40. Immune Deficiency and Immunosuppression (HT)

Question 1

Give some examples of landmarks in transplant history.

[EXTRA]

Answer 1

Question 2

What is the success of transplantation linked to and what is it limited by?

Answer 2

• Success is linked with the development of effective immune suppression
• So the success of transplantation continues to be limited by immunological rejection, even in the long-term
• Nevertheless, transplantation is now the treatment of choice for end-stage organ failure since there are so fewe alternatives

Question 3

Name some sources of organs for transplant.

Answer 3

• Living-related donors
• Living donors
• Cadaveric donors
• Unrelated species

Question 4

Define an autograft.

Answer 4

Tissues derived from the patient themselves that can be used for autotransplantation.

(e.g. skin to treat lifethreatening burns)

Question 5

Define an isograft.

[IMPORTANT]

Answer 5

Tissues or organs harvested from an identical twin that can be used for transplantation and for which immune intervention is not required.

Question 6

Define an allograft.

[IMPORTANT]

Answer 6

Tissues or organs taken from unrelated members of the same species that can be used for transplantation.

Question 7

Define a xenograft.

[IMPORTANT]

Answer 7

Organs harvested from an unrelated species that can be used for transplantation.

(e.g. the use of replacement heart valves harvested from pigs)

Question 8

What proteins underlie the majority of transplant rejection?

Answer 8

HLA genes

Question 9

How many genes encode the MHC class I and II?

Answer 9

• 6 genes encode the two MHC classes
• The maternal and paternal alleles are co-expressed, meaning that they determines the individual’s immunological identity that is important in transplantation

Question 10

Describe how acute rejection of a transplant works.

[IMPORTANT]

Answer 10

• The allograft contain donor antigen-presenting cells (APCs) that have donor MHC molecules on them
• Since transplants don’t usually involve joining up lymphatics, the APCs exit the allograft via the blood and enter the spleen
• The donor MHC molecules presented by the donor APCs are recognised by the recipient T cells in spleen, leading to their activation -> About 1 in 10 T cell precursors can recognise the MHC molecule
• This only happens acutely because the donor APCs die after some time

Question 11

Describe how chronic rejection of a transplant works.

[IMPORTANT]

Answer 11

• When donor APCs in the allograft die, they release antigens, such as the donor MHC molecules
• These molecules are taken up by recipient APCs, just like with any other antigens
• The donor MHC molecules are processed into peptides, which are then presented on the recipient APCs for T cells, activating them
• Only about 1 in 10⁶ T cells can recognise the donor peptide this way, so the immune response in weaker chronically, but it is continuous because donor cells keep dying over time

Question 12

Compare acute (direct pathway) and chronic transplant (indirect pathway) rejection.

Answer 12

Question 13

Describe the concept of major and minor histocompatibility antigens.

[IMPORTANT]

Answer 13

The immunogenicity of an allograft is determined by:

• Major histocompatibility antigens -> These are the MHC molecules that are the most important determinant of whether an allograft will be rejected.
• Minor histocompatibility antigens -> These include various other antigens.

Question 14

Name some minor histocompatibility (mH) antigens.

Answer 14

• ABO blood group antigens
• Epitopes from naturally-occurring polymorphic proteins
• Retrovirally-encoded antigens
• Mitochondrial proteins
• Male-specific gene products encoded on the nonrecombining arm of the Y chromosome

Question 15

Describe how identifying of an appropriate donor for transplants is done.

Answer 15

• Donors are always matched according to their ABO blood group
• The other minor histocompatibility antigens are not matched since there are so many and they are not well defined in humans yet
• In terms of HLA genes:
  
  • Identical twins are the best options, since all HLA loci and mH antigens are shared
  • Siblings are the next best option, since they are ‘haploidentical’ which means they share approximately half of their HLA loci
  • Unrelated donors are matched using mainly just the HLA-A, B and DR loci, since these are the best predictors of rejection and there is diminishing return to matching the other loci

Question 16

How does the type of transplanted organ affect the risk of rejection?

Answer 16

The level of disparity that may be tolerated depends on the organ or tissue: skin and HSC require stringent matching while liver is far more permissive.

