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Immunolgy > Transplantation Immunology > Flashcards

Transplantation Immunology Flashcards

1
Q

what is graft rejection

A

inflammatory reaction that is the result of an adaptive immune response

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2
Q

define autologous graph

A

a graph transplanted from individual to the same individual

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3
Q

define syngeneic graft

A

a graft transplanted between two genetically identical individuals

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4
Q

define allogenic graft (or allograft) and alloantigens

A

graft transplanted between two genetically different individuals of the same species
alloantigens= the molecules that are recognized as foreign on the allografts

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5
Q

define xenogeneic graft (xenograft)

A

a graft transplanted between individuals of different species

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6
Q

the lymphocytes/antibodies that react to allografts/xenografts are described as being

A

alloreactive or xenoreactive

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7
Q

what are the antigens that stimulate adaptive immune response against allographs (responsible for for strong/rapid rejections)

A

histocompatibility proteins/molecules (or HLA)

->encoded by polymorphic genes that differ among individuals

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8
Q

what are the basic rules of transplantation immunology (4)

A
  1. cells/organs transplanted b/w genetically identical individuals are never rejected
  2. cells/organs transplanted b/w genetically different individuals are always rejected
  3. the offspring of a mating b/w two different inbred strains of an animal will not reject graphs from either parent (not true with BM transplants)
  4. a graft from the offspring of a mating of two different inbred strains will be rejected by either parent
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9
Q

the direct and indirect pathways

A

the different ways that allogenic MHC molecules on a graft can be presented for recognition by the recipient’s T cells (both are an initial step to allograft rejection)

direct recognition of alloantigens: T cells of a graft recipient recognize intact, unprocessed MHC molecules in the graft
indirect: recipient’s T cells recognize graft MHC molecules only in the context of of the recipient’s self MHC molecules on APCs

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10
Q

blocking what costimulator is a therapeutic strategy for inhibiting graft rejection in humans

A

B-7 molecules on APCs

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11
Q

what is the mixed lymphocyte reaction ?

A

the response of alloreactive T cells to foreign MHC molecules

  • model of graft rejection
  • establish the role of class 1 (for CD8+) and class 2 MHC (for CD4+) molecules (alloantigens)
  • both CD4+ and CD8+ T cells from donor X react to donor T APC that has both MHC class 1 and 2 molecules
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12
Q

how do alloreactive CD4+ and CD8+ T cells activated by graft alloantigens cause rejection ?

A 
CD4+: differentiate into cytokine producing effector cells that damage grafts by cytokine-mediated inflammation, similar to a delayed type hyper-sensitivity reaction
CD8+: differentiate into CTLs which kill cells in the graft that express the allogeneic class 1 MHC molecules. they also secret inflammatory cytokines which can contribute to graft damage
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13
Q

what are the only T cells that can cause killing of the graft cells

A

cytotoxic T lymphocytes that are generated by direct allorecognition
(the other T cells will not be able to kill the graft cells because they are self MHC restricted and the graft cells dont express self MHC alleles displaying allogeneic peptides

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14
Q

activation of alloreactive B cells

A

is an example of indirect presentation of alloantigens
->The alloreactive antibodies produced in graft recipients engage the same mechanisms that antibodies use to combat infections
-the antigens most frequently recognized by by alloantibodies are donor HLA including MHC class 1 and 2 proteins
(mostly targeted at the graft vasculature bc the the HLA antigens are expressed on endothelial cell)
-activates neutrophils, macrophages and NK cells through the Fc receptor binding

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15
Q

hyperacute rejection

A

characterized by thrombotic occlusion (blood vessel blockage) of the graft vasculature that begins within mins to hours after host blood vessels are anastomosed to graft vessels

  • mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens causing platelet adhesion and complement activation, endothelial damage, inflammation and thrombosis
  • (now usually IgG antibodies that are directed against protein alloantigens such as donor MHC molecules)
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16
Q

acute rejection

A

a process of injury to the graft parenchyma and blood vessels mediated by alloreactive T cells and anti-bodies
-divided into cellular (mediated by T cells) and humoral (mediated by antibodies) that both typically coexist in an organ undergoing acute rejection

