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IMS: Immunology > Transplantation > Flashcards

Transplantation Flashcards

1
Q

Autograft

(Autologous)

A

Self-tissue transferred from one site of the body to another on the same individual.

Histocompatible.

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2
Q

Isograft

(Syngeneic)

A

Tissue transferred between genetically identical individuals.

Histocompatible.

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3
Q

Allograft

A

Tissue transferred between genetically different members of the same species.

Histoincompatible.

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4
Q

Xenograft

A

Tissue transferred between members of different species.

Histoincompatible.

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5
Q

Histocompatible

A

A tissue that is antigenically similar to the recipient’s tissue and does NOT induce an immunological response that leads to tissue rejection.

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6
Q

Histoincompatible

A

A tissue that is antigenically dissimilar to the recipient’s tissue and induces an immunological response that leads to tissue rejection.

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7
Q

Transfusion

A

Involves the transfer of blood from one individual to another.

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8
Q

Transplantation

A

Involves the transfer of any organ or tissue from one individual to another.

  • Whole organs: kidney, liver, lung, heart, pancreas etc.
  • Tissues: bond, skin, cornea etc.
  • Cellular: bone marrow, pancreatic islet cells etc.
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9
Q

Genes Determining Histocompatibility

A
  1. ABO antigens
    • most important parameter in solid organ grafts
    • blood group type can change with bone marrow transplantation
  2. MHC/HLA
    • Matching class II MHC important in solid organ transplant
    • Must match both class I and II for bone marrow transplantation
  3. Minor histocompatibility antigens
    • > 40 different genes important in preventing rejection
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10
Q

Host-versus-Graft

(HvG)

A
  • Alloreactive host lymphocytes damages the graft
  • Follows transplantation of a histoincompatible tissue organ
  • May lead to destruction of the organ
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11
Q

Graft-versus-Host

(GvH)

A
  • Follows transfer of immunologically competent alloreactive lymphocytes into an immunocompromised host
    • bone marrow transplant
    • passenger lymphocytes in an organ
  • Graft mounts an immunological attack on the host.
    • CD4 T-cells promote damaging immune function
    • CD8 T-cells destroy tissue
    • Host cells can aid donor cells in tissue destruction
  • Removal of T cells using T-cell reactive mAb and complement decreases incidence and severity of GvH
  • If bone marrow completely purged of T cells using anti-CD3+ complement treatment engraftment failure dramatically increases
  • Occurs in HLA matched siblings and during autologous transplants
  • Acute GvH:
    • epithelial cell necrosis of skin, liver, and GI tract
    • rash
    • jaundice
    • diarrhea
  • Chronic GvH:
    • fibrosis of skin, liver, and/or GI tract without necrosis
    • can lead to complete organ dysfunction
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12
Q

Hyperacute Rejection

A

HvG following allograft solid organ transplant.

Occurs within minutes to ~12-24 hours post reperfusion of the organ.

Type II hypersensitivity.

Preformed Ab binds to tissues → complement activation → recruitment of phagocytic cells, platelet activation and deposition → thrombosis, swelling, hemorrhage, and necrosis.

Cell-mediated immunity is generally NOT involved.

Characterized by thrmobotic occlusions with endothelial injury, neutrophil influx, and fibrinoid necrosis.

No treatment, only prevention through ABO matching and PRA screening for pre-existing Ab.

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13
Q

Explanations for Pre-existing Antibodies

A
  • ABO incompatible organ.
  • Multiple pregnancies.
  • Prior incompatible transplants.
  • Prior blood tranfusions.
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14
Q

Acute Rejection

A

HvG following allograft solid organ transplant.

Occurs within 10-14 days in non-immunosuppressed patient and within several months with suppresion.

Due primarily to T-cell mediated immunity.

Transplant desctruction by CTLs → phagocytosis → presentation of transplanted Ag to TH cells → further organ degradation.

Characterized by lymphocytic and macrophage infiltration.

Preventative treatment with immunosuppresion such as cyclosporin.

Therapeutic treatment with corticosteroids if symptoms develop.

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15
Q

Chronic Rejection

A

HvG following allograft solid organ transplant.

Occurs after months to years.

Similar to a chronic DTH reaction.

Mediated by both humoral and cell-mediated reactions.

Activated macrophages secrete growth factors → fibrosis → ischemia and cell death.

Appears as fibrosis and scarring in transplanted organs.

Treatment generally ineffective and re-transplantation commonly needed.

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16
Q

T-cell

Direct Alloreactivity

A
  • T-cells can respond to both:
    • foreign Ag peptide + self-MHC
    • “foreign” MHC + normal self-peptides
  • T-cells from patient X are stimulated by cells from patient Y in a non-MHC restricted manner
  • T-cell alloreactivity to foreign MHC stimulates a mixed lymphocyte reaction (MLR)
    • A significantly higher number of total lymphocytes able to react to any given allograft antigen
17
Q

Direct Alloreactivity

Mechanism

A
  1. Transplanted organs cary passenger APCs (interstitial dendritic cells)
  2. Ischemia generates DAMPs and a non-specific inflammatory response.
  3. Danger signal activates passenger APC’s causing increased density of allo-MHC and B7.
  4. Activated foreign APC’s travel to the LN and stimulate the recipient’s naïve T-cells.
  5. Following replication and differentiation the alloreactive effector T-cells return to the organ causing acute (allo) rejection.
18
Q

