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SMP - MIM Part 1 > Lecture 12 - Transplant Immunology > Flashcards

Lecture 12 - Transplant Immunology Flashcards

1
Q

What is the most common tissue transplant? How does it differ from all others?

A

The most common tissue “transplant” is blood transfusion

It differs from the transplant of solid organs (eg, kidney, heart) or hematopoietic stem cells because the transfused cells have short life spans => we aren’t struggling to maintain the tissue within the patient for long periods of time but we do need to worry about an initial immune attack aimed at mismatched blood group antigens

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2
Q

List solid organ transplants in order of prevalence.

A
  1. Kidney
  2. Liver
  3. Heart
  4. Lung
  5. Intestine
  6. Multi-organ
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3
Q

List solid organ transplants in order of graft survival.

A
  1. Heart
  2. Liver
  3. Kidney
  4. Pancreas
  5. Heart-lung
  6. Lung
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4
Q

Are hematopoietic stem cell transplants more common than solid organ transplants?

A

NOPE

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5
Q

Purpose of allogeneic hematopoietic stem cell transplants?

A

To treat fatal blood diseases:

  1. Leukemia
  2. Stem cell disorders (e.g. severe aplastic anemia)
  3. Lymphoproliferative disorders (e.g. non-Hodgkin’s lymphoma)
  4. Liposomal storage diseases
  5. Congenital immune system disorders (SCID)
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6
Q

What are 3 potential sources of allogeneic hematopoietic stem cell transplants?

A
  1. Bone marrow
  2. Growth factor stimulated peripheral blood
  3. Umbilical cord blood
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7
Q

3 barriers to transplant?

A
  1. Ability to preserve and transplant organs
  2. Limited supply of organs
  3. Recognition of the graft as foreign by the patient’s immune system
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8
Q

4 types of grafts? Describe each.

A
  1. Autologous graft: given to self
  2. Syngeneic graft: given to genetically identical being
  3. Allogeneic: given to genetically different member of the same species (related or not)
  4. Xenogeneic: given to genetically different member of a different species
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9
Q

Consequence of graft to syngeneic recipient?

A

Tolerance

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10
Q

Consequence of graft to allogeneic recipient? What to note?

A

Nonself (foreign tissue) is rejected in about 2 weeks after the transplant = first-set rejection

Note: prior exposure to nonself causes stronger and more rapid rejection response (individual is “sensitized” to foreign tissue) = second-set rejection

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11
Q

What does it mean for the immune response to foreign tissue to be specific?

A

It means the immune response to foreign tissue can distinguish between tissue from different individuals so the recipient is not sensitized to tissue from a second donor

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12
Q

What is the immune responding to when rejecting a graft? Example of this?

A

Responding to human leukocyte antigens (HLAs) on foreign tissue

Example: pregnant women recognize proteins expressed in father’s blood due to these genes being encoded in the child as well => leukocyte and AB agglutination

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13
Q

2 directions of allorecognition?

A
  1. Response to nonself tissue and rejection (solid organ primarily)
  2. Graft vs host disease (GVHD) (hsc transplant primarily): graft responds to recipient
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14
Q

What do solid organ grafts contain?

A
  1. Graft cells

2. Possibly passenger leukocytes

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15
Q

What do hematopoietic stem cell transplants contain?

A
  1. Stem cells

2. Immune cells

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16
Q

How are hematopoietic stem cell transplant treated to reduce rejection?

A

Irradiation/chemotherapy to compromise the immune system

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17
Q

What is GVHD mediated by in solid organ transplants?

A

Passenger leukocytes

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18
Q

What is the adaptive immune response to alloantigens?

A

Immune response to foreign tissue involves both T and B lymphocytes

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19
Q

Describe the 3 stages of first set rejection of a solid organ. What is it mediated by?

A
  1. Revascularization: days 3-7
  2. Cellular infiltrate: days 7-10
  3. Necrotic tissue, damaged blood vessels, blood clots: days 10-14

Mediated by T cells that primarily target the vascular endothelium

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20
Q

Describe second set rejection of a solid organ.

A 
1. Loss of graft function
AND/OR
2. Reduced graft survival 
AND/OR
3. Hyperacute rejection
AND/OR
4. Accelerated acute rejection
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21
Q

What could have sensitized a patient to a second set rejection?

A
  1. Prior transplant
  2. Transfusion
  3. Pregnancy
22
Q

What is a hyperacute rejection? 5 characteristics.

A
  1. Pre-exisiting serum antibody specific for graft
  2. Complement mediated
  3. Within 24 hours post-transplant, often immediately with vascularized grafts
  4. Infiltration of neutrophils into grafted tissue leading to inflammatory reaction
  5. Blood clots within capillaries
23
Q

What is a accelerated acute rejection? 4 characteristics.

A
  1. Activation of memory lymphocytes: memory B cells secrete antibody specific for graft + memory T cells
  2. Lymphocyte infiltrate
  3. Complement C4d deposition in tissues
  4. Happens in first week
24
Q

How to minimize risk of hyperacute and accelerated acute rejections? What to note?

A

Selecting the right donor to which the recipient is not sensitized

Note: it is rare for this to happen these says because of good testing methods

25
Q

2 types of GVHD? Describe each.

A
  1. Acute:
    - Occurs early (first 1-3 mos)
    - Affects skin (rash), eyes, stomach (nausea), intestine (diarrhea)
    - Grade I (mild) - Grade IV (life threatening)
  2. Chronic:
    - Occurs later (>3 mos)
    - Rash, skin thickening, dry eyes, mouth sensitivity
    - Autoimmune-like mechanism
26
Q

What are the 3 laws of transplantation?

