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Immunology > Transplantation of Tissues and Organs > Flashcards

Transplantation of Tissues and Organs Flashcards

1
Q

*What are the 3 fundamental problems with organ transplantation?

A

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2
Q

*Describe the cross-match testing for blood transfusion- ABO, HLA

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3
Q

*Differentiate between graft versus host disease

A

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4
Q

*Describe hyperacute, acute and chronic rejection

A

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5
Q

*Explain what alloantigens, alloreaction (direct and indirect pathways)

A

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6
Q

*Explain what occurs in mixed lymphocyte reaction

A

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7
Q

*What is the role of inflammation in hematopoietic stem cell transplantation

A

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8
Q

What are the 3 fundamental problems with organ transplant?

A

3 problems with Organ transplant:

  1. Transplant must be introduced in ways that allows for normal physiological functions
  2. health of recipient and transplant must be maintained during surgery and other procedures
  3. Recipient’s immune system must be prevented from responding to the transplant and causing its rejection
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9
Q

Differentiate between Autologous and allogenic stem cells. What does it mean when someone’s tissues are histocompatible?

A

Autologous stem cells- stem cells are from your OWN body
Allogenic stem cells- are DONATED from another human being
Histocompatible- Donor and recipient have COMPATIBLE tissue types that can coexist without provoking too strong an immune response.

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10
Q

What is the most commonly transported organ?

A

BLOOD

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11
Q

What is the most transported solid organ?

A

KIDNEY

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12
Q

Describe the components of Blood transfusion and possible combos. How many donor/recipient ABO combos are there?

A

Blood transfusion:
-most commonly transported organ (blood)
-Antigens- ABO and Rhesus D blood groups- erythrocyte surface antigens.
-Structural polymorphism in the carbohydrate component of glycolipids and of a glycoprotein called band 3 of the RBC membrane
-A and B antigens are structurally similar to cell-surface carbohydrates of common commensal bacteria.
-Serum of blood group O individuals contain IgGs antibodies against A and B antigens
16 possible donor/recipient ABO combos: 9 are compatible and 7 are NOT compatible.
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13
Q

What makes blood type O so unique?

A

Blood type O has anti-antibodies against A and B blood type. Hence O can only receive from type O. and O can donate blood to all kinds of blood (type A, B, AB and O)

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14
Q

List the possible donor/recipient combos: successful and not compatible

A 
Compatible donor/recipient ABO combos:
O can donate blood to type 
1. A, 
2. B, 
3. AB,
4 and O
A can donate blood to type: 
5. A
6. AB
B can donate blood to type: 
7. B 
8. AB
AB can donate blood to type 
9. AB.
-O can only receive blood from type O; has anti A and anti B antibodies
-A can only receive from type O and A; has anti B antibodies
-B can only receive from type O and B: has anti A antibodies
-AB can receive from A, B, AB, O; hence has NO antibodies against A, or B (however it only donates to AB).
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15
Q

What is the function of Rhesus D antigen?

A

Rhesus D antigen- occurs when transfusion of recipients lacking RHD with blood from an RHD+ donor induces an antibody response.
Second exposure is MORE DANGEROUS

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16
Q

What are components that lead to process taking longer for transplants to occur.

A

Transplant process takes longer if:

  1. looking for transplant for blood type O-, since it has to be a donor with same O- blood type
  2. Being a LARGER individual (in size), takes longer for these individuals to find transplant match (require larger organ)
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17
Q

What are the other polymporphic blood group antigens? what is cross-match testing?

A

Other polymorphic blood group antigens:
-30 additional polymorphic blood group antigens
-CROSS-MATCH Testing- before transfusion, look for agglutination (clumping) of donor red blood cells, determine if antibody is present in the serum.
Antibodies to the non-ABO and non-Rhesus blood group antigens

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18
Q

what happens after having multiple transfusions and why?

A

After multiple transfusions, it may be difficult to find compatible donor. Since you will become very sensitized (antibodies against non-ABO and non-rhesus blood group antigens will be made.

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19
Q

What does agglutination signifiy?

A

If you find clumps of donor red blood cells, it signifies that transfusion is incompatible. It also means that antibodies have been formed against donor.

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20
Q

What kind of hypersensitivity can incompatibility cause?

A

Incompatibility (receive wrong blood type for transfusion) can cause type II hypersensitivity. This leads to hemolytic reactions that can cause fevers, chills, renal failure, shock and death.

