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Foundations of Disease > Exam 2: Transplantation > Flashcards

Exam 2: 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.

(E.g. monozygotic twins)

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.

  • There are 40 other factors affecting histocompatibility other than ABO, Rh, and HLA.
  • All transplants are histoincompatible except for autograft or isograft
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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

Types

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

Histocompatibility

Genes

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

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 ⇒ destroys tissue
    • Host cells can aid donor cells in tissue destruction
  • Preventative measures:
    • Removal of T cells using T-cell reactive mAb and complement
      • ↓ incidence and severity of GvH
    • However, if bone marrow purged completely of competent T-cells using anti-CD3+ complement treatment
      • ↑↑↑ engraftment failure
  • Occurs even in HLA matched siblings and during autologous transplants
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11
Q

Acute GvH

Symptoms

A
  • Epithelial cell necrosis of skin, liver, and GI tract
  • Rash
  • Jaundice
  • Diarrhea
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12
Q

Chronic GvH

Symptoms

A
  • Fibrosis of skin, liver, and/or GI tract without necrosis
  • Can lead to complete organ dysfunction
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13
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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14
Q

Allograft Rejection

Types

A

Host-versus-graft reactions following solid organ transplants:

  1. Hyperacute rejection
  2. Acute rejection
  3. Chronic rejection
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15
Q

Hyperacute Rejection

A

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
      • ABO matching
      • PRA screening for pre-existing Ab
      • Cross matching
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16
Q

Renal Transplant

Hyperacute Rejection

A
  • Fever
  • Leukocytosis
  • Little or no urine output
17
Q

Explanations for Pre-existing Antibodies

A
  • ABO incompatible organ
  • Multiple pregnancies
  • Prior incompatible transplants
  • Prior blood tranfusions
18
Q

Acute Rejection

A

Occurs within 10-14 days in non-immunosuppressed patient and within 3-4 months with suppresion.

1° 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 immunosuppression
  • Therapeutic treatment with corticosteroids if symptoms develop
19
Q

Renal Transplant

Acute Rejection

A
  • Rapid loss of kidney function
  • Kidney enlargement and pain/tenderness
  • Rapid ↑ serum creatinine
  • ↓ urine output
  • ↓ renal blood flow
  • Blood cells and proteins in urine
20
Q

Chronic Rejection

A

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
    • Re-transplantation usually needed
21
Q

Renal Transplant

Chronic Rejection

A

See a slow decline in kidney function over time

22
Q

T-cell

Direct Alloreactivity

A
  • T-cells can respond to both:
    • Foreign Ag peptide + self-MHC
    • “Foreign” MHC + normal self-peptides
      • Non-MHC restricted manner
  • T-cells have innate ability to recognize foreign MHC
    • Generates a mixed lymphocyte reaction (MLR)
      • ↑ # of total lymphocytes able to react to any given allograft Ag
23
Q

Direct Alloreactivity

Mechanism

A
  1. Transplanted organs carry passenger APCs (interstitial dendritic cells)
  2. Ischemia ⇒ DAMPs ⇒ non-specific inflammatory response
  3. Danger signal ⇒ activates passenger APC’s ⇒ ↑ density of allo-MHC and B7
  4. Activated foreign APC’s travel to the LN and stimulate the recipient’s naïve T-cells
    • Replication and differentiation
  5. Alloreactive effector T-cells return to the organ causing acute (allo) rejection
24
Q

Rejection Response

Modifying Factors

A
  1. Type of tissue
    • Based on the amount of immunosurvaillence of the tissue
      • Skin grafts ⇒ rapid and relentless
      • Heart ⇒ slow and more possiblity to prevent
  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
25
Q

Histocompatibility

Determination

A
  1. ABO determination by agglutination
  2. Panel Reactive Antibody test (PRA)
  3. Cross-match
  4. Serological (Microcytotoxicity) / Complement Dependent Ab Lysis
  5. PCR epitope genotyping
  6. Mixed lymphocyte reaction (MLR)
  7. One-way mixed lymphocyte reaction
  8. 51Cr release assay (class I MHC mismatch and CTLs)
26
Q

Panel Reactive Antibody Test

(PRA)

A

Pre-transplant evaluation

  • Recipient 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
27
Q

Cross-match

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
28
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
29
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 incoorporation
    • Greater mismatch = greater proliferation = more radioactivity
  • Traditional MLR looks at total matching/mismatching
30
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

Proliferation = class II MHC mismatch

Lympholysis = class I MHC mistatch

  • 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
31
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
32
Q

Allograft Rejection

Control Methods

A
  1. Make graft less immunogenic
    • ABO matching
    • HLA matching
    • Decrease cold-ischemia time
  2. Immunosuppresive therapy
    • Corticosteroids
    • Calcineurin inhibitors
    • Monoclonal and polyclonal immunotherapies
    • Antiproliferative agents
    • Cytotoxic drugs
33
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
34
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

35
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

36
Q

Xeljanz

(Tofacitinib)

A

JAK1 and JAK3 inhibitor

Disrupts the JAK-STAT intracellular signaling pathway

associated with cytokine and growth factor transduction

37
Q

Rituximab

A

Anti-CD20 monoclonal Ab

Inhibits B-cells

Used in treatment of:

Rhematoid arthritis

MS

Pemphigus vulgaris

Certain B-cell mediated leukemias

38
Q

Cyclosporin

A

Calcineurin inhibitor.

Blocks T-cell proliferation and cytokine production

Important in transplant immunosuppresion

Foundations of Disease (46 decks)

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