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Block 6; Week 2-Michelle > Hunter-Transplantation immunology > Flashcards

Hunter-Transplantation immunology Flashcards

1
Q

What are some common organs to transplant?

A

Kidney, liver, pancreas, intestine, heart, lung

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2
Q

What is the biggest difficulty facing transplants?

A

Not surgical technique. Supply of organs & difficulties of immunosuppression.

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3
Q

What are the transplants that have the highests 5 year graft survival?

A

Kidney (81%)
Heart (74%)
Cornea (70%)

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4
Q

Why does the cornea have such a high rate of survival?

A

b/c it is not highly vascularized—difficult for the immune system to get to it.

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5
Q

What does allogeneic mean?

A

We are genetically different. Almost all transplants are allogeneic.
This means that antigenic differences between individuals (alloantigens) induce alloreactive immune responses.

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6
Q

What is the most important alloantigen?

A

MHC proteins—this has the greatest number of alleles-so much room for differences!!

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7
Q

Which MHC is more important in transplantations?

A

MHC I is more important. This is found on all cell types, not just on hematopoietic cells.

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8
Q

Where is the HLA complex located? What does it code for?

A

Located on chromosome 6 & codes for MHC!

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9
Q

What are the alleles for MHCI?

A

6 alleles. A, B, C (from both parents)

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10
Q

What are the alleles for MHC II?

A

6 alleles

HLA-DQ, HLA-DP, HLA-DR

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11
Q

T/F The MHC portion of the genome is polygenic, but not polymorphic.

A

False. It is both polygenic & polymorphic. Multiple genes, and a large number of alleles.

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12
Q

T/F MHC genes have the most alleles of any loci in human genome

A

True

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13
Q

What is codominance w/ respect to MHC?

A

Both alleles (from both parents) are expressed on the cell surface.

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14
Q

What is the one case where it is possible that 2 people will have the same MHC haplotype?

A

Monozyogtic identical twins.

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15
Q

What is an autograft? Is it usually successful?

A

This is a transplant b/w one site on your own body & another site. Usu successful.

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16
Q

What is a syngeneic graft?

A

This is a transplant b/w 2 genetically identical humans. Usu successful.

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17
Q

Which types of grafts often cause acute rejection if no additional treatment is given?

A

Allografts (from a different person)
Xenografts (from a different species)
**can cause rapid death of transplanted tissue
**NOTE: this could happen with a 1 AA difference b/w 2 people’s MHC.

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18
Q

What is the most common & successful tissue transplant? Why is it so much more successful than others?

A

Blood transfusions! RBCs & platelets only have a few MHC molecules. Only really need to match it for ABO & Rh. 4 Major blood types w/ the Rh consideration.

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19
Q

How do you get syngeneic grafts in mice?

A

You inbreed them until they are totally genetically identical.

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20
Q

What is first-set rejection?

A

This is rejection of a graft that is MHC allogeneic in 10-13 days. The first time this graft has been seen. Primary immune response.

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21
Q

What is second-set rejection?

A

A second graft on the same animal is rejected even faster b/c of immunological memory. Less than 10 days.

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22
Q

What happens when you do a T cell transfer from a sensitized mouse to a naïve mouse & then do an allogeneic transplant?

A

You get second-set rejection rate b/c of the immunological memory of the T cells.

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23
Q

T/F If you have a donor who is a sibling with the same MHC haplotype, there will be absolutely no graft rejection.

A

False. It will delay it, but not eliminate it. There are minor histocompatibility antigens that eventually induce T cell mediated immune responses that destroy the graft.

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24
Q

Describe direct allorecognition that leads to graft rejection.

A

APCs from graft present graft peptides & migrate in blood to lymphoid organs. They present the graft peptide on their MHC to host T cells with costimulation.
Effector T cells (CD4 & CD8) are activated.
CD8 kill the grafts directly.
CD4 release cytokines & cause inflammation & fibrosis of the graft.

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25
Q

Describe indirect allorecognition that leads to graft rejection.

