Term
Transplantation Lecture: Clancey
1. Autograph
2. Isograph
3. Allograph
4. Xenograph |
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Definition
1. Autologous Graft = Graft self to self, like part of your elbow skin to your butt skin.
2. Graft between identical twins = Living Related
3. Person to person. What most of this lecture deals with. Not identical twins! = Living non-related
4. Species to species graft, like getting an orangutange heart. Or, Engineered pigs to have human phenotypes...
- Can also receive donation from a cadaver...ewww. |
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Term
| What are some barriers to graft / donor / organ rejection? |
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Definition
| - MHC!!! Immune reactions commonly occur to donor's MHC! - the system that allows us to see self from non self! = Defense against multicellular organisms... - T cells recognize and react to foreign MHCs |
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Term
| What's a classic way to measure transplant compatibility? |
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Definition
- 2 ways to assess histocompatability between host + donor, using mixed lymphocyte co-culturing: - T cell proliferation = an immune reaction - Cell lysis by CTLs reacting with foreign MHC on mixed lymphocyte (from Donor...)
3H-thymidine measures T cell proliferation
51Cr measures cell lysis by CTLs
- Also by Complement-Dependent Cytotoxic Assay
= See if Abs are activating / killing cells. Via ADCC (Ab-Dependent Cell mediated Cytotoxicity) or Complement activation.
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Term
| How can you find out if ADCC and complement are reacting to the MHCs of the lymphocytes in the donor tissue (allotypic reaction)? |
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Definition
- Remember: Ab can bind to a foreign Ag and activate the complement pathway
- Cells + Ab (Anti-MHC)
- Serum (has complement)
- Visualize cells
- Stain = dead, lysed by complement
- Unstained = alive, not active complement via Abs. |
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Term
| What are 2 forms of Ag presentation / allorecognition when recieving a transplant? |
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Definition
Direct Allorecognition (Heresy):
- Donor APCs (DCs, macrophages) activate recipient (Host) T cells = Graft is rejecting its new environment, the host.
- DCs as passenger lymphocytes from the donor tissue
Indirect Alloreaction (Classic):
- Host APCs (DCs, etc) process and present proteins from the graft (Donor) tissue as Ags = host attacks the graft / host vs. Graft
[image] |
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Term
| What are the multiple pathways of graft rejection? What immune responses are activated by graft rejection? |
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Definition
- Refering to acute rejection reactions and the cells that are involved:
- NK cells = Cytotoxic (for infected cells (Viral) see MHC I)
- CD8+ CTLs
- B cells = Abs = anti allotype / anti MMHC. Also bind to complement to activate complement cytotoxicity
- Th1 = INFy = Activate macrophages. IL-21 activates CD8+ CTLs, and for germinall center reaction (B cell maturity, etc…)
- Th2 = IL-4 = class switching of Abs = an increase in antibodies…
- Th17 = activate macrophages, bring neutrophils into the graft / recruit neutrophils. |
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Term
| What are 3 types of rejection and the cells involved in their pathways? |
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Definition
- Hyperacute Rejection:
Occurs from Pre-exisitng Abs reacting with the graft. Akin to transfusion rejection to blood type Ags (ABO).
- Acute Rejection:
Defines by the sudden appearance of effector cells in the graft (seen by biopsy). Can occur from gender (Y), Mismatch of MHCs, lack of immunosuppression.
NK, T cells (Th1, Th2), CTLs, B cells which act as APCs here!
Chronic rejection
Caused by thickening of the graft vasculature = graft ischemia: Big problem with grafts today!
Cycling cells: Cyclins, which indicate cells are cycling, proliferating...
Drug toxicity / infection causing graft rejection. (meaning the immune system is depeleted?)
Macrophages, fewer T cells.
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Term
What's the ultimate goal of transplantation?
How can this be acheived?
5 ways...
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Definition
Tolerance to the graft (donor) tissue!
1. Increase Tregs to suppress T cell reaction / activation / proliferation. In circulation but need to get them to the donor tissue!
2. Optimize MHC matching, especially MHC II, HLADR....
3. Block T cell responses with anti-CD3.
4. Provide inhibitory signals to T cell activation like CTLA-4
CTLA-4 binds to CD80.86 co-stimulatory factors preventing activation by B7.
5. Cytokines (IL-21 (CTLs), 23 (Th17), 10, TGF-B) to over ride Th1 (macrophages), Th17(neutrophils) and CD8 (CTLs via MHC I) responses. |
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Term
| What's a way to use Tregs to induce host's tolerance to a grafted tissue? A method... |
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Definition
- Take Tregs out of a patient before they undergo the transplantation.
- Grow up the Tregs, stimulate them with growth factors...
- Put them back into the graft recipient after surgery to reduce T cell activation and possible destruction fo the graft tissue. |
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Term
What transplant is done for a patient with Leukemia?
What's a sign of a successful treatment? |
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Definition
1. Irradiate the patient to kill any B or T cells.
2. Match HLAs (MHCs)
3. Just so Bone Marrow transplant isn't rejected...
4. Want a little bit of GVSHD / rejection... Indicates the new T cells from the new BM are getting rid of the leukemia T cells... |
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Term
What are 2 ways GVSHD can occur?
How can GVSHD not occur? |
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Definition
Mature T cells from the Graft tissue attack the host's tissues.
- Like Direct alloreaction but with T cells!
Mature T cells from the host attack the Graft tissues.
- Like Indirect alloreaction but with T cells! |
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Term
What has been done to xenotransplantation to make it more accomadating?
What problems remain with xenotransplantation?
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Definition
1. Higher primates have deleted a-1,3 GT = pigs have anti-a-1,3 GT gene.
2. Human complement regulating proteins on the surfaces of the pig's cells.
- Remaining problem: Anti-pig, non-gal Abs.
- Still can undergo acute / chronic rejection |
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Term
How does nature deal with transplantation? What's an example of transplantation in nature and how is it remedied?
6 examples
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Definition
- Pregnancy = Fetus is an allograph in the mother's womb.
- Grow similar to cancer...
1. Fetal tissues do not display MHCs, just a "public" MHC = HLA-G
2. HLA-G inhibits NK cells, don't express FcR.
3. Tregs promoted by HLA-G and TGF-B
4. Maternal yd T cells promote tolerance to the fetus.
5. Fetal trophoblast upregulates a gene that prevents complement activation.
6. Fetal lymphnodes are predominately Tregs, also a lot of Tregs in the cord blood.
= Inhibit everything!
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Term
| What happens to T cells during pregnancy? Why? How? |
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Definition
Shift to Th2 cells via progesterone.
- Th1 cells cause INFy release and macrophage activation
(also IL-21 release to activate CTLs)
= More destructive T cell response
- Th2 cause class switching
= A more suppressed T cell response = Good for fetus.
- Progesterone also:
- Increases the display of DAF = inhibits complement reactions.
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Term
What are a few pregnancy complication, and what can cause them?
- What image should you be able to draw? |
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Definition
- Maintenace of Th2 (Act. Abs). With Th2 and not Th1.
- Have Th1 = bad for pregnancy!
= Increased risk of desseminated infection (infection spreads from its origin) that need TMMI and CD4 / Th1.
= Th17 responses for other pathogens as well.
- Need Th1 after embryo implantation and not before!
- Promotion of Th2 and Tregs could increase the chance of a successful pregnancy.
- Infection to the fetus could cause the fetus to become tolerant to that infection (Like crack babies) = unable to respond / tolerized to that infection.
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