To transfer (tissue or organ) from one body or body part to another.
What are the two main forms of organ transplantation?
Solid organ transplant and bone marrow transplant.
What are the 3 problems associated with transplantation?
1. Introducing the transplant in a way that allows it to perform its normal function. 2. Guarding the health of both the recipient and the donor 3. And preventing the recipient's immune system from rejecting the grafted tissue.
What is true regarding the relationship of a patient's immune system and transplant success?
A strong immune system works against the patient. The stronger the patient's immune system, the fast the grafted tissue rejection.
What are the hallmarks of a successful transplantation?
Matching the tissue type between donor and recipient and successfully suppressing the immune system to inhibit a response to grafted tissue.
What is the universal rule of transplantation?
Engrafted tissue will be rejected by the immune system if any histocompatibility antigens on the graft are absent from the recipient.
What is an autograft?
Graft from one part of the body to another location on the same individual.
What is an isograft?
Graft between genetically identical individuals (such as identical twins).
What is an allograft?
A graft from a genetically dissimilar donor to a recipient of the same species. This is most common.
What is a xenograft?
Graft from a donor of another species.
What is impossible, even in isograft?
For every HLA to match between donor and recipient. The immune system must be suppressed in all cases.
Why are some tissues more commonly rejected than others?
Some tissues are evolutionarily able to withstand inflammation better than other tissues. For example, a tendon graft vs a kidney graft: tendon tissue can withstand an immune response better than the delicate kidney tissue.
What is an alloreaction?
An immune response provoked by alloantigen
What is alloantigen?
Antigen that differs between members of the same species. An example would be blood group antigens in humans.
What causes immune response to transplanted tissue?
Minor histocompatability antigens are allelic forms of normal cellular proteins that are different between donor and recipient. We a new antigen is introduced, lymphocytes consider this antigen as foreign since it was never negatively selected out.
How does the immune system act when a kidney is transplanted?
The recipient's T-cells initiate an immune response to the transplant tissue.
How does the immune system act when bone marrow is transplanted?
The T-cells in the transplanted marrow initiate an immune response against the recipient's tissues.
What is graft-versus-host disease?
When transplanted marrow produces lymphocytes that do not recognize the new host's tissue as self. Donor marrow produces an immune response against the recipient's tissues.
What improves the survival duration of transplanted organs?
HLA (MHC) matching decreases the severity of allograft rejection.
Generally, the lower the number of HLA mismatches...?
The longer the duration of transplanted tissue survival.
When is a transplant considered self tissue and safe from being rejected?
Never. All transplant tissue will eventually be rejected by the host's immune system. The goal of matching HLA is to delay this eventual rejection as long as possible.
Which is more important, matching HLA or minor histocompatibility antigens?
Generally, matching HLA is a priority when matching a donor and recipient. However, multiple minor histocompatability mismatching can be as severe as HLA mismatch.
Which MHC mismatch often causes more rapid and severe rejection?
MHC II (HLA-DQ, DP, and specifically DR was mentioned as the important one)
How does blood type O relate to types A and B?
O is the core glycolipid structure. A and B both have an additional terminal sugar that O lacks.
What is the differentiating feature of A blood group antigen?
GalNAc terminal sugar.
What is the differentiating feature of B blood group antigen?
Gal terminal sugar.
Individuals of one blood type have antibodies...?
Against blood type antigens of all other blood types.
Where do the antibodies against non-self blood groups originate?
From gut bacteria which bear antigens similar or identical to blood group antigens.
Who can type O blood be received by?
Types A, B, and AB
Who can type A blood be received by?
Types A and AB
Who can type B blood be received by?
Type B and AB
Who can type AB blood be received by?
Only type AB
What is the cross match test?
Cells from donor and serum from recipient are combined and observed for agglutination reaction. Clumping mean imminent immune response by recipient to donor cells and lack of compatibility.
What is cross match test for as far as donation?
