Transplant

Question 1

Transplantation

Answer 1

Process of removing cells, tissues, organs (called the graft) from an individual and placing them either back into the same individual or into another individual (host or recipient).

Question 2

Orthotopic transplantation

Answer 2

graft is transplanted into its usual anatomic location

Question 3

Heterotopic transplantation

Answer 3

graft is transplanted into a site other than its usual anatomic location
Example: transplanted kidneys are usually placed in the lower abdomen (pelvis) rather than in their usual retroperitoneal location.

Question 4

Autologous transplantation (autograft)

Answer 4

graft is transplanted back into the same individual

Example: bone marrow stem cells

Question 5

Allogenic transplantation (allograft)

Answer 5

graft is transplanted into a genetically different individual of the same species

Question 6

Syngeneic transplantation

Answer 6

graft is transplanted into a genetically identical individual (transplant between monozygotic (identical) twins)

Question 7

Xenogeneic transplantation (xenograft)

Answer 7

graft is transplanted between individuals of different species

Question 8

Types of organs and tissues transplanted

Answer 8

Kidney, heart, lung, liver, pancreas, small intestine

Bone marrow, cornea, skin, bone, and heart valves

Question 9

Acquired/Adaptive Immune System and Rejection

Answer 9

Neutrophils take care of extracellular pathogens like bacteria by phagocytosis.
B cells make antibodies
T cells coordinate amongst one another to destroy cells deemed abnormal; fight off viral/fungal/mutated cells.

Question 10

Hyperacute rejection

Answer 10

In the operating room, the graft is pink, but seconds later is turns pale and fails.
Due to pre-existing antibodies in recipient’s blood stream from B cells or antibodies against blood group antigens that recognize the proteins in the graft as foreign and bind them.
When this process occurs in the blood vessels, it occludes them and the graft rapidly becomes ischemic and fails.
Bound antibodies activate the complement/coagulation cascade.
Antibodies against human leukocyte antigens (HLA) can cause this if patient has had a previous transplant, blood transfusion, or pregnancy.

Question 11

Acute rejection

Answer 11

Stems from the capacity of the T cells to discriminate between cells from our own body and cells that are foreign.
This rejection takes one or two weeks to manifest.
T cells can recognize his or her own MHC pattern as self-any foreign cells will have a different MHC pattern and will be recognized as non-self and targeted for destruction.
Use cytotoxic T cell, B cells, macrophages, and neutrophils in T cell coordinated attack against graft.
Highest risk for acute rejection is 3 months after transplantation.
Signs of organ dysfunction

Question 12

Human Leukocyte Antigen (HLA), also called major histocompatibility complex (MHC)

Answer 12

Set of proteins expressed on surface of cells; class 1, all cells; class 2, special immune cells.
Tremendous diversity-each individual has different HLA expression pattern.
Chromosome 6 encode these.
Children are haploidentical to parents (half match their parents, only match one of their parents).

Question 13

Chronic rejection

Answer 13

Also T cell mediated
These days, it is the main cause of graft failure.
There is a low grade T cell mediated anti-graft immune response that leads to chronic inflammation and subsequent fibrosis/scarring in the graft.
Develops over months/years, there is a slow progressive decline of graft function.
Repair mechanisms lead to this.

Question 14

Rejection can be mitigated by…

Answer 14

1. immunosuppression of the host by drugs
2. minimizing the immunogenicity of the graft by minimizing the differences in the blood type antigens (ABO matching) and MHC patterns (HLA matching) between the graft and the host.

Question 15

Calcineurin blockers

Answer 15

Cyclosporine and Tacrolimus: peptide secreted by a fungus
Blocks calcineurin (a protein phosphatatse) thereby inhibiting T cell activation.
Drug that inhibits T-cell function and was critical in facilitating solid organ transplantation.
These drugs must be given for lifetime, and there is a balance between the risk of infection with too much immunosuppression and the risk of rejection with too little immunosuppression.

Question 16

Corticosteroids

Answer 16

Have broad anti-inflammatory effects including suppressing the activation of B and T cells.