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21
Q

What kind of reactions occur when donors and recipients are NOT compatible?

A

HYPERSENSITIVITY REACTIONS occur when donors and recipients are NOT compatible.

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22
Q

What are the structural differences of different A, B, O blood type antigens?

A

blood type O: has same main structure as all blood types:
Type O: ceramide, glucose , acetlyglucosamide, Galactose and fucose
Type A: Hade extra n-acetlyglucoasmine
type B: had leftover Galactose

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23
Q

How many different combos are there for and RHD combos?

A

There are 64 ABO/RHD combos: 27 are compatible, and 37 are noncompatible.

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24
Q

What is the histocompatibility for ABO type vs RhD+?

A

Type O Rhd- only receive type O Rhd- ; type O Rhd- can donate to OrHd+/-, A, B, AB RhD- or D+
type O Rhd+ only receive type O rhd+ or type O rhd-
; but can donate type O rhd+. A Rhd+ and B RhD+;
type A Rhd - can receive O Rhd- and A Rhd-
type A RhD+ can receive O Rhd-/+ and A Rhd-/+

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25
Q

Where are ABO antigens present?

A

ABO antigens are present on erythrocytes and endothelial cells of blood vessels.

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26
Q

Which organ is highly vascularized?

A

Highly vascularized organs= KIDNEYS

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27
Q

What happens when you have an incompatible donor for recipient transplant?

A

Incompatible Donor/Recipient transplant:
ex: type A donor and type O recipient
-Antibodies quickly and extensively bind the blood vessels of the graft and complement is fixed throughout the graft’s vasculature- RAPID REJECTION
called Hyperacute rejection

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28
Q

What is hyperacute rejection? what is the most devastating rejection of organs? What occurs to avoid hyperacute rejection?

A

Hyperacute rejection- rejection process that occurs a few minutes after transplant; when antigens are unmatched.
This is when antibodies develop in recipient and recognizes antigens in donor organ.
The most devastating rejection of organs (hyperacute rejection in Kidney)
-Typing and cross-matching for ABO blood group antigens are performed to avoid hyperacute rejection.

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29
Q

What is a graft?

A

Graft- the transplantation of an organ or tissue to a different location (goal of replacing or missing a damaged organ or tissue)

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30
Q

elaborate more on the process of hyperacute rejection when you have incompatible donor/recipient transplant

A

hyperacute rejection process:

  1. Healthy kidney grafted into patient with kidney failure and preexisting antibodies against donor blood group antigens.
  2. Antibodies against donor blood group antigens will BIND vascular endothelium of graft, and initiate an inflammatory response that occludes (obstructs) blood vessels.
  3. The graft becomes engorged and purple-colored because of hemorrhage.
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31
Q

Differentiate between HLA Class I and HLA class II

A 
Antibodies against HLA class I can contribute to Hyperacute rejection- and HLA class I is expressed on vascular endothelium
HLA Class II- expression induced on vascular endothelium by infection, inflammation and trauma
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32
Q

What is the use of cross-match testing? Differentiate between the antibodies for anti-HLA class I and anti-HLA class II.

A 
Cross-match testing- detects antibodies in patient serum that trigger COMPLEMENT mediated lysis of donor lymphocytes
Anti-HLA class I antibodies- react with both B and T cells, 
Anti-HLA class II antibodies- react with only B cells- separate B and T cells for assay and can distinguish if HLA class I or II reactivitiy.
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33
Q

What is flow cytometry?

A

Flow Cytometry- more SPECIFIC cross-matching- which detects ALL antibody binding, not just those that fix complement

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34
Q

Describe where anti-HLA antibodies can be seen and what occurs during pregnancy. What HLA does fetus express?

A

Anti-HLA antibodies

  • seen in pregnancy, blood transfusion, previous transplant
  • Pregnancy- fetus expresses PATERNAL HLA allotypes- Fetal and maternal circulation is SEGREGATED. So NO response- mother is exposed to antigen during trauma to birth
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35
Q

What is the main source of anti-HLA antibodies in Serological HLA typing?

A 
Multiparous women (more than one birth)- main source of anti-HLA antibodies used in serological HLA typing
HLA antibodies- Transplantation antigens- MHC. (helps match recipients with donors compatible for transplant)
36
Q

Explain what happens to HLA during pregnancy.