A

Graft peptides are presented on host APC. You still get host effector T cells activated & direct killing & inflammation.

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26
Q

What is hyperacute graft rejection?

A

Occurs within minutes of transplantation and is characterized bythrombosisof graft vessels and ischemicnecrosisof the graft
Mediated by pre-existing recipient natural antibodies specific for antigens on graft endothelial cells (e.g. blood group antigens)
**complement & clotting systems are activated.

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27
Q

Why doesn’t hyperacute graft rejection happen anymore?

A

We do blood typing & cross matching. We find a good match. See if the recipient has any antibodies to the donor’s RBCs or WBCs.

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28
Q

What is cross matching?

A

Testing to see if the recipient of a graft has any antibodies to the donor’s WBCs

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29
Q

Acute graft rejection happens in what time period?

A

Days-weeks after the graft has been placed.

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30
Q

What mediates acute graft rejection?

A

CD8T cells recognize alloantigens on the graft.
Antibodies & complement also contribute to this.
Get inflammation, attack of b.v. & loss of blood supply to the organ.

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31
Q

Why doesn’t acute graft rejection happen anymore?

A

Current immunosuppressive therapy

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32
Q

An 18-year-old student with end-stage renal failure due to chronic glomerulonephritis was given a cadaveric kidney transplant. He had been on maintenance hemodialysis for 2 months. His major blood group was A and his tissue type was HLA-A1, -A9, -B8, -B40, -Cw1, -Cw3, -DR3, -DR7. The donor kidney was also blood group A and was matched for one HLA-DR antigen and four of six HLA-ABC antigens. He was given triple immunosuppressive therapy with cyclosporin, azathioprine and prednisolone. He passed 5 L of urine on the second post-operative day and his urea and creatinine fell appreciably. However, on the seventh postoperative day, his graft became slightly tender, his serum creatinine increased and he had a mild pyrexia (37.8°C).What is this patient experiencing?

A

Acute graft rejection.

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33
Q

His major blood group was A and his tissue type was HLA-A1, -A9, -B8, -B40, -Cw1, -Cw3, -DR3, -DR7. The donor kidney was also blood group A and was matched for one HLA-DR antigen and four of six HLA-ABC antigens. Is this a good match?

A

No, this is allogenic definitely.

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34
Q

If you did a fine needle aspiration of this patient…what would you expect to find?

A

A lymphocytic infiltration consistent with acute graft rejection.

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35
Q

What is the treatment for acute graft rejection?

A

IV corticosteroids. Daily immunosuppressive drugs.

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36
Q

T/F If you have a transplant (aside from a corneal transplant) you will be on immunosuppressive drugs for the rest of your life.

A

True.

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37
Q

A 22-year-old welder was given a cadaveric renal graft after a month of hemodialysis for end-stage renal failure. His immediate post-operative course was uneventful and he was discharged home on maintenance immunosuppressive therapy (cyclosporin A 5 mg/kg, prednisolone 30 mg and tacrolimus 0.20 mg/kg body weight daily). He was readmitted on the 37th day with general malaise, muscle aches and fever but able to maintain a reasonable urine output (1700 ml/24 h). On examination, he had tender muscles and hepatomegaly; the transplanted kidney was not tender. Investigation showed a leucopenia but a normal serum creatinine. Stored pre-transplant serum samples showed no evidence of anti-cytomegalovirus (CMV) antibodies or CMV antigen by polymerase chain reaction (PCR) analysis. However IgM anti-CMV antibodies were detected in a current serum sample accompanied by a positive PCR signal for CMV DNA.
What does this patient have?

A

Primary Cytomegalovirus Infection in Renal Transplant Recipient due to a transplant of a CMV-pos. kidney into a CMV-neg recipient.

38
Q

When can CMV really be an issue?

A

It is an opportunistic virus—causes serious disease in immunocompromised people. This includes immunosuppressed transplant recipients.

39
Q

What should be used to treat this patient with a primary CMV infection?

A

Combo of ganciclovir (for CMV) & CMV-specific immune globulin

40
Q

What is chronic graft rejection? What is its time frame?

