Introduction to Transplantation Immunology Flashcards

Question

Rejection of the graft that is mainly mediated by T-cells and occurrs within weeks to months is called ... ...

Answer 1

Rejection of the graft that is mainly mediated by T-cells and occurrs within weeks to months is called **ACUTE REJECTION (**It can be reduced/prevented by HLA-matching of donor and recipient. Antibodies developing against the donor HLA after transplantation can also make a contribution to acute rejection.)

Answer 2

Rejection of the graft that is mainly mediated by T-cells and occurrs within weeks to months is called ACUTE REJECTION (It can be reduced/prevented by **HLA**-matching of donor and recipient. **Antibodies** developing against the donor **HLA** after transplantation can also make a contribution to acute rejection.)

Answer 3

* Another important kind of antibody that can interfere with the graft is directed at HLA antigens. Remember that HLA is the human MHC. The text on the slide explains the mechanisms that may contribute to graft destruction. * The image shows a vascular cross section in a solid organ graft. Different mechanisms of graft damage are illustrated, ranging from T-cell recognising 'non-self' MHC to monocytes being activated by the Fc-portions of anti-HLA antibodies and P-selectin

Answer 4

* Antibodies with the same coloration of the Fc region are of the same **subclass**, whereas the various colors within the F(ab’)2 denote unique antigenic specificities. (legend adapted) * Anti class-**I** MHC antibodies can induce changes in the donor vasculature, for example, causing endothelial cell (EC) activation with class-II MHC expression, and, as a result, **CD4** T cell proliferation.

Answer 5

* Complement-activating antibodies trigger the **classical** pathway through binding of C1q, resulting in production of the anaphylatoxins C3a and C5a, which have the potential to directly augment **leukocyte** recruitment and T cell **allo**-responses.

Answer 6

* Monocytes, neutrophils, and natural killer (NK) cells also express **Fc** receptors (**FcγRs**), which can interact with the heavy chain of HLA antibodies bound to donor ECs. *FcγR* functions augment leukocyte recruitment and mediate phagocytosis and antibody-dependent cellular cytotoxicity (ADCC).

Answer 7

* Activated ECs express **P**-selectin, which promotes recruitment of **leukocytes** via interactions with **P**-selectin glycoprotein ligand-1 (PSGL-1). * Recruited monocytes differentiate into CD68+ macrophages, which can infiltrate the subendothelial space.

Answer 8

* We conclude that anti-**HLA** Antibodies can severely **damage** the graft. There are also antibodies to a range of other antigens including: * Red Blood Cell (RBC) antigens (mainly ABO system) * Endothelial Cell Antigens * They can also induce significant graft damage. We will not look at these in detail here in the interest of time. But we will come back to antibodies to RBC antigens in the next section.

Answer 9

* We conclude that anti-**HLA** Antibodies can severely damage the graft. There are also antibodies to a range of other antigens including: * Red Blood Cell (RBC) antigens (mainly **ABO** system) * **Endothelial** Cell Antigens * They can also induce significant graft damage. We will not look at these in detail here in the interest of time. But we will come back to antibodies to RBC antigens in the next section.

Answer 10

* Very early **destruction** of the graft (minutes/hours/days) caused by antibodies to **HLA**, RBC, and EC antigens is called **HYPERACUTE** **REJECTION**. It can be prevented partially by matching donor and recipient **HLA**-types and **blood** groups. There is no known way of matching for antigens recognised by anti-**EC** antibodies as these are thought to recognise damaged **EC** and are not donor-specific..

Answer 11

There is no known way of matching for antigens recognised by anti-EC antibodies as these are thought to recognise damaged EC and are not **donor**-specific..

Answer 12

* **HLA**-matching – hwo good does the match have to be? * Minimum requirements depend on the situation * A kidney transplant can wait, a **liver** cannot, a heart transplant is in between since artifical hearts can bridge the gap sometimes * There are some exceptions: **liver** transplants are generally not matched as they induce chimerism., i.e. the parallel existence of two mutually tolerant immune systems (chimerism is the result of immune cells from the donor settling in the recipient‘s bone marrow and supports graft acceptance) * It is sometimes induced by combining **stem** cells and organs in a transplantation

Answer 13

* HLA-matching – hwo good does the match have to be? * Minimum requirements depend on the situation * A kidney transplant can wait, a liver cannot, a heart transplant is in between since artifical hearts can bridge the gap sometimes * There are some exceptions: liver transplants are generally not matched as they induce **chimerism**., i.e. the parallel existence of two mutually tolerant immune systems (**chimerism** is the result of immune cells from the donor settling in the recipient‘s bone marrow and supports graft acceptance) * It is sometimes induced by combining stem cells and organs in a transplantation

Answer 14

**Chimerism** is the result of immune cells from the donor settling in the recipient‘s bone marrow and supports graft acceptance

Answer 15

* HLA-matching * For solid organ transplantation, traditionally A,B, and DR are considered, the maximum is **6** mismatches (3 molecules inherited from each parent in both donor and recipient). * Alleles are usually not considered in **kidney** transplantation (i.e HLA-B\*07:01 and HLA-B\*07:02 are both HLA-B\*07).

Answer 16

* HLA **epitope** matching * A newer approach uses antibody **epitope** predictions to analyse if a mismatch is acceptable or not. For example, a software package called ‚matchmaker‘ provides such information. * This approach is based on HLA sequence similarity between mismatched HLA-alleles and predicts if a mismatch is likely to give rise to an **antibody**

Answer 17

* Cross matching = **Incubation** of **washed** donor cells with recipient **serum**. * This is an essential test that should not be left out. * Subsequently, **antibody** binding is detected.