A
  1. Mother and Father usually differ in HLA class I and HLA class II type
  2. During gestation, cells of the fetus and fetal circulation are exposed to cells of the maternal adaptive immune system
  3. The trauma of birth exposes the maternal circulation to fetal cells and stimulates the production of antibodies against paternal HLA.
37
Q

What are alloantigens? What are alloreactions?

A

Alloantigens: self-antigens which vary between members of the SAME species
Alloreactions: the immune response induced by alloantigens.

38
Q

What is Immunogenetics? Describe the two types of alloantigens.

A

Immunogenetics- field devoted to the study of genetics of alloantigens and their impact on the immune system.
Two types of alloreactions in transplantation:
-Transplant rejection- solid organ transplant (ex: kidney) -Graft-versus host reaction (GVHR)

39
Q

Elaborate on process of Hematopoietic Stem Cell Transplantation

A

Hematopoietic Stem Cell Transplantation process:
helps treat patients with severe genetic immunodeficiency and hematopoietic cancers
Process:
1. recipients hematopoietic system is destroyed by irradiation and chemotherapy
2. Then by intravenous transfusion, patient receives liquid graft containing healthy hematopoietic stem cells from donor.
3. Over the next 12 months, stem cells from graft gradually form new hematopoietic system and have healthy patient.

40
Q

Compare and contrast what occurs in transplant rejection vs graft-versus host disease

A

Transplant rejection: When a kidney is transplanted, the RECIPIENT’s T cells attack the transplant (acute rejection)
Graft versus-host disease: When hemaotopoietic cells are transplanted, the T cells in the transplant (like bone marrow) attack the recipient’s tissues

41
Q

What occurs in Graft versus Host disease? What type of hypersensitivity is it?

A

GVHD (graft vs. Host disease)- when donor T-cells in the graft respond to and attack the recipient’s healthy tissue- Type IV Hypersensitivity response.

42
Q

Differentiate between isograft and autograft

A

Autograft- patient’s tissue is transplanted from one site to another. This is seen in:
- Skin graft (Burn victims)- skin from unaffected parts of body transferred to burn areas.
-Bone grafts
-Ligament repairs
Isograft- Syngeneic transplant; type of transplant between two genetically identical individuals
ex: transplant from one twin given to another twin.

43
Q

Discuss the type of patients that receive transplants, and how the donated organs appear.

A

Transplant patients usually have a history of disease- may involve immune system- often in inflammatory state before transplantation (kidney- dialysis)
Donated organs are usually Inflamed- often due to trauma and harvest/transport- ischemia (blood derived)

44
Q

Describe what occurs in Acute rejection. What kind of reaction is it? What will patients be conditioned with?

A

Acute rejection:

  • type IV Hypersensitivity
  • Recipient’s native T-cell population contains clones that recognize HLA allotypes of the transplanted tissue
  • CD8-T cells respond to HLA class I (MHC class I)
  • CD4 T -cells respond to HLA class II (MHC class II)
  • it takes Several days to develop
  • patients are conditioned with immunosuppressive drugs before and after transplantation
45
Q

Describe the state of the transplanted organ during acute rejection.

A

During Acute rejection:
there is an INFLAMED state of transplanted organ- induces donor-derived dendritic cells to secondary lymphoid tissue- T cell zone- present donor-derived antigen to recipient’s T-cells.

46
Q

Why is the alloreactive response stronger than vaccine in acute rejections?

A

Alloreactive response is STRONGER than response to vaccine or pathogen due to thymic selection- different HLA allotypes bind different self-peptides, so will bind self peptide: HLA complex of donor.

47
Q

What is the direct pathway of alloerecognition in acute rejection? what happens when effector T cells migrate to transplanted tissue?

A

Direct pathway of allorecognition: Recipient T-cells are stimulated by direct interaction of their receptors with the allogenic HLA molecules expressed by donor dendritic cells.
Effector T cells migrate to transplanted tissue- TH1 cells activate the resident macrophages to inflame the tissue more and CD8-T cells kill the transplanted tissue.

48
Q

Describe what happens to kidney that has been acutely rejected.

A

Acutely rejected kidney: undergo hemorrhage (blood from broken vessel) and necrosis (death of body tissue) visible

process:
1. Kidney graft with dendritic cells
2. Dendritic cells migrate to the spleen, where they activate effector cells
3. effector T cells will migrate to graft via blood
4. Graft destroyed by effector cells.