A

Insidious form of graft damage that occurs over months or years, leading to progressive loss of graft function
Presents as graft fibrosis and narrowing of graft blood vessels (graft arteriosclerosis)

41
Q

What exactly is happening in chronic graft rejection?

A

CD4 T cells react with graft alloantigens and secretecytokines that stimulate the proliferation and activities of fibroblasts and vascular smooth muscle cells

42
Q

Today, what is the most common form of graft rejection?

A

Chronic graft rejection

43
Q

How does chronic graft rejection appear in the heart?

A

accelerated coronary artery atherosclerosis

44
Q

How does chronic graft rejection appear in the lung?

A

bronchiolitis obliterans

45
Q

How does chronic graft rejection appear in the liver?

A

vanishing bile duct syndrome

46
Q

How does chronic graft rejection appear in the kidney?

A

chronic allograft nephropathy

47
Q

What are some factors that increase the risk of chronic rejection?

A

Previous episode of acute rejection
Inadequate immunosuppression
Donor-related factors (e.g., old age, hypertension)
Long cold ischemia time; reperfusion injury to organon ice for hours & hours while being transported
Recipient-related factors (e.g., diabetes, hypertension, hyperlipidemia)
Posttransplant infection (e.g., cytomegalovirus [CMV])

48
Q

A 22-year-old man was treated for acute myeloid leukaemia (AML) with cyclical combination chemotherapy, and complete clinical remission was obtained after three courses. However, remission in AML is generally short; half the patients relapse within a year and second remissions are difficult to achieve. Stem cell transplantation after high-dose chemoradiotherapy is therefore considered in young patients with suitable family members. The brother of this patient was HLA identical and willing to act as a marrow donor. The patient was given cyclophosphamide (120 mg/kg) followed by a dose of total body irradiation that is ordinarily lethal. Immediately after irradiation, he was given an intravenous transfusion of 109 unfractionated bone marrow cells per kg obtained from his brother. He was supported with granulocyte colony-stimulating factor and platelet transfusions during the days of aplasia before engraftment occurred. Methotrexate was administered intermittently to try to prevent GVHD. He was discharged home, well, 7 weeks after transplantation, and remains free of leukemia 7 years later.
Why was this patient given a hematopoietic stem cell transplantation?

A

To correct hematopoietic defects or to restore bone marrow cells damaged by irradiation or cancer chemotherapy. Used in treatment of leukemia.

49
Q

T/F Careful HLA matching of donor & recipient is required for bone marrow transplants, as they are allogenic.

A

True.

50
Q

What are reasons for myeloablative therapy?

A

Sometimes for cancer treatment. Sometimes to make room for bone marrow transplant.

51
Q

Why was methotrexate given to this bone marrow transplant recipient?

A

To prevent graft v. host disease.

52
Q

Once again, what are allogeneic bone marrow transplants often used to treat?

A

(ABMT) are used to treat certain leukemias and lymphomas, some immunodeficiency diseases, and some inherited hematopoietic stem cell deficiencies

53
Q

What is graft v. host disease? What causes it & what is the result?

A

In ABMT mature donor T cells attack recipient tissues causing GVHD even in HLA-identical siblings; alloantigens include MHC I, MHC II, and minor H antigens
Acute graft-versus-host-disease is characterized by selective damage to the liver, skin (rash), mucosa, and the gastrointestinal tract. It has a high mortality rate

54
Q

Much of the therapeutic efficacy of ABMT on leukemia is due to a graft-versus-_____ effect

A

Leukemia!

55
Q

T/F In a SCID kid, you have to worry about the host rejecting a bone marrow transplant.

A

False. But you have a slight concern about graft v. host disease & the graft T cells attacking the host.