Answer 18

This slide shows you, how practical tests can be performed in the lab to be absolutely sure that there are no preformed antibodies against the graft tissue in the donor.

Answer 19

* **Cytotoxicity** after addition of **complement** (**Complement**-dependent **cytotoxicity**) * Detects only **complement**-binding, functional antibodies * **Less** sensitive, risk of false negatives (missing antibodies that cause damage but do not bind **complement**) * Staining of antibodies bound to recipient cells (using mouse anti-human antibody) followed by detection by flow-**cytometry** * Detects all **bound** antibodies including non-functional ones or can be modified to stain complement-fixing antibodies only * **Higher** risk of false positives (detecting antibodies that bind but cause no damage)

Answer 20

* Cytotoxicity after addition of complement (Complement-dependent cytotoxicity) * Detects only complement-binding, functional antibodies * Less sensitive, risk of **false negatives (missing antibodies that cause damage but do not bind complement)** * Staining of antibodies bound to recipient cells (using mouse anti-human antibody) followed by detection by flow-cytometry * Detects all bound antibodies including non-functional ones or can be modified to stain complement-fixing antibodies only * **Higher risk of false positives (detecting antibodies that bind but cause no damage)**

Answer 21

* A test of the ability of recipient serum to bind to T-cells representing a group of **potential** donors * An entire collection of cells with different **HLA**-types is exposed to recipient serum * The read-out can be based on either method shown on the previous slide * The multiplex method using microspheres with immobilised **HLA**-molecules is very well suited for this purpose

Answer 22

* Bedside testing for RBC transfusion: * Do you know/remember how it works? * A drop of fresh blood is added to each indicated section on the test card * Within a short time, a reaction is visible, it looks either ‘curdled’ like on the left,…or smooth like in the middle, …and curdled again, on the right * What is the blood group? * Anti-A curdled: A-antigen present * Anti-B smooth: B antigen absent * Anti-D curdled: D-antigen present * **A-POS (RHESUS +)**

Answer 23

In organ transplantation the same ABO rules apply as with blood transfusion – the donor organ is similar to a red blood cell that could be **lysed** if there are antibodies to its surface antigens

Answer 24

ABO **incompatibility** is a major concern. Rhesus **incompatibility** is less of a worry and usually taken care of by sufficient immunosuppression.

Answer 25

* lower part of the slide shows you the principle of HLA-gene inheritance. The chance of siblings being HLA-identical is 1:4. * Identical twin - identical in all genes, identical sibling only HLA, may differ with respect to other genes

Answer 26

* Antibodies to **HLA** & endothelial cell antigens entertain **proinflammatory** cytokine production and inflammation * Media **proliferation** & thickening of vascular wall * Reduction of vascular **lumen** * Reduced **blood** supply

Answer 27

* Antibodies to HLA & **endothelial** cell antigens entertain proinflammatory cytokine production and **inflammation** * Media proliferation & **thickening** of vascular wall * Reduction of vascular lumen * Reduced blood supply

Answer 28

* Chronic **rejection** is a complex process and probably depends to a large extent on the damage done to the **graft** between removal from the donor and being reperfused in the recipient. * Ischemic time, in particular **warm** ischemic time seems to be a major problem. * But **minor** histocompatibility antigens may also contribute, and other factors, like infection or atherosclerosis. So, it is fair to say that the process is multifactorial and there is no specific therapy to stop it.

Answer 29

* **Activation** signals represent interesting target molecules for immunosuppression

Answer 30

* **Biologicals** are probably the future (there are hundreds, some used in **renal** transplantation are highlighted) * visilizumab (Nuvion) * **eculizumab (anti-C5, Soliris)** * adalimumab (Humira) * anakinra (Kineret) * certolizumab (Cimzia) * etanercept (Enbrel) * golimumab (Simponi) * infliximab (Remicade) * **alemtuzumab (anti-CD52)** * natalizumab (Tysabri) * **rituximab (anti-CD20, Rituxan)** * secukinumab (Cosentyx) * tocilizumab (Actemra) * vedolizumab (Entyvio) * **basiliximab (anti-IL2, Simulect)** * **daclizumab (anti-CD25, Zinbryta)**

Answer 31

* **Calcineurin** inhibition * Cyclosporin A, Tacrolimus * Inhibition of cytokine synthesis: IL-2, IFNg ... * Anti-**proliferative** * Azathioprine, MMF * Inhibition of clonal expansions * Anti-**inflammatory** * Corticosteroids * NFkb inhibition, cytokine synthesis and action

Answer 32

* Calcineurin inhibition * Cyclosporin A, Tacrolimus * Inhibition of **cytokine** synthesis: IL-2, IFNg ... * Anti-proliferative * Azathioprine, MMF * Inhibition of clonal **expansions** * Anti-inflammatory * **Corticosteroids** * NFkb inhibition, **cytokine** synthesis and action

Answer 33

* The biggest problem after successful transplantation is **immunosuppression**.

Answer 34

* Ischaemia/**reperfusion** injury * **APC** activation * **Cytokine** synthesis (acute inflammation)

Answer 35

* Traditional view: * The immune system differentiates between ‘**self**‘ and ‘**non-self**‘ * Opposing (modern) view : * The immune system discriminates between ‘**dangerous**‘ and ‘not **dangerous**‘ (while **self** and **non-self** are not important). * Is **non-self** really enough to trigger an immune response? Why is an embryo not rejected?

Answer 36

* **Surgery** also provides danger signals: trauma, inflammation, ischemia/reperfusion, etc. * **Warm** ischemic time is a very significant problem with respect to **graft** survival

Introduction to Transplantation Immunology Flashcards

(68 cards)