49
Q

what occurs in a mixed lymphocyte reaction? What are the PBMCS?

A

Mixed lymphocyte reaction: cellular test used to assess how a patient’s cells might respond to a transplanted organ from a living donor.
PBMCs -peripheral blood mononuclear cells (lymphocytes and monocytes) that are isolated from donors and recipients- donor cells are irradiated to prevent reactivity
-Activated cells will clonally expand when cultured cells from donor and recipient are cultured (5 days)
during culture- T cell proliferation is measured and at end of culture period, effector T cell population is assayed for its capacity for graft rejection (kill donor cells).
- This reaction is an in vitro model of acute graft rejection- rarely used to match donor/recipient (takes too much time)

50
Q

What occurs in chronic rejection? What kind of hypersensitivity is this?

A

Chronic rejection
-reactions in the vasculature of the graft that cause thickening of vessel walls and a narrowing of their lumens
-Blood supply becomes inadequate- ischemia, loss of function and death of graft
-Cause of >50% of all kidney and heart graft rejections within 10 years of post-transplantation.
This is a Type III hypersensitivity response- caused by IgG antibodies against HLA class I molecules of the graft.

51
Q

Describe the acute rejection of a kidney graft through direct pathway of allorecognition.

A

Acute rejection of kidney graft: direct pathway of allorecognition:

  1. dendritic cells in the kidney graft are of donor origin
  2. Dendritic cells travel in the blood to the spleen, where they activate recipient’s alloreactive T cells
  3. Effector alloreactive T cells leave the spleen and travel in the blood to the grafted allogenic kidney.
  4. effector T cells damage and kill the epithelial cells of the kidney stopping all kidney function
52
Q

Further elaborate on Chronic rejection process. What is used to treat chronic rejection?

A

Chronic rejection process:-
Ig G antibodies against HLA Class I molecules of the graft form immune complexes that deposit in blood vessels of the transplanted organ.
Grafts become infiltrated with CD40-ligand expressing B cells and helper T cells expressing CD40 ligand
Anti-B-cell antibody (Rituximab)- used to treat chronic rejection (helps stop b cell response)

53
Q

What are the two main steps of chronic rejection?

A

Chronic rejection:

  1. immune complexes deposited in the blood vessel walls of the transplanted kidney recruit inflammatory cells
  2. increasing damage enables immune effectors to enter tissue of the blood vessel wall and to inflict increasing damage.
54
Q

Differentiate between direct vs indirect allorecognition

A 
Direct allorecognition- DECREASES over time-  donor dendritic cells are replaced by recipient dendritic cells
(alloreactive HLA I and II interact directly with T-cell receptor of recipient's CD4 or CD8 T cells)
Indirect allorecognition: recipient dendritic cells cause reactivity- cross-match testing selected for lack of serum antibody to transplanted organ- no memory B-cells to be stimulated. 
(present HLA class II to CD4 t cells; present HLA Class I to CD8 T cells)
55
Q

further elaborate on the indirect pathway of allogenic recognition. What is the transfusion effect?

A

indirect pathway of Allogenic recognition:
-Activation of helper CD4 T-cells after transplantation through indirect pathway could initiate response against graft HLA if naive B cells are capable of reacting with graft HLA
-T cells can induce naive B cells to become plasma cells
Transfusion effect: regulatory CD4 T cells (T reggs) suppress alloreactive CD4 and CD8 T cells (helps clinical outcome of kidney transplantation)- more active in patients with previous blood transfusions with shared HLA-DR allotype of graft

56
Q

Where do alloantibodies that cause chronic rejection come from?

A

The alloantibodies that cause chronic rejection of organ transplants are the result of an immune response stimulated by the indirect pathway of allorecognition

57
Q

What improves transplantation success? Describe the trend with years and survival rate of grafts

A 
HLA class I and II matching improves transplantation success
As the years increase, there is DECREASING survival of grafts
58
Q

What is the purpose of Anti-CD52?

A

Anti-CD52 is effective at depleting leukocytes before organ transplantation
-they will fix complement (increase likelihood of C3b being formed) and stop the immune response
Anti-CD52 has small size

59
Q

Explain the process of immunosuppressive drugs preventing T cell activation by alloantigens. What is purpose of cyclosporin drug?

