Organ transplantation Flashcards

Question

Describe the different assessments of kidney transplants

Answer 1

DBD kidney transplant patients are assessed nationally. DCD kidney transplant patients are assessed locally. This is so the kidneys can be implanted with less warn ischaemia.

Answer 2

Living donor- 12 years | Deceased- 10 years

Answer 3

 50% of potential donors after brain death donate organs – mainly due to declined consent by the family.  This is aiming to be raised by: o UK Gov. Dept. of Health initiatives. o Public engagement. o Improved quality of organ retrieval and transplantation. o Donor transplant co-ordinators – critical care nurses and carry out family interviews to gain consent.

Answer 4

The immune system recognises someone else’s organ as foreign Most relevant protein variations in clinical transplantation 1. ABO blood group 2. HLA (human leukocyte antigens) coded on chromosome 6 by Major Histocompatibility complex (MHC)

Answer 5

A and B proteins with carbohydrate chains on red blood cells but also endothelial lining of blood vessels in transplanted organ Naturally occurring anti-AB antibodies

Answer 6

o O+ = 1x fructose, 1x n-acetyl-glucosamine, 2x galactose. o A+ = 1x fructose, 1x n-acetyl-glucosamine, 2x galactose, 1x n-acetyl-galactosamine. o B+ = 1x fructose, 1x n-acetyl-glucosamine, 3x galactose.

Answer 7

Heart transplant from blood group B donor – i.e. cells express blood group B Patient: blood group A Red cells express A Patient serum contains naturally occurring anti-B antibodies Circulating, pre-formed, recipient anti-B antibody binds to B blood group antigens on donor endothelium = antibody-mediated rejection Complement cascade, thrombi formation in organ- organ will go purple after a few minutes of donating

Answer 8

``` Remove the antibodies in the recipient (plasma exchange) Good outcomes (even if the antibody comes back) Kidney, heart, liver ```

Answer 9

Discovered after first failed attempts at human transplantation Cell surface proteins Highly variable portion Variability of HLA molecules important in defense against infections and neoplasia Foreign proteins are presented to immune cells in the context of HLA molecules recognised by the immune cells as “self

Answer 10

APC ingests foreign peptides and presents them in the context of HLA (MHC) which the T cell recognises. T cell recognises foreign peptide in the context of host MHC. Donor graft cell can 'shed off' its own HLA molecules, which can be recognised as foreign by the recipient's APC cells and presented to CD4+ T cells to activate them- leading to an immune response against the donor graft cell

Answer 11

``` Class I (A,B,C)– expressed on all cells Class II (DR, DQ, DP) – expressed antigen-presenting cells but also can be upregulated on other cells ``` Highly polymorphic – lots of alleles for each locus (for example: A1, A2, …, A341… etc.) Each individual has most often 2 types for each HLA molecule (for example: A3 and A21)