Question 17

Anti-proliferative agents

Answer 17

Azathioprine, Mycophenolate mofetil
Inhibit DNA replication in dividing cells, thereby preventing the proliferation of activated T cells that mediate rejection.
The effects are not specific for activated T cells-they prevent the proliferation of all dividing cells-they can have profound effects on the bone marrow; can result in neutropenia, anemia, and thrombocytopenia.

Question 18

HLA Matching

Answer 18

Can identify certain members of the MHC that are important in mediating graft rejection-mathcing these MHC is important for decreasing the risk for rejection in kidney transplants.
Also important to ensure that blood types are compatible to minimize risk for hyper acute rejection.

Question 19

Rejection-Complication

Answer 19

Graft function and immunosuppressive therapy is carefully monitored and adjusted.
Graft function can be monitored by appropriate lab tests such as liver enzymes for liver transplants, creatinine clearance for kidney transplants and imaging studies (echocardiograms) for heart transplants.
If there is a suspicion for rejection, a biopsy of the graft is performed.
Distinctive histologic features: infiltrate of lymphocytes (T cells) with associated tissue injury.

Question 20

Graft Dysfunction-Complicaiton

Answer 20

Associated with chronic rejection
Heart transplants: primary cause of graft dysfunction is an accelerated form of atherosclerosis (graft vasculopathy) that occludes the coronary vessels and is the major limitation of long term survival.
Kidney transplants: long term graft dysfunction is attributed to chronic allograft nephropathy, characterized by progressive scarring of the kidney graft associated with chronic rejection and non-immune mediated injury such as hypertension.
Liver transplants: fewer issues with long term dysfunction, but associated with more immediate post-op dysfunction manifesting as biliary stricture or vascular thrombosis.
Viral, fungal, or bacterial infection in a graft is a contributor to graft dysfunction.

Question 21

Immunsuppression and Infection-Complication

Answer 21

The effects of corticosteroids and bone marrow suppression of anti proliferative drugs increases the risk for both hospital acquired and community acquired bacterial infections.
Transplant are particularly prone to viral and fungal infections-most immunosuppressive regimens focus on suppressing T cells that are key players in mediating rejection and typically clear viral and fungal infections.
Epstein-Barr Virus (EBV), can lead to malignant lymphoma.
Cytomegalovirus (CMV), can lead to graft dysfunction and profound immunosuppression.
BK (polyoma) Virus, can lead to kidney graft failure.
Fungal infections: pneumonia secondary to pneumocystis jiroveci (found in lungs of healthy people).
Meningitis due to Cryptococcus neoformans; encapsulated yeast, found in soil.
Soft tissue abscesses due to Nocardia.
Tissue destruction due to Aspergillus; respiratory infection that can be invasive and cause massive tissue destruction by cavitary lesions in the lung, necrotic tissue)

Question 22

Immunosuppression and Cancer-Complication

Answer 22

One of the jobs of out immune system is to seek out and destroy any mutated cells; immunosuppression increases our risk for cancer; in transplant patients, particularly skin cancer and lymphoma.
Lymphoma is a malignant proliferation of mature B or T-lymphocytes; when this develops in a transplant patient, it is called post-transplant lymphoproliferative disorder (PTLD); pathogenesis if likely a combined effect of immunosuppressive agents and EBV infection (reactivation=Burkitt Lymphoma).

Question 23

Graft verus Host Disease

Answer 23

Allogenic bone marrow transplantation
The bone marrow is the source of cells that comprise our immune system-a transplant replaces our native B and T cells with the B and T cells derived from the graft-this immune system derived from the graft with recognize the host as foreign and attack the host cells.
Most profoundly affects the skin, mucosal lining of the GI tract, and the liver; increase liver enzymes and decrease hepatic function)
Most succumb to infections related to treatment of immunosuppression.

Question 24

Factors that need to be assessed to calculate risk/benefit

Answer 24

1. Underlying infections including AIDS and systemic or uncontrolled infection.
2. Significant uncontrolled life-limiting medical conditions.
3. Active untreated or untreatable malignancy
4. Social and psychiatric issues including substance abuse, emotional instability, lack of cognitive ability, and history of non-compliance.
   WEIGH THE RISK OF TRANSPLANT AGAINST THE RISK OF MORTALITY FROM ORGAN FAILURE!