A

Process:
1. signals from T-cell receptor activate AP-1 and increase intracellular calcium concentration
2. Raised Intracellular Calcium activates calcineurin, a phosphatase (removes phosphate from NFAT) that activates NFAT.
3. Activated NFAT migrates to the nucleus and binds to AP-1 to form an active transcription factor.
Activation of the IL-2 gene and other genes leads to clonal expansion of T cell.
However, cyclosporin is an immmunosuppressive drug that can inhibit T cell activation and prevent phosphatase from happening with calcineurin.
1) Immunosuppressive drugs cyclosporine (CsA) and tacrolimus act in the cytosol
2) cyclosporin binds to cyclophillin (CyP) and tacrolimus bins to FK-binding protein (FKBP)
3) CsA:CyP and tacrolimus:FKBP bind calcineurin, preventing its activation by Ca2+ and blocking NFAT activation leading to NO activation of transcription.

60
Q

Explain the role of Betacept in T cell activity.

A

Betacept- soluble chimera of Ig Fc region and CTLA4.
process:
1. alloreactive T-cell receptor binds Foreign MHC receptor and generates signal 1 (betacept not involved)
2. Betacept binds B7 and prevents engagement of CD28 and generation of signal 2.

61
Q

Differentiate between which receptor Anti-CD25 engages in vs not engage.

A

*Anti-CD25 does NOT engage in low affinity IL-2 receptor on naive autoreactive T cells
*Anti-CD25 binds to HIGH affinity IL-2 receptor on activated T cells and prevent generation of signal 3.
the anti-CD25 only bind alpha portion of mature T cell.

62
Q

Explain how immunosuppressive drugs act at different stages in the activation of alloreactive T cells.

A

Immunosuppressive drugs on activation of Alloreactive T cells:
-rATG (rabbit antithymocyte globulin) and anti-CD52 monoclonal antibody (alemtuzumab) are used to deplete T cells and other leukocytes before transplantation
Anti-CD3 monoclonal antibody prevents generation of signal 1 from T-cell receptor complex, whereas cyclosporin and tacrolimus interfere with delivery of signal 1 (inhibit action of calcineurin)
-the CTLA-fusion Fc protein Belatacept binds B7 and prevents generation of signal 2 from CD28, the co-stimulator receptor.
-the anti-CD25 antibody (basiliximab) binds to the high- affinity IL-2 receptor on partly activated T cells and prevents the generation of signal 3.
-Sirolimus interferes with the delivery of signal 3.
Azathiopine, mexathotrexate, mycophenolate and cyclphosphamide sabotage replication and proliferation of activated T cells.

63
Q

Describe the U.S statistics for organ transplants. what i is the most common organ transplant? what has happened over the years?

A

U.S. Statistics:

  • average wait for organ transplant- 2-3 years
  • 6000 patients die per year (waiting for organ transplant)
  • Over the years (increasing years), there is an INCREASE in patients on waiting list for an organ transplant.
64
Q

Compare and contrast opt-out vs opt-in donor programs. which is more prevalent in the world.

A

Opt-out donor program- organ donation is automatically required unless a specific request is made before death for organs to not be taken (seen in U.S. Belgium, France, Italy, Poland, Spain)
opt-in donor program- people have to actively sign up to register for donating organs after death (seen in UK, Denmark, Germany, by Dutch)
More donors are with opt-out program compared to opt-in.

65
Q

What is the most common solid organ transplant? How has this affected the process in the world?

A

80% of solid organ transplants are KIDNEYS: demand has led to unregulated international organ trade (selling from poor to rich countries).

66
Q

explain the transplant gaps with organ transplant in U.S. What was a result of this?

A

over the years, several hundred thousand people were on waiting list for organ transplant in the U.S. and there were only less than 15,000 donors. Hence the transplant gap: is that more people are on waiting list for organ transplant than there are available donors. This resulted in patients from affluent (rich) countries to travel to poorer countries for transplants.

67
Q

What country do kidney sellers in receive the most money for kidney transplant?

A

People who illegally sell one of their kidneys receives the most money in United states. The asking price for kidney transplant in America is $30,000. However, in a country like India, the kidney will sell for less than $2000.
Hence, you can sell kidneys for higher prices in rich countries, compared to developing countries (India, Philippines) that only sell for smaller amount of money,

68
Q

Compare and contrast the poor organ sellers vs rich Buyers. Who are the people selling their organs in each division?