Answer 12

Peptide binding groove between a2 and a1 a3 (membrane spanning) b2-macroglobulin

Answer 13

Peptide binding groove between b1 and a1 | b2 and a2 membrane spanning domains

Answer 14

``` A B DR These are immunogenic- so relevant BUT also- highly polymorphic ``` Number of mismatches : 0 to 6 Expressed as a ratio of A:B:DR E.g 2:1:0 - 3 mismatches Fewer mismatches between donor and recipient HLAs associated with Better outcomes in kidney transplants

Answer 15

Parent to child: ≥3/6 matched Sibling to sibling: 25% - 6MM 50% - 3MM 25% - 0MM

Answer 16

Exposure to foreign HLA molecules results in an immune reaction to the foreign epitopes The immune reaction can cause immune graft damage and failure = rejection

Answer 17

Most common cause of graft failure Diagnosis = histological examination of a graft biopsy Treatment = immunosuppressive drugs

Answer 18

 Rejection can be T-cell mediated or anti-body mediated. |  Rejection can be hyper-acute, acute or chronic.

Answer 19

Hyperacute rejection takes place within hours of transplantation and is caused by preformed antibodies binding to either ABO blood group or HLA class I antigens on the graft (Fig. 34.1A). The recipient may have formed anti-HLA class I antibodies after exposure to allogeneic lymphocytes during pregnancy, blood transfusion, or a previous transplant. Antibody binding triggers a type II hypersensitivity reaction, and the graft is destroyed by vascular thrombosis. Hyperacute rejection can be prevented through careful ABO and HLA cross-matching and is now quite rare.

Answer 20

Acute rejection is a type IV (cell-mediated) delayed hypersensitivity reaction and therefore takes place within days, and sometimes weeks, of transplantation. Acute rejection takes several days to develop because donor dendritic cells must first stimulate an allogeneic response in a local lymph node for responding T cells to proliferate and migrate into the donor kidney. Acute rejection takes place if there is HLA incompatibility. Recipient T cells can respond to donor peptides presented by recipient major histocompatibility complex (MHC) or to donor MHC molecules (see Fig. 34.1). Although attempting to minimize any HLA mismatch of the donor and recipient can reduce acute rejection, the shortage of donor kidneys often means that a partially mismatched kidney is used. The survival of the kidney is related to the degree of mismatching, especially at the HLA-DR loci

Answer 21

Alternatively, the recipient may respond to minor histocompatibility antigens presented by donor or recipient cells (see Box 34.1). Minor antigens are proteins that have different amino acid sequences in the donor and recipient; they are encoded by genes situated outside the HLA. Minor histocompatibility antigen mismatches are not detected by standard tissue-typing techniques. The term minor antigens may be misleading in terms of importance; even when an HLA-matched, living related donor is found, these antigens can cause graft rejection in up to one-third of transplants.

Answer 22

Acute rejection is more likely to develop if the donated kidney has been damaged. For example, if the kidney is not immediately placed on ice, it will be damaged by hypoxia. The damage-associated molecular patterns (DAMPs) induced by hypoxia are detected by pattern recognition molecules, which in turn stimulate the production of danger signals

Answer 23

Chronic rejection takes place months or years after transplant. An element of allogeneic reaction is often mediated by T cells in chronic rejection, which can result in repeated acute rejection. In some cases, chronic rejection may be caused by recurrence of preexisting autoimmune disease. In other cases, no direct evidence of damage caused by the adaptive immune system is apparent.

Answer 24

Host and donor APC present donor HLA and migrate to lymphoid organs APC meet T cells in secondary lymphoid organs Naive and central T cells recirculate between secondary lymphoid organs Traffic controlled by S1P receptors and chemokine receptors Effector T cells attack graft

Answer 25

T cells pass through endothelium via diapedesis This leads to lymphocytic interstitial infiltration can then rupture the basement membrane and invade tubular cells- leading to tubilitis Ischaemia or damage to the organ during transplant process can precipitate to diapedesis

Answer 26

Graft infiltration by alloreactive CD4+ cells

Answer 27

``` “Cytotoxic” T cells Release of toxins to kill target Granzyme B Punch holes in target cells Perforin Apoptotic cell death Fas -Ligand ```

Answer 28

``` Macrophages Phagocytosis Release of proteolytic enzymes Production of cytokines Production of oxygen radicals and nitrogen radicals ```

Answer 29

PAS stain CD3 Will show T cell infiltration and tubulitis

Answer 30

Antibody against graft HLA and AB antigen Antibodies arise Pre-transplantation (“sensitised”) Post-transplantation (“de novo”)

Answer 31

Fab region binds to antigen (HLA antigen expressed on graft) Can activate classic complement pathway- leading to formation of MAC FcyR on macrophages can then bind to Fc region of bound antibody and phagocytose the cell

Answer 32

Ab- intravascular process- glomerulitis, per tubular capillaritis T cell- interstitial process

Answer 33

Complement fragment C4d Stain for this using immunohistochemistry- will see it stacked on the endothelial cells

Answer 34

Deteriorating graft function Kidney transplant: Rise in creatinine, fluid retention, hypertension Liver transplant: Rise in LFTs, coagulopathy Lung transplant: breathlessness, pulmonary infiltrate Subclinical Kidney Heart (no good test for dysfunction, regular biopsies)

Answer 35