Question 17

What recipient cells are involved in the mechanism of allograft rejection?

[IMPORTANT]

Answer 17

• CD4+ Helper T cells -> Activate other cells and also have slight cytotoxic activity
• CD8+ Cytotoxic T cells -> Kill allograft cells
• NK cells -> Kill allograft cells if they do not recognise the MHC class I presented on them (since they appear as if they have downregulated their MHC class I)
• B cells -> Produce alloantibodies (and lead to complement)
• Activated macrophages -> Appear to be most important in causing damage since they release cytokines and ROS

Question 18

What are the 4 types of allograft rejection?

Answer 18

• Hyperacute rejection
• Acute rejection
• Chronic rejection
• Graft vs Host Disease (GvHD)

Question 19

Explain briefly each of the 4 types of rejection in transplantation.

Answer 19

• Hyperacute rejection
  
  • Occurs over hours
  • Caused by antibodies that exist within the host before transplantation
  • The antibodies bind to ABO blood group antigens (in the case of blood group mismatch) causing RBC lysis and complement activation
  • When endothelial cells are bound to, there are thrombi and organ infarcts
• Acute rejection
  
  • Occurs over 2-3 weeks
  • Involves the direct pathway (see flashcard) where the donor MHC class II molecules on APCs are recognised by recipient T cells, activating them
  • The response is strong because the fraction of recipient T cells that can recognise the foreign MHC molecule is high, but it is also brief due to the short lifespan of the APCs
• Chronic rejection
  
  • Occurs over months/years
  • Involves the indirect pathway (see flashcard) where allograft cells die and release antigens, such as the donor MHC molecules, which are taken up and presented by recipient APCs as peptides to T cells
  • The reaction may be precipitated by infection
  • Involves T cells and alloantibodies, which can lead to occlusion of blood vessels due to thickening of arteriolar walls
  • The response is weak because only a small fraction of T cells can recognise the donor peptide this way, but it is continuous because donor cells keep dying over time
• Graft vs Host Disease (GvHD)
  
  • Opposite of allograft rejection, since the allograft attacks the recipient
  • Some mature T cells from the donor are reactive with recipient proteins, leading to expansion and cytokine release

Question 20

What is a common feature of chronic allograft rejection?

Answer 20

Involves T cells and alloantibodies, leading to occlusion of blood vessels due to thickening of arteriolar walls.

Question 21

What can precipitate chronic allograft rejection?

Answer 21

Concominant infection (presumably because it leads to damage to the allograft, which releases donor proteins)

Question 22

When is graft-versus-host disease (GVHD) commonly observed?

Answer 22

Often following bone marrow transplantation, since bone marrow contains mature T cells.

Question 23

What is graft-versus-host disease (GVHD) and what is the pathology?

[IMPORTANT]

Answer 23

• It is when mature T cells in an allograft attack the recipient body after transplantation
• It involves polyclonal expansion of donor effector T cells, which results in systemic tissue damage (e.g. via cytokines)
• Gut and liver are especially affected
• Skin involvement is evident from the appearance of a systemic rash

Question 24

When might a similar condition to graft-versus-host disease occur?

Answer 24

A similar pathology may occur in pregnancy if T cells from the fetus enter the maternal circulation, potentially causing systemic sclerosis.

Question 25

When might graft-versus-host disease be useful?

Answer 25

GvHD may prove beneficial for eradication of leukaemias, known as the Graft vs Leukaemia (GVL) effect

Question 26

What are drugs for immunosuppression following transplantation?

Answer 26

* Corticosteroids -\> Anti-inflammatory action inhibits macrophage recruitment and activation * Calcineurin inhibitors (Cyclosporin A, Tacrolimus) -\> Inhibit signal transduction in T cells and IL-2 secretion * Rapamycin -\> Targets the mTOR signalling pathway in dendritic cells preventing their maturation * Mycophenolate mofetil -\> Inhibits purine synthesis and clonal expansion of lymphocytes * Azathioprine -\> Targets and kills dividing cells

Question 27

What are some side effects of immunosuppression after transplantation?