56
Q

John was healthy until he was 7-years-old, when his mother noticed that he had become very pale. After talking with his pediatrician John was sent to a hematology consultant for a bone marrow biopsy.The biopsy showed aplastic anemia (bone marrow failure) of unknown cause. Aplastic anemia is ultimately fatal but can be cured by a successful bone marrow transplant. Fortunately, John had an HLA-identical 11-year-old brother who could be the bone marrow donor. John was admitted to the Children’s Hospital and given a course of fludarabine and cyclophosphamide to eradicate his own lymphocytes. He was then given 2 × 108 nucleated bone marrow cells per kg body weight obtained from his brother’s iliac crests. He was also started on cyclosporin A (CsA) to prevent GVHD. John did well for 3 weeks after the bone marrow transplant and was then sent home to recover. However, in spite of GVHD prophylaxis with CsA, on the 24th day after the transplant he was readmitted to hospital with a skin rash and watery diarrhea consistent with acute GVHD.
What are the characteristics & symptoms of this child that signal GVHD?

A

Rash, watery diarrhea. Pneumonitis & liver damage also possible.
This child needs more immunosuppressive drugs. There is still hope that this will work.

57
Q

Which molecules are thankfully lacking in a trophoblast? What does this allow?

A

MHC molecules are lacking. Keeps mom’s T cells from viciously attacking dad’s MHC.

58
Q

What is the special placental enzyme that is required for tolerance of the fetal allograft? What does it do?

A

Indole amine dioxygenase. Catabolizes tryptophan. Starves any of mom’s T cells that make it into the baby’s house.

59
Q

Placental secretion of ____ causes immune deviation.

A

Cytokines.

60
Q

What is the balance required with immunosuppression following tissue transplants?

A

Too little immunosuppression, their grafts will be rejected; too much immunosuppression, they will die from infections

61
Q

When do you need immunosuppression following transplants?

A

Unless you have a graft from an identical twin—always!

62
Q

What is the most useful immunosuppressive drug for clinical transplantation? What does it do?

A

Cyclosporin A—a fungus.
Blocks T cell phosphatase calcineurin & prevents NFAT (nuclear factor for activated T cells) from activating cytokine genes.
This focuses on stopping T cells from dividing.

63
Q

What is the main problem with immunosuppressive drugs (aside from cyclosporin)?

A

Nonspecific immunosuppression. Inhibit more than just the graft!
So pts become vulnerable to infections & even certain cancers

64
Q

What is the mechanism of action for the immunosuppressive drug–corticosteroids?

A

inhibits inflammation; inhibits many targets including cytokine production by macrophages.

65
Q

What is the mechanism of action for the immunosuppressive drug–azathioprine, cyclophosphamide, mycophenolate?

A

inhibits proliferation of lymphocytes by interfering with DNA synthesis

66
Q

What is the mechanism of action for the immunosuppressive drug–CyclosporinA? Which soil bacteria did this come from?

A

inhibits the calcineurin-dependent activation of NFAT–blocks IL-2 production & proliferation by T cells
**comes from tacrolimus soil bacteria

67
Q

What is the mechanism of action for the immunosuppressive drug–Rapamycin? What is this also known as?

A

aka sirolimus–from easter island!

inhibits proliferation of effector T cells by blocking Rictor-dependent mTOR activation.

68
Q

What is the mechanism of action for the immunosuppressive drug–Fingolimod-FTY270?

A

blocks lymphocyte trafficking out of lymphoid tissues by interfering w/ the signaling of sphingosine-1 phosphate receptor.

69
Q

Once again, what do corticosteroids do? What are the side effects?

A

Suppresses inflammation in allergy, autoimmune diseases, and allografts
Binds to intracellular receptors releasing complex that crosses nuclear membrane, binds to NF-kB promoter, and inhibits transcription
Down-regulates proinflammatory cytokines, nitric oxide, prostaglandins, leukotrienes, and adhesion molecules
Side Effects: hunger, weight gain

70
Q

What are the physiologic effects of corticosteroid’s ability to down regulate IL-1, TNFa, GM-CSF, IL-3, IL-4, IL-5, CXCL8?

A

This reduces inflammation that is caused by cytokines.

71
Q

What are the physiologic effects of corticosteroid’s ability to down regulate NOS?