``` Prevention of rejection maximise HLA compatibility Life-long immunosuppressive drugs Treatment of rejection more drugs… ```

Answer 36

Targeting T cell activation and proliferation | Targeting B cell activation and proliferation, and antibody production

Answer 37

``` Anti-cd3 mAb Calcineurin inhibitor (signalling pathway upon activation)- cyclosporine or tacrolimus ```

Answer 38

Anti-CD25 mAb mTOR inhibitors (sirolimus, everolimus)- signalling pathway proliferation- azathiproin, MMF

Answer 39

Anti- CD52 mAb

Answer 40

 Immunosuppressive drugs: o Target T-cell activation and proliferation.  Anti-CD3 ABs, JAK3 inhibitors, Azathioprine, cyclosporine. o Target B-cell activation, proliferation and antibody production.  Splenectomy, anti-CD20 ABs (rituximab) , Bortezomib (proteasome inhibitor), anti-C5, intravenous immunoglobulin plasma exchange (IVIG).

Answer 41

Pre-transplantation - Induction agent (T-cell depletion or cytokine blockade) From time of implantation - Base-line immunosuppression Signal transduction blockade, usually a CNI inhibitor: Tacrolimus or Cyclosporin; sometimes mTOR inhibitor (Rapamycin) Antiproliferative agent: MMF or Azathioprine Corticosteroids If needed - Treatment of episodes of acute rejection T-cell mediated: steroids, anti-T cell agents Antibody-mediated: IVIG, plasma exchange, anti-CD20, anti-complement

Answer 42

Increased risk for conventional infections Bacterial, viral, fungal ``` Opportunistic infections – normally relatively harmless infectious agents give severe infections because of immune compromise Cytomegalovirus BK virus Pneumocytis carinii (jirovecii) Kaposi's sarcoma ``` Drug toxicity is also important Balance determines success of transplant

Answer 43

Prophylactic anti-viral therapy (acyclovir for CMV) | Pneumositsis infections prevented by giving septrin post-transplantation - prevent pneumonia

Answer 44

Owls eyes inclusion sin tubular epithelial cells- can cause graft loss Mucormycosis- fungal

Answer 45

Skin cancer Post transplant lymphoproliferative disorder – Epstein Barr virus driven- viral driven- kaposi's sarcoma others

Answer 46

Transplantation is life-saving/life-enhancing Not without risks – surgery, immunosuppressive burden (infections, malignancy, drug toxicity) Issues related to supply/demand, ethics, biology limit its use

Answer 47

Surgical problems (blood vessels, ureter anastomosis) Poor quality organ – established fibrosis; poor blood supply Rejection Recurrence of original disease causing kidney failure (for ex. Glomerulonephritis) Infection Conventional micro-organisms – increased incidence Opportunistic infections CMV Pneumocystis BK virus Drug side effects – cardiovascular morbidity and mortality Malignancy UV-induced skin cancer post-transplant lymphoproliferative disease (PTLD; mostly B cell, EBV-driven) conventional malignancies are marginally increased

Answer 48

• Hyperacute rejection o Caused by pre-existing antibodies to donor AB or HLA o Historical sensitisation e.g. through previous transplant, transfusion or pregnancy o Antibody binds to graft endothelium in minutes and destroys the graft in hours o Autoantibodies can be identified and removed by plasma exchange • Acute rejection: weeks-years after transplant • Chronic rejection: often associated with non-compliance to immunosuppressant drugs o Months-years post transplant