Answer 27

* Increased incidence of malignancy * Increased likelihood of opportunistic infection

Question 28

What are some novel approaches for protecting against transplant rejection? [EXTRA]

Answer 28

They all relate to inducing tolerance: * Medawar was the first to demonstrate that transplantation tolerance can be achieved by injecting donor cells into mice in utero (i.e. while tolerance is developing) * A state of mixed hematopoietic chimerism can be established by bone marrow transplant ahead of the other organ transplant -\> Each bone marrow produces dendritic cells that induce tolerance (e.g. through AIRE expression) to that body's cells * Treg cells can be induced to expand and then administered along with the transplant, so that the recipient's immune response is suppressed * Induction of permanent tolerance across a full MHC barrier can be achieved in mice through a short course of non-depleting monoclonal antibodies specific for CD4, CD8 and CD40L -\> Not possible in humans yet

Question 29

Give some clinical relevance for techniques that could improve organ delivery for transplantation. [EXTRA]

Answer 29

Normothermic perfusion of organs was approved by NICE in January 2019. It involves keeping the organ perfused well at body temperature, which: * Reduces ischemic time and the damage it causes to tissues * Reduces the impact of reperfusion injury * Purges the organ of passenger leukocytes, reducing the incidence of acute rejection * Increases the pool of usable donor organs

Question 30

Describe some experimental advances in xenotransplantation. [EXTRA]

Answer 30

* Pigs are considered the most appropriate species due to size, physiological compatibility and lack of ethical sensitivities * Hyperacute rejection has been addressed by producing pigs deficient in the a1,3-Gal transferase enzyme: endothelial cells are not targeted by natural IgM antibodies * Swine have also undergone genome editing to remove porcine endogenous retroviruses (PERV) to reduce the likelihood of zoonosis

Question 31

Give some experimental evidence for interspecies organogenesis. [EXTRA]

Answer 31

(Kobayashi, 2010): * Investigated the possibility of growing human organs in a different species * This was done by creating apancreatic mice via Pdx1 gene disruption * The mice blastocyst was injected with rat iPS cells labelled with GFP, creating a chimeric mouse * The resulting organs were a mix of mice and rat cells, but the pancrease was entirely rat cells, since these were the only cells with capacity to grow into a pancreas (due to a functional Pdx1) (Chang, 2018): * Managed a similar thing with the forebrain (Goto, 2019): * Managed a similar thing with kidneys (Yamaguchi, 2017): * Produced and transplanted functional pancreatic cells for the treatment of diabetes in mice in this way

Question 32

Give an example of how interspecies organogenesis could be used as a solution to the shortage of organs for transplantation. [EXTRA]

Answer 32

Question 33

What do T cell deficiencies, B cell deficiencies and innate immune system deficiencies result in?

Answer 33

* T cell deficiencies -\> Susceptibility to infections by viruses and facultative intracellular pathogens * B cell deficiencies -\> Susceptibility to pyogenic infections * Innate immune system deficiencies -\> Susceptibility to pyogenic infections

Question 34

Give some causes of T cell deficiencies.

Answer 34

* Inherited: Thymic aplasia (lack of T cells) * Acquired: Loss of CD4+ in AIDS

Question 35

Give some causes of B cell deficiencies.

Answer 35

* Inherited: Agammaglobulinemia (a group of inherited immune deficiencies characterized by a low concentration of antibodies in the blood due to the lack of particular lymphocytes in the blood and lymph)

Question 36

What are two types of innate immune system deficiencies?

Answer 36

* Cellular defects (e.g. in neutrophils) * Deficiencies of secreted molecules (e.g. cytokines)

Question 37

What is Chédiak-Higashi syndrome?

Answer 37

* A rare autosomal recessive disorder that arises from a mutation of a lysosomal trafficking regulator protein, which leads to a decrease in phagocytosis. * The decrease in phagocytosis results in recurrent pyogenic infections, albinism, and peripheral neuropathy.

Question 38

Name some possible treatments for immune deficiency.

Answer 38

* Replacement therapy e.g. give immunoglobins. * Bone-marrow transplantation. * Chemotherapy e.g. in AIDS.