Factors Affecting

Rejection Response

A
  1. Type of tissue
    • skin grafts - rapid and relentless
    • heart - slow and more possiblity to prevent
    • based on the amount of immunosurvaillence of the tissue
  2. Specificity and Memory
    • First-set rejection
      • ​the first time a transplant is rejected
    • Second-set rejection
      • ​an accelerated rejection of the second transplant because of Ag similarity to first transplant
  3. Solid Organ Transplants
    • ABO >>>>>> Class II MHC > Class I MHC
19
Q

Determination of Histocompatibility

Methods

A
  1. ABO determination by agglutination
  2. Panel Reactive Antibody test (PRA) and cross-match
  3. Serological (Microcytotoxicity) / Complement Dependent Ab Lysis
  4. PCR epitope genotyping
  5. Mixed lymphocyte reaction (MLR)
  6. One-way mixed lymphocyte reaction
  7. 51Cr release assay (class I MHC mismatch and CTLs)
20
Q

Panel Reactive Antibody Test

(PRA)

A

Pre-transplant evaluation.

  • Precipient serum + pooled leukocytes from human peripheral blood + complement + blue dye
  • If patient has Ab against multiple individual’s leukocytes they will bind to Ag on many cells → MAC formation → blue stain enters cell
  • High PRA indicative of preformed Ab against many different donors
    • Contraindication for transplant
21
Q

Crossmatch

A

After potential donor identified.

  • Recipient’s serum tested against donor’s peripheral blood cells.
  • Positive crossmatch = presence of donor specific preformed Ab → contraindication for transplant
22
Q

Serological (Microcytotoxicity)

Complement Dependent Ab Lysis

A
  • Donor or recipient cells mixed with Ab of known specificity against HLA antigens.
  • Complement added and cells monitored for lymphocyte damage or lysis
23
Q

Mixed Lymphocyte Reaction

(MLR)

A
  • Lymphocytes from donor & recipient cultured together for several days with radioactive T nucleotides
  • Allogeneic T cell activation and proliferation occur with a class II MHC mismatch.
    • Measured through amount of DNA synthesis with [3H] - thymidine incorporation
    • Greater mismatch = greater proliferation = more radioactivity
  • Traditional MLR looks at total matching/mismatching.
24
Q

One-way Mixed Lymphocyte Reaction

A

Allows the reactivity of the donor cells against the recipient’s cells or vice versa.

Reflects the initial recognition events seen in alloreactivity.

  • Test donor reactivity to recipient’s cells
    • Recipient’s cells irradiated to prevent proliferation
    • Detect incompability leading to graft vs. host
    • For bone marrow transplantation
  • Test recipient’s reactivity to donor’s cells
    • Donor’s cells irradiated to prevent proliferation
    • Detect incompability leading to host vs. graft
    • For solid organ transplantation

Proliferation = class II MHC mismatch.

Lympholysis = class I MHC mistatch.

25
Q

51Cr Release Assay

A

Test for class I MHC mismatch.

Assess capacity to generate a CTL response.

  • Target cells loaded with 51Cr
    • Donor cells used for HvG
    • Recipient cells used for GvH
  • Target cells mixed with responding cells
  • If responding cells recognize target cells as foreign (via CD8+ T-cell reaction against class I MHC) → CTLs kill target cells releasing 51Cr into medium
26
Q

Controlling Allograft Rejection

A
  1. Make graft less immunogenic
    • ABO matching
    • HLA matching
    • Decrease cold-ischemia time
  2. Immunosuppresive therapy
    • Corticosteroids
    • Calcinurin inhibitors
    • Monoclonal and polyclonal immunotherapies
    • Antiproliferative agents
    • Cytotoxic drugs
27
Q

Corticosteroids

A

Blocks T-cell and APC derived cytokine and cytokine-receptor expression.

  • Significant inhibition of IL-1 and IL-6
  • Lesser inhibition of IL-2, IFN-γ, and TNF-α.
  • Inhibits lymphoproliferation
  • Inhibits APCs
  • Alters leukocyte trafficking
  • Net result of fewer lymphocytes in circulation
28
Q

Remicade

(Infliximab)

A

Anti-TNF-α chimeric IgG.

Used in the treatment of:

Rheumatoid arthritis

Psoriatic arthritis

Ulcerative colitis

Crohn’s disease

Ankylosing spondylitis

Severe plaque psoriasis.

29
Q

Enbrel

(Etanercept)

A

Chimeric TNF-α-receptor attached to IgG.

Used in the treatment of:

Rheumatoid arthritis

Plaque psoriasis

Psoriatic arthritis

Ankylosing spondylitis

Juvenile idiopathic arthritis

30
Q

Xeljanz

(Tofacitinib)

A

JAK1 and JAK3 inhibitor.

Disrupts the JAK-STAT intracellular signaling pathway

associated with cytokine and growth factor transduction.

31
Q

Rituximab

A

Anti-CD20 monoclonal antibody.

Inhibits B-cells.

Used in treatment of:

Rhematoid arthritis

MS

Pemphigus vulgaris

Certain B-cell mediated leukemias

32
Q

Cyclosporin

A

Calcineurin inhibitor.

Blocks T-cell proliferation and cytokine production.

Important in transplant immunosuppresion.

IMS: Immunology (19 decks)

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