A 
In developing (poor) country (Philipines): typical organ seller is Male, under age 30 and has family income less than $500.
In Developed (richer) countries, like Israel; Buyers are older and have family incomes above $50,000.
69
Q

What is transplant tourism? How does it relate to kidney transplants?

A

Transplant tourism: Donor, recipient, and surgeon are brought together by a broker in medical center of country with intermediate wealth- accounts for 10% of kidney transplants yearly.

70
Q

Describe Xenotransplantation and what occurs in the process. What are the negative affects of xenotransplantation?

A

Xenotransplantation- procedure that involves the transplantation or infusion of live cells or organs of nonhuman animal source into human recipient.
In Xenotransplantation: Donor and recipient are Different species
Pigs- most Suitable donor species for humans.
Downsides of xenotransplantation:
-pigs are farmed, slaughtered and consumed by humans in Large numbers (pigs exploited)
-Xenoantibodies form- antibodies that bind to pig endothelial cells- cause hyperacute rejection- bind to xenoantigens- likely produced by infections with common bacteria whose surface carbohydrates resemble those of pigs.
-Complement regulatory proteins on pig cells do NOT inhibit human complement.
-Could this be a route for pig retroviruses to infect human population?
-

71
Q

Define Hematopoietic stem cell transplantation. What are the benefits of Hematopoietic stem cell transplantation?

A

Hematopoietic Stem Cell Transplantation- transplant that involves intravenous infusion of hematopoietic stem cells to reestablish blood cell production in patients whose bone marrow is damaged or immune system is defective.
Benefits :
-Number of willing donors EXCEEDS the number of patients in need
-Greater sensitivity to HLA Difference
-easy to do
-Reconstitutes recipients immune system, RBC’s, platelets, and bone marrow.

72
Q

Describe the engraftment process of Hematopoietic stem cell transplantation. What occurs in myeloablative therapy?

A

In Hematopoietic Stem cell transplantation:

  • Engraftment- process of transplanted stem cells travel to blood to bone marrow, where they begin to make White blood cells, RBC’s and platelets.
  • 2-3 weeks post-transplantation- RBC’s produced
  • complete Reconstitution takes- 1 year
  • Intravenous Infusion- NO surgery required
  • Myeloablative therapy- high intensity stem cell transplant that uses high doses of chemotherapy and radiation to kill cancer cells; however destroys bone marrow/stem cells in the process.
  • cripples the recipient’s immune system
  • Creates space for donor cells- bone marrow niche.

-

73
Q

Differentiate between what occurs when transplant patient received hematopoietic stem cells of completely different HLA allotypes vs receive cells that have HLA class allotypes in common.

A

Transplant patient receives hematopoietic cells of completely DIFFERENT HLA type from their own:

  1. donor derived thymocytes are positively selected on recipient HLA allotypes
  2. circulating T cells are restricted by recipient but not donor HLA allotypes
  3. Antigen-presenting cells in tissues present antigens on donor HLA allotypes
  4. Upon infection NO T cells can respond to pathogen derived antigens presented by APCs.
  5. No Adaptive immune response is the infection persists

Transplant patient who receives hematopoietic stem cells having some HLA class I and II allotypes in common with their own

  1. Donor-derived thymocytes are positively selected on recipient and some donor HLA allotypes
  2. Circulating T cells are restricted by recipient and some donor HLA allotypes
  3. Antigen-presenting cells in tissues present antigen on some recipient HLA allotypes.
  4. Upon infection, some T cells do respond to pathogen-derived antigens.
  5. An adaptive IMMUNE response is made that TERMINATES infection.
74
Q

How do HLA class I and II allotypes affect immune response?

A

The more common HLA Class I an II allotypes, the more ROBUST the immune response.

75
Q

What malignant diseases are treatable by hematopoietic cell transplant?

A 
Malignant disease treatable by Hematopoietic cell:
Allogenic transplant-
-Aplastic anemia leukemia,
- Chronic myelogenous leukemia (CML)
-Myelodysplasia
Autologous transplant
-Leukemia
-Solid tumors
-ovarian
-Testicular
-Neuroblastoma
Both Allogenic/autologous transplant can treat:
-Acute myelogenous leukemia (AML)
-acute Lymphocytic leukemia (ALL)
-multiple myeloma
-Non-Hodgkin's lymphoma
-Hodgkin's disease
76
Q

Describe what occurs in Graft-versus host response

What is the major cause of morbidity and mortality?