Blood type compatibility for blood donation.
What is tissue typing?
Detection of HLA antigens on the surface lymphocytes to determine donor/recipient compatibility.
What are the three types of tissue typing?
1. Serology 2. DNA / molecular 3. Mixed lymphocyte culture
What is tissue typing by serology?
The microcytotoxicity test or lymphocyte cross-match places patients serum with the donor's lymphocytes to determine if there is compatibility.
What is tissue typing DNA/molecular techniques
PCR methodology looks at all the HLA loci
What is tissue typing by mixed lymphocyte culture?
Looks at DR, DQ, and DP molecules looking at culture in vitro of leukocytes from both patients.
What are the steps of the microcytotoxicity test?
Host an donor cells are placed in vitro. One antibody to a specific HLA is added to the an in vitro sample, followed by dye to make the cells leaky, and dye to color the leaky cells.
What does a color change in an in vitro microcytotoxicity test mean?
That the patient has that particular antigen being tested for. (For example, if the sample was give anti-HLA-A antibody, the patient has antigen HLA-A)
Donor 1 because he shares the same HLA as the recipient according to the assay.
In mixed lymphocyte reaction, uptake of thymidine indicates...?
A bad match. It indicates alloreactive cells being produces as aberrants. They more aberrants, the greater the rejection response.
What are the 3 types of rejection?
1. Hyperacute 2. Acute 3. Chronic
What is a hyperacute rejection?
Antibodies fix donor tissue and initiate an inflammatory response in the vascular endothelium, This results in occlusion and eventually graft failure.
What can cause a hyperacute rejection?
Preexisting antibodies against A, B, O, or HLA antigens in recipient's serum.
Who are more likely to have a hyperacute reaction?
Mulitparous women (especially if fathers differ for fetuses), recipients of multiple blood transfusions, and those who have had previous transplants.
What is direct allorecognition?
The donor cells act as APC's to activate the recipient T-cells. HLA antigens activate CD4 and CD8 cells directly.
What is indirect allorecognition?
Donor peptides are presented on recipient APC's after being picked up and processed via endocytosis. MHCII activates CD4 T-cells.
What is acute rejection?
Mediated through direct pathway of allorecognition and dependent on whether antigen is MHCI or MHCII. Can activate CTL or macrophages and inflammation respectively.
What happens in MHC I mediated acute rejection?
CD8 alloreactive cells migraste to the graft site and attack the transplant tissue.
What happens in MHC II mediated acute rejection?
CD4 alloreactive cells migrate to the graft and active the macrophages exacerbating inflammatory response.
Hyperacute rejection compares to what type of hypersensitivity?
Type 3 Hypersesitivity
Acute rejection compares to what type of hypersensitivity?
Type 4 hypersensitivity
What is chronic rejection?
Mediate by the indirect pathway of allorecognition, alloantibodies recruit inflammatory cells to the walls of blood vessels of transplanted organ.
What is the determination of a successful transplantation?
Moving the host response away from acute toward chronic rejection.
What will happen to every transplantation?
Chronic rejection and eventually graft failure.
In chronic rejection, how does the organ eventually fail?
Antibodies initiate inflammatory response. Vessel walls thicken at the expense of the lumen. The smooth muscle is eventually infiltrated. Organ becomes ischemic and fails.
How long does chronic rejection take to destroy transplantation tissue?
Depending on the HLA matching can take anywhere from months to years.
What effect does corticosteriods have on the transplantation?
They are used to suppress global immunity and inflammatory response.
What are the cytotoxic drugs common to transplantation?
Azathioprine, cyclophophamise, and methotrexate
What are the types of immunosuppressive drugs associated with transplantation?
Corticosteroids, cytotoxic drugs, and T-cell inactivators (including ab's specific for T-cells).
What is the common corticosteroid and how is it used in transplantation?
Prednisone is an effective anti-inflammatory. It is a pro-drug that is biologically activated in body. Given in combination with cytotoxic drug.
