterine wall) and promote tolerance, increase during pregnancy and secrete immunosuppressive cytokines

Question 25

complement activation in pregnancy

Answer 25

inhibited by the fetal trophoblasts which upregulate a gene complex to inhibit.

Question 26

what happens to maternal T lymphocytes that come into contact with fetal lymphocytes (paternal and maternal MHC)

Answer 26

• this can happen at the placenta interface or in the fetus itself
• they are converted by fetal TGF-B to paternal specific T-regs

Question 27

Systemic (maternal) immunologic strategies

Answer 27

Pregnancy induced hormones, especially progesterone, strongly suppress uterine and systemic Th1 reactions
Placenta produces IL-10 which acts globally
Progesterone also promotes increased display of DAF on uterine cells which further inhibits complement reactions
T regs generated locally in the uterus circulate systemically

Question 28

Maintenance of a Th2 bias during gestation is associated with

Answer 28

success but… Increases the risk of disseminated intracellular infections that require TMMI and CD4 help (think H1N1maternal mortality) and Th17 responses to fungi and other pathogens

Question 29

Maintenance of a local Th1 bias

Answer 29

during the implantation phase decreases the possibility of successful pregnancy

Question 30

Promotion of maternal Th2 or T regs

Answer 30

could enhance the chance of a successful pregnancy

Question 31

failure of maternal ly conversion to paternal specific T regs

Answer 31

might lead to spontaneous abortion

Question 32

clinical implications of Infection of the fetus

Answer 32

could lead to tolerance to the pathogen and could lead to subsequent inability to respond appropriately to a future infection!

Question 33

NK cells in the non-pregnant uterus

Answer 33

increase towards the end of a menstrual cycle and appear similar but not identical to peripheral NK cells

Question 34

what converts NK cells in the pregnant uterus

Answer 34

progesterone and especially uterine produced TGF-B (they convert to different NK cells that will be 70% of the lymphocytes in the endometrium during pregnancy)

Question 35

Differences in Maternal NK cells

Answer 35

• do NOT express CD16- the Fc receptor necessary for antibody-directed cytotoxicity (ADCC)
• cytokine receptors are inhibited by HLA-G
• inhibitory cytokine profile
• produce angiogenic factors to increase blood supply to the fetus

Question 36

relative Th1 and Th2 responses in maternal immune system

Answer 36

Th1 is suppressed by Th2 is relatively normal