A

Graft vs Host response:
1. Allogenic hematopoietic cell transplant contains mature and memory T cells
2. T cells circulate in blood to secondary lymphoid tissues. Alloreactive cells interact with dendritic cells and proliferate
3. Effector CD4 and CD8 T cells enter tissues inflamed by conditioning regimen and cause further tissue damage\
Major cause of morbidity and mortality- usually involves the skin, intestines, and liver

77
Q

What are the grades of tissue reactions in graft vs host disease?

A

Tissue reactions in 4 grades of graft vs host disease:
Grade I- maculopapular rash on skin (< 25% of body surface), low serum bilirubin in Liver, small amount of diarrhea
Grade II- rash on <25%-50% of body surface on skin, low levels of bilirubin in liver (little higher than grade I), higher amount of diarrhea
Grade III - generalized erytrhoderma; serum bilirubin (6-15), greater diarrhea
Grade IV- Generalized erythroderma with blistering and desquamation, Highest level of bilirubin in liver, severe abdominal pain with or without intestinal obstruction

78
Q

Further elaborate on tissue reactions graft vs host disease. What cells are stimulated? How much of Graft vs host disease is needed for immunodeficincy?

A

Skin, liver, and GI tract inflammation from conditioning regimen
“cytokine storm”- activates dendritic cells- migrate to secondary lymphoid organs and stimulate alloreactive T cells.
-Methotrexate and cyclosporin can decrease severity
-occurs First few months until mature T-cells from donor are gone
- 25-45% chronic GVHD can produce severe immunodeficiency.

79
Q

What factor correlates with severity of GVHD? what is the best and second best donor? Describe how many donors use HLA internationally

A

The severity of GVHD (graft vs host disease) correlates with HLA mismatch
-The more HLA classes that are mismatch, the lower the probability of survival
-Identical twin- BEST donor
HLA-identical sibling- Second best donor (25% chance)
International registries: 20 million donors have been HLA typed.

80
Q

Describe components of minor histocompatibility H-Y antigens

A

Minor Histocompatibility H-Y antigens- allogenic difference is due to bound peptide, NOT MHC molecule

  • Observed in transplants from female to HLA-identical male sibling
  • GVHD-caused by T-cells specific for self-peptide- antigens that are from peptides derived from proteins encoded by the Y chromosome and differ in sequence from homologous proteins coded by X chromosome.
81
Q

where do minor histocompatibility H-Y antigens also come from?

A

Minor-histocompatibility H-Y antigens also arise from AUTOSOMAL genes with allotypic differences.

82
Q

What gives rise to minor histocompatibility antigen differences between donor and recipient?

A

POLYMORPHIC SELF PROTEINS that DIFFER in AMINO ACID SEQUENCE between individuals give rise to minor histocompatibility antigen differences between donor and recipient.

83
Q

How can 4 haplotypes lead to becoming haploidentical donors?

A

Four HLA haplotypes randomly segregate in a nuclear family and most family can be haploidentical donors (donors that match exactly half your HLA (example parents are your haploidentical donors)

84
Q

What occurs in the haploidentical transplant?

A

Haploidentical transplant:

  1. Donor has C1 and C2, whereas the recipient only has C2
  2. Donor hematopoietic cells INHIBIT ALL Donor NK cells
  3. Recipient Leukemia cells are killed by donor NK cells that detect their lack of C1 HLA-C
85
Q

Explain how GVHD (graft vs host disease) helps engraftment and prevents relapse. When do you have higher chance for graft failure? What is the purpose of acute GVHD?

A

You can reduce GVHD severity- with specific antibody or lectin treatment removes mature T-cells from donor prep before transplant- higher incidence of graft failure and higher incidence of relapse in cancer patients.
-Graft failure and relapse are higher with NO alloreactivity (identical twin or autologous)
Acute GVHD improves the Long-term clinical outcome between HLA-identical siblings.

86
Q

Explain what occurred in immune cells of non-identical twin pairs. What occurs as a result of combining hematopoietic stem cells after kidney transplant?

A

8% of non-identical (non-fraternal) twin pairs had joined blood circulations during gestation

  • After birth- CHIMERA containing cells with other twins genotype- IMMUNOTOLERANT
  • Exploratory trial- combining hematopoietic stem cell transplantation after transplant from kidney donor- led to transient CHIMERISM and LONG-TERM TOLERANCE

Immunology (11 decks)

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