A
  1. Immune cells responding to non-self can be derived from recipient, or graft or both
  2. Substantial B and T lymphocyte activate in response to foreign tissue = allorecognition
  3. Long term immune memory can cause the recipient to be “sensitized” to specific histocompatibility antigens
27
Q

What does the immune system see as foreign between graft donor and recipient? What are the alloantigens?

A
  1. Blood group antigens: ABO and Rh
  2. Major histocompatibility molecules
  3. Minor histocompatibility molecules (other polymorphic proteins)
28
Q

What mediates the rejection of different blood group antigens?

A

Naturally occurring antibodies (isoagglutinins) mediate rejection

29
Q

Where is ABO expressed?

A
  1. RBCs

2. Vascular endothelium of donor organs

30
Q

Is ABO matching required for hsc transplants?

A

Preferred but not required

31
Q

Why is it difficult to match alleles at all the HLA genes?

A

Because of the extensive allelic diversity in the human population, so it is difficult to find two unrelated people who share HLA alleles

32
Q

What are cross-reactive TCRs?

A

TCRs that see self MHC+foreign peptide and foreign MHC+some peptide if these complexes are almost indistinguishable to the TCR (i.e., they must be similar in shape, charge, hydrophobicity)

33
Q

What are cross-reactive T cells often specific for? What type of T cells are these?

A

Often specific for antigens from viruses and are memory T cells

34
Q

What is it called when a foreign HLA is recognized by a TCR?

A

Direct cellular recognition

35
Q

Which cause a stronger immune response: Major or Minor HistoCompatibility molecules?

A

Major ones

36
Q

What are Minor HistoCompatibility molecules? Can these be HLAs? Immune response to them?

A

Antigens due to polymorphisms (alleles)

YUP, they can be HLAs

Immune response is slower and indirect compared to Major HC molecules because they interact with a piece of it, not the whole foreign HLA

37
Q

Example of a Minor HistoCompatibility molecule?

A

Male proteins coded for on the Y chromosome recognized as antigens by a female recipient

38
Q

5 ways to prevent an immune response to transplant?

A
  1. Match histocompatibility molecules and ABO blood group
  2. Monitor sensitization of the recipient prior to transplant
  3. Suppress immune response
  4. Use less immunogeneic tissue
  5. Induce specific tolerance
39
Q

Do RBCs express MHCs?

A

NOPE

40
Q

How is blood transfused to avoid immune response?

A

Separated components are transfused

41
Q

When are HLAs matched for blood transfusions?

A

If patients is given platelets and many transfusions

42
Q

Matching needed for HSC transplants?

A

Precise HLA matching to achieve immune reconstitution and low GVHD with minimal immune suppression

43
Q

What does solid organ rely on most to avoid rejection? Why?

A

Immune suppression more so than HLA matching (but donors with HLAs that the recipient is sensitized to should be avoided AND better matched grafts survive longer and patients don’t become as sensitized)

Reason: because some patients will be at a huge disadvantaged if you try to find them an HLA match

44
Q

What solid organ transplant does not require HLA matching? Why?

A

Liver because its cells have low HLA expression (more resistant to rejection)

45
Q

How does solid organ preservation time affect transplant?

A

Limited time prevents matching for some organs like the heart

46
Q

What are immunologically privileged sites? Example?

A

Transplant sites where no matching is necessary because:

  1. Extracellular fluid from these sites does not pass through conventional lymphatics
  2. These sites are surrounded by tissue barriers that exclude naïve lymphocytes
  3. These sites express Fas ligand and induce apoptosis of Fas-bearing effector lymphocytes
  4. Antigens leaving these sites are accompanied by anti-inflammatory cytokines such as TGF-β

E.g. eye (cornea transplant), brain, testis, uterus (fetus)

47
Q

Best donors for HSC transplants? What if not possible?

A

Nuclear family and extended family, particularly siblings because there is a 1 in 4 chance that two sibs inherit the same copies of chromosome 6 from their parents

If there is not an available sibling (the case 70% of the time), the search moves on to the unrelated population where the chances of finding an HLA identical person drops dramatically because of the extensive polymorphism in the HLA genes

48
Q

How do we monitor sensitization of the recipient prior to transplant?

A
  1. Monitor recipient for presence and specificity of antibodies to foreign HLA
  2. Perform crossmatch: test serum from patient with cells from specific donor to identify reactivity to donor’s HLA
  3. New protocols to remove antibodies from sensitized patients (limited by extent of sensitization)
49
Q

2 ways of suppressing the immune system. Describe each.

A
  1. Specifically:
    - Block T cell signals
    - T/B cell depletion
  2. Non-specifically
    - Anti-inflammatory agents
    - Inhibit mitosis
    - Interfere with immune cell activation
    - Remove antibody
50
Q

5 limitations of immune suppression?

A
  1. Toxic effects of agent
  2. Infections/malignancies due to failure of immune surveillance
  3. Failure in immune reconstitution for hsc transplants
  4. Patient compliance/cost
  5. Graft failure causes sensitization reducing success of second transplant
51
Q

What is an example of using less immunogeneic tissue to prevent rejection of transplant?

A

This is done in hsc transplant where it is hypothesized that umbilical cord blood might be less likely to cause allorecognition than bone marrow which contains mature T cells

52
Q

What does it mean to induce specific tolerance to avoid transplant rejection? How is it accomplished?

A

Goal is for the graft to become SELF => specific unresponsiveness to the graft without immunosuppression BUT maintain immune responses to pathogens

Procedures to routinely accomplish this being developed (approaches might involve deleting or inactivating alloreactive T cells)

SMP - MIM Part 1 (14 decks)

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