Exam 2: Transplantation Flashcards
Autograft
(Autologous)
Self-tissue transferred from one site of the body to another on the same individual.
Histocompatible.
Isograft
(Syngeneic)
Tissue transferred between genetically identical individuals.
(E.g. monozygotic twins)
Histocompatible.
Allograft
Tissue transferred between genetically different members of the same species.
Histoincompatible.
Xenograft
Tissue transferred between members of different species.
Histoincompatible.
Histocompatible
A tissue that is antigenically similar to the recipient’s tissue and does NOT induce an immunological response that leads to tissue rejection.
Histoincompatible
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
Transfusion
Involves the transfer of blood from one individual to another.
Transplantation
Types
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.
Histocompatibility
Genes
-
ABO antigens
- Most important parameter in solid organ grafts
- Blood group type can change with bone marrow transplantation
-
MHC/HLA
- Matching class II MHC important in solid organ transplant
- Must match both class I and II for bone marrow transplantation
-
Minor histocompatibility antigens
- > 40 different genes important in preventing rejection
Graft-versus-Host
(GvH)
- 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
- Removal of T cells using T-cell reactive mAb and complement
- Occurs even in HLA matched siblings and during autologous transplants
Acute GvH
Symptoms
- Epithelial cell necrosis of skin, liver, and GI tract
- Rash
- Jaundice
- Diarrhea
Chronic GvH
Symptoms
- Fibrosis of skin, liver, and/or GI tract without necrosis
- Can lead to complete organ dysfunction
Host-versus-Graft
(HvG)
- Alloreactive host lymphocytes damages the graft
- Follows transplantation of a histoincompatible tissue organ
- May lead to destruction of the organ
Allograft Rejection
Types
Host-versus-graft reactions following solid organ transplants:
- Hyperacute rejection
- Acute rejection
- Chronic rejection
Hyperacute Rejection
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
- Only prevention
Renal Transplant
Hyperacute Rejection
- Fever
- Leukocytosis
- Little or no urine output
Explanations for Pre-existing Antibodies
- ABO incompatible organ
- Multiple pregnancies
- Prior incompatible transplants
- Prior blood tranfusions
Acute Rejection
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
Renal Transplant
Acute Rejection
- Rapid loss of kidney function
- Kidney enlargement and pain/tenderness
- Rapid ↑ serum creatinine
- ↓ urine output
- ↓ renal blood flow
- Blood cells and proteins in urine
Chronic Rejection
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
Renal Transplant
Chronic Rejection
See a slow decline in kidney function over time
T-cell
Direct Alloreactivity
-
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
- Generates a mixed lymphocyte reaction (MLR)
Direct Alloreactivity
Mechanism
- Transplanted organs carry passenger APCs (interstitial dendritic cells)
- Ischemia ⇒ DAMPs ⇒ non-specific inflammatory response
- Danger signal ⇒ activates passenger APC’s ⇒ ↑ density of allo-MHC and B7
- Activated foreign APC’s travel to the LN and stimulate the recipient’s naïve T-cells
- Replication and differentiation
- Alloreactive effector T-cells return to the organ causing acute (allo) rejection
Rejection Response
Modifying Factors
-
Type of tissue
- Based on the amount of immunosurvaillence of the tissue
- Skin grafts ⇒ rapid and relentless
- Heart ⇒ slow and more possiblity to prevent
- Based on the amount of immunosurvaillence of the tissue
-
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
-
First-set rejection
-
Solid Organ Transplants
- ABO >>> Class II MHC > Class I MHC
Histocompatibility
Determination
- ABO determination by agglutination
- Panel Reactive Antibody test (PRA)
- Cross-match
- Serological (Microcytotoxicity) / Complement Dependent Ab Lysis
- PCR epitope genotyping
- Mixed lymphocyte reaction (MLR)
- One-way mixed lymphocyte reaction
- 51Cr release assay (class I MHC mismatch and CTLs)
Panel Reactive Antibody Test
(PRA)
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
Cross-match
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
Serological (Microcytotoxicity)
Complement Dependent Ab Lysis
- Donor or recipient cells mixed with Ab of known specificity against HLA antigens
- Complement added and cells monitored for lymphocyte damage or lysis
Mixed Lymphocyte Reaction
(MLR)
- 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
One-way Mixed Lymphocyte
Reaction
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
51Cr Release Assay
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
Allograft Rejection
Control Methods
-
Make graft less immunogenic
- ABO matching
- HLA matching
- Decrease cold-ischemia time
-
Immunosuppresive therapy
- Corticosteroids
- Calcineurin inhibitors
- Monoclonal and polyclonal immunotherapies
- Antiproliferative agents
- Cytotoxic drugs
Corticosteroids
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
Remicade
(Infliximab)
Anti-TNF-α chimeric IgG
Used in the treatment of:
Rheumatoid arthritis
Psoriatic arthritis
Ulcerative colitis
Crohn’s disease
Ankylosing spondylitis
Severe plaque psoriasis
Enbrel
(Etanercept)
Chimeric TNF-α-receptor attached to IgG
Used in the treatment of:
Rheumatoid arthritis
Plaque psoriasis
Psoriatic arthritis
Ankylosing spondylitis
Juvenile idiopathic arthritis
Xeljanz
(Tofacitinib)
JAK1 and JAK3 inhibitor
Disrupts the JAK-STAT intracellular signaling pathway
associated with cytokine and growth factor transduction
Rituximab
Anti-CD20 monoclonal Ab
Inhibits B-cells
Used in treatment of:
Rhematoid arthritis
MS
Pemphigus vulgaris
Certain B-cell mediated leukemias
Cyclosporin
Calcineurin inhibitor.
Blocks T-cell proliferation and cytokine production
Important in transplant immunosuppresion
