Exam 2: Transplantation

Question 1

Autograft

(Autologous)

Answer 1

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

Histocompatible.

Question 2

Isograft

(Syngeneic)

Answer 2

Tissue transferred between genetically identical individuals.

(E.g. monozygotic twins)

Histocompatible.

Question 3

Allograft

Answer 3

Tissue transferred between genetically different members of the same species.

Histoincompatible.

Question 4

Xenograft

Answer 4

Tissue transferred between members of different species.

Histoincompatible.

Question 5

Histocompatible

Answer 5

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

Question 6

Histoincompatible

Answer 6

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

Question 7

Transfusion

Answer 7

Involves the transfer of blood from one individual to another.

Question 8

Transplantation

Types

Answer 8

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.

Question 9

Histocompatibility

Genes

Answer 9

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

Question 10

Graft-versus-Host

(GvH)

Answer 10

• 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

Question 11

Acute GvH

Symptoms

Answer 11

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

Question 12

Chronic GvH

Symptoms

Answer 12

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

Question 13

Host-versus-Graft

(HvG)

Answer 13

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

Question 14

Allograft Rejection

Types

Answer 14

Host-versus-graft reactions following solid organ transplants:

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

Question 15

Hyperacute Rejection

Answer 15

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

Question 16

Renal Transplant

Hyperacute Rejection

Answer 16

• Fever
• Leukocytosis
• Little or no urine output

Question 17

Explanations for Pre-existing Antibodies

Answer 17

• ABO incompatible organ
• Multiple pregnancies
• Prior incompatible transplants
• Prior blood tranfusions

Question 18

Acute Rejection

Answer 18

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 T_H cells → further organ degradation

• Characterized by lymphocytic and macrophage infiltration
• Preventative treatment with immunosuppression
• Therapeutic treatment with corticosteroids if symptoms develop

Question 19

Renal Transplant

Acute Rejection

Answer 19

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

Question 20

Chronic Rejection

Answer 20

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

Question 21

Renal Transplant

Chronic Rejection

Answer 21

See a slow decline in kidney function over time

Question 22

T-cell

Direct Alloreactivity

Answer 22

• 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

Question 23

Direct Alloreactivity

Mechanism

Answer 23

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

Question 24

Rejection Response

Modifying Factors

Answer 24

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

Question 25

Histocompatibility Determination

Answer 25

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)

Question 26

Panel Reactive Antibody Test | (PRA)

Answer 26

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

Question 27

Cross-match

Answer 27

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

Question 28

Serological (Microcytotoxicity) Complement Dependent Ab Lysis

Answer 28

* **Donor or recipient cells mixed with Ab of known specificity against HLA antigens** * Complement added and cells monitored for lymphocyte damage or lysis

Question 29

Mixed Lymphocyte Reaction | (MLR)

Answer 29

* **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

Question 30

One-way Mixed Lymphocyte Reaction

Answer 30

**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**

Question 31

⁵¹Cr Release Assay

Answer 31

**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

Question 32

Allograft Rejection Control Methods

Answer 32

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

Question 33

Corticosteroids

Answer 33

**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

Question 34

Remicade | (Infliximab)

Answer 34

**Anti-TNF-α chimeric IgG** _Used in the treatment of:_ Rheumatoid arthritis Psoriatic arthritis Ulcerative colitis Crohn's disease Ankylosing spondylitis Severe plaque psoriasis

Question 35

Enbrel | (Etanercept)

Answer 35

**Chimeric TNF-α-receptor attached to IgG** _Used in the treatment of:_ Rheumatoid arthritis Plaque psoriasis Psoriatic arthritis Ankylosing spondylitis Juvenile idiopathic arthritis

Question 36

Xeljanz | (Tofacitinib)

Answer 36

**JAK1 and JAK3 inhibitor** Disrupts the JAK-STAT intracellular signaling pathway associated with cytokine and growth factor transduction

Question 37

Rituximab

Answer 37

**Anti-CD20 monoclonal Ab** Inhibits B-cells _Used in treatment of:_ Rhematoid arthritis MS Pemphigus vulgaris Certain B-cell mediated leukemias

Question 38

Cyclosporin

Answer 38

**Calcineurin inhibitor.** Blocks T-cell proliferation and cytokine production Important in transplant immunosuppresion