A

A decrease in NO

72
Q

What are the physiologic effects of corticosteroids’ ability to down regulate phospholipase A2 & cyclooxygenase type 2 & upregulate annexin-1?

A

A decrease in prostaglandins & leukotrienes

73
Q

What are the physiologic effects of corticosteroids’ ability to downregulate adhesion molecules?

A

Reduced emigration of leukocytes from vessels

74
Q

What are the physiologic effects of corticosteroids’ ability to upregulate endonucleases?

A

Induction of apoptosis in lymphocytes & eosinophils.

75
Q

What is the effect of these immunosuppressive cytotoxic drugs: azathioprine, mycophenolate, and cyclophosphamide?

A

These drugs block DNA synthesis and kill dividing cells (originally used as anti-tumor drugs)
Dividing lymphocytes are good targets, but so are many non-immune cells. Thus, unwanted side effects.

76
Q

What does cyclophosphamide turn into once it is in your body?

A

Phosphoramide mustard. Ingredient of mustard gas—keeps cells from dividing.

77
Q

What are 3 immunosuppressive drugs that are considered microbial inhibitors? What do they all bind to? What is their common fcn?

A

Cyclosporin A—affects T cells more than other cells.
Tacrolimus
Rapamycin
**all bind to immunophilins
**inhibit T & B cell proliferation & granulocyte function.
BUT—unwanted side effects b/c nondescriminate.

78
Q

Describe the pathway that cyclosporin acts on? How does it function normally? What does cyclosporin do?

A

Normally: Calmodulin is activated by Ca++. It binds the enzyme calcineurin & activates it. Then calcineurin is able to dephosphorylate the transcription factor NFAT. NFAT can enter the nucleus & stimulation IL-2 transcription (T cell growth factor).
With Cyclosporin-A: Cyclosporin A binds an immunophilin. This complex inhibits calcineurin’s activation by calmodulin. Therefore, NFAT can’t be dephosphorylated & can’t increase IL-2 transcription.

79
Q

T/F Rapamycin & Cyclosporin A act on different pathways, and can therefore be used together to treat a patient.

A

True.

80
Q

Which immunophilin does Rapamycin bind & form a complex with?

A

Immunophilin FKBP.

81
Q

What does the RAPTOR-mTOR pathway lead to?

A

Cell proliferation
Protein Translation
Autophagy

82
Q

What does the RICTOR-mTOR pathway lead to?

A

Actin cytoskeleton
Adhesion
Cell Migration

83
Q

The rapamycine complex with FKBP acts on which pathway? What is the end result?

A

It acts to inhibit the RAPTOR-mTOR pathway. End result: selectively reduces cell growth & proliferation. Acts on T cells.

84
Q

Muromomab is also known as what? What does it act on?

A

Aka OKT3. This is anti-CD3 (found on T cells)

85
Q

What does daclizumab act on?

A

Anti-IL2 receptor

Blocks the proliferation & differentiation of T cells that have been activated.

86
Q

What does basiliximab act on?

A

Anti-IL-2 receptor

Blocks the proliferation & differentiation of T cells that have been activated.

87
Q

What does an ending for a monoclonal antibody –omab mean?

A

This is a fully mouse monoclonal antibody.

88
Q

What does an ending for a monoclonal antibody –ximab mean?

A

Chimeric

89
Q

What does an ending for a monoclonal antibody –zumab mean?

A

Humanized

90
Q

What does an ending for a monoclonal antibody –umab mean?

A

Fully Human

91
Q

Once again, what do corticosteroids do? What do they down regulate? What are the unwanted side effects?

A

Suppresses inflammation in allergy, autoimmune diseases, and allografts
Binds to intracellular receptors releasing complex that crosses nuclear membrane, binds to NF-kB promoter, and inhibits transcription
Down-regulates proinflammatory cytokines, nitric oxide, prostaglandins, leukotrienes, and adhesion molecules
Side Effects: Weight Gain & Acne

Block 6; Week 2-Michelle (8 decks)

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