17
Q

acute cellular rejection

A

inflammation caused by cytokines produced by helper T cells and CTL-mediated killing of graft parenchymal cells and endothelial cells
-cellular infiltrates present in grafts undergoing acute cellular rejection include both CD4+ helper T cells (TH1 and TH17 cells) and CD8+ CTLs and both may contribute to parenchymal cell and endothelial injury

18
Q

acute antibody-mediated rejection

A

alloantibodies cause acute rejection by binding to alloantigens, mainly HLA molecules on vascular endothelial cells causing endothelial injury and intravascular thrombosis that results in graft destruction

19
Q

chronic rejection

A
  • the major cause of the failure of vascularized organ allografts
  • different pathological changes for different transplanted organs
20
Q

Dominant lesion of chronic rejection in vascularized grafts

A

= arterial occlusion as a result of the proliferation of innermost smooth muscle cells

  • the grafts eventually fail mainly because of the resulting ischemic damage
  • blood flow to the graph parenchyma is compromised as arterial lesions of graft arteriosclerosis progresses
  • the parenchyma is slowly replaced with non-functional fibrous tissue
21
Q

what is the major strategy to reduce graft immunogenicity in human transplantation? what are the names of the tests done

A

to minimize alloantigenic differences between the donor and the recipient

  • ABO blood typing
  • determination of HLA alleles expressed on donor and recipient cells (tissue typing or HLA matching)
  • detection of preformed antibodies in the recipient that recognize HLA of donors leukocytes (cross matching)
22
Q

what is cross matching

A

testing for the presence of performed antibodies against donor MHC molecules or other cell surface antigens (the test determines if the patient has antibodies that will react with the donors cells)

  • mixing the recipients serum with the donors blood lymphocytes
  • other tests tell you if antibodies in the recipient serum have bound to the donor cells
  • if preformed antibodies are present in the recipients serum it would be a positive cross-match and the donor is not suitable for that recipient.
23
Q

principle agents used to treat or prevent graft rejection

A

immunosuppressive drugs that inhibit or kill T lymphocytes

24
Q

describe the role of the following drugs in the inhibition of T cell signalling pathways:

  • Cyclosporine
  • FK506
  • Rapamycin
  • azathioprine
  • Mycophenolate mofetil
  • anti-T cell antibody(OKT3 and anti-thymocyte globulin)
  • CTLA-4-Ig
A
  • Cyclosporine and FK506: calcineurin inhibitors that inhibit transcription of genes encoding for IL-2
  • Rapamycin: inhibits growth factor-mediated T cell proliferation by inhibiting the enzyme mTOR
  • Azathioprine and Mycophenolate: metabolic toxins that kill proliferating T cells stimulated by alloantigens
  • anti-T cell antibody: deplete circulating T cells
  • CTLA-4-Ig: blocks T cell costimulatory pathways by binding to B7 molecules on APCs. B7 expression on APC is required for activation so therefore Anti-B7 therapy helps reduce graft rejection
25
Q

one way to prevent acute allograft rejection

A

using Mycophenolate mofetil (MMF) in combination with cyclosporine or FK506
-CD8+ is dominant in acute graft
rejection

26
Q

First-set rejection

A

Rejection occurs 7-14 days post transplant

27
Q

sensitization

A

Activation of naïve T cells is called

28
Q

negative effects of immunosuppressive drugs

A

Immunosuppression therapy leads to much longer graft survival BUT..
Purpose is to reduce activated T cells, which leads to:

  • Increased susceptibility to intracellular infections and virus-associated tumors
  • Reactivation of latent herpes viruses is common
  • More prone to opportunistic infections
  • Higher risk for cancer development
  • various types of skin cancers
  • HPV
  • Epstein-Barr virus
  • B cell lymphomas
29
Q

major barrier to xenotransplantation

A

Natural antibodies in human recipients that cause hyperacute rejection. 95% of primates have natural IgM Abs that react with carbohydrate determinants expressed on evolutionary distant animals
-Pigs are the preferred animal for xenotransplantation

30
Q

Rh-negative individuals

A

are not tolerant to the RhD antigen and make Ab
for it if exposed to Rh-positive blood cells
-Can be an issue in pregnancy (second pregnancy)
Largely preventable today

31
Q

Graft vs Host Disease

A

Graft tissue rejection of recipient

-Grafted mature T cells in HSC that react against minor histocompatibility antigens (Usually a strong match for MHC)

Immunolgy (8 decks)

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