How do corticosteroids reduce inflammatory response?
Inhibition of inflammatory mediators such as cytokines, inhibition of cell migration via adhesion molecule down regulation, and promotion of apoptotic death of leukocytes via endonucleases.
What is azathiaprine?
A biologically activated pro-drug that inhibits DNA replication on level of adenine and guanine nucleotide synthesis. Inhibits active cell division. Given in post transplant period.
What is cyclophosphamide?
A pro-drug that inhibits normal cell division and DNA replication. It is used in pre- and post- transplant period. Is also very toxic to bladder.
What is methotrexate?
Drug of choice to inhibit GVHD in bone marrow transplants. Prevents DNA replication on thymidine level.
What are the T-cell inhibiting drugs?
Cyclosporine, Tacrolimus, and Rapamycin
How does cyclosporine inhibit T-cells?
Disrupts signal transduction from TCR leading to decreased IL-2 production and subsequent deactivation of proliferation and differentiation of T-cells.
How does Tacrolimus inhibit T-cells?
Also decreases IL-2 production similar to cyclospoine.
How does Rapamycun inhibit T-cells?
Prevents the signal transduction from IL-2 receptors negating IL-2 effect.
Reduction of cytokine expression is key to the effects.
What are the sources of anti-T-cell antibodies?
Usually developed in large (for large output quantity) animals that have been immunized with human thymocytes or produce from hybridoma cell line against specific T-cell surface proteins (CD3).
What is a bone marrow transplant?
The permanent replacement of an individual's entire hematopoetic system with the aim of improving function of one or more hematopoetic cells due to genetic disease.
Why is the entire immune system ablated by combined radiation and immunosuppression for bone marrow transplants?
The whole hematopoietic system is affected, including the immune system. The dysfunctional bone marrow must be wiped out so the donor marrow can produce all new cells.
What is myeloablative therapy?
Combined radiation and immunosuppression to prevent host rejection of graft cells and provide room for the transplanted stem cells to interact with bone marrow stromal cells.
How is bone marrow transplant different than solid organ transplant?
Collection is done under anesthesia, but infusion is not a surgical procedure.
What is graft-versus-host-disease?
Donor bone marrow contains mature lymphocytes that actively recognize host tissue inducing a sever inflammatory disease in recipient.
How is Acute GVHD characterized?
By area affected. Skin = rash. GI = diarrhea. Lung = Pneumonitis. Liver = hepatic damage.
How is chronic GVHD characterized?
By fibrosis and atrophy of one or more of the same organs without evidence of cell death. Can be dysfunction of organ in severe cases.
Factors for the development of GVHD...?
The graft must contain immunocompetent cells, the recipient must express MHC lacking in the graft donor, and the recipient must be incapable of rejecting the graft.
What is a good indication of GVHD in a bone marrow transplant patient?
Bright red spreading skin rash.
How does HLA mismatch relate to GVHD?
Survival is directly related to how closely the patient and donor match. The more mismatches, the lower the probability of survival.
In order to reduce severity of GVHD, what is taken out?
The donor's T-cells. However this leads to an increased risk of graft failure and higher incidence of recurring disease.
What is graft vs tumor(leukemia) effect?
The effect of alloreactive T-cell in graft eliminating the residual cancer cells from recipient.
What is autologous bone marrow transplantation?
For patients in need of bone marrow transplant who cannot find and HLA match, some of their own bone marrow is taken before ablative therapy. They are then reinfused. No problems with GVHD, but cancer relapse likely.
What is hematopoietic stem cell transplantation?
CD34 stems cells are gathered from periphery of donor of from embryological tissue and used as a transplant similar to bone marrow. Half billion cells can be required for success.
What is leukapheresis?
Similar to dialysis, the blood is removed, immune cells are separated, and the blood is returned. Remove immune cells are usually taken to lab an augmented to fight the host's disease.
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