Final Exam - Tissue Transplantation and Graft Rejection

Acute rejection

transplant rejection occurring days to weeks after transplantation. It is mediated by the activation of allospecific T cells.

Allospecific T cells

activation of these cells trigger acute transplant rejection. Once activated, these cells migrate to the organ and cause tissue damage by effector mechanisms such as generation of cytotoxic T cells and delayed type hypersensitivity reactions.

Donor dendritic cells (Passenger leukocytes)

donor cells present in the organ being transplanted that migrate to the lymph nodes of the recipient to cause a primary alloimmune response in acute transplant rejection

Direct pathway

pathway that predominates in acute rejection.

Indirect pathway

pathway that contributes slightly to acute rejection

CD4 and CD8

Acute rejection involves both ______ T cells.

Chronic rejection

transplant rejection occurring months to years after transplantation

Occlusion of blood vessels, Smooth muscle cell proliferation, Macrophage infiltrate

Chronic rejection involves these three vascular tissue changes

blockage of blood vessels, ischemia

Vascular changes occurring in chronic rejection result in _____ and _____

T cell, antibody

Chronic rejection involves low grade _____ response and ____ involvement.

Response of graft to injury, Recurrence of original underlying disease, Drug related toxicities

Three non-immunological Mechanisms of Chronic Rejection

less

Immunosuppressive therapy is (more or less) effective for chronic rejection than for acute rejection.

chronic

Corneal graft rejection is classified as a ______ rejection

50%

Corneal graft rejection occurs in what percent of patients within the first post-operative year?

endothelial, stromal edema, reduced vision

The most symptomatic and severe form of corneal rejection is _____rejection which involves ______ and ______

Lack of specificity, Side effects, Expensive, Poor patient compliance

Four disadvantages of pharmacological strategies against corneal transplant rejection...

HLA (human leukocyte antigen) matching

the matching of genes encoding for MHC molecules. Can be used to minimize the likelihood and strength of a transplantation rejection. Can be difficult because there is a high level of polymorphisms occurring in these genes.

bone marrow, kidney

HLA matching is most useful for these two transplantations

heart and liver

HLA matching is less useful for these two transplantations because there are very few donors available

Inhibitor of T cell activation, Antiproliferative, Anti-inflammatory agent

Drug cocktail following kidney transplantation in the early post-transplant period

Immunosuppressive Drugst

he major influence on increased transplantation success rate.

Nonspecific toxicity, Long term use, Increased cancer and infection

three drawbacks to immunosuppressive therapy in the prevention of transplant rejection

Antiproliferative Drugs

drugs that inhibit T cell activation by inhibiting the de-novo synthesis of purines

6 mercaptopurine, azathioprine, mycophenolic acid

three antiproliferative drugs used in the prevention of transplant rejection

Azathioprine

an antiproliferative drug that is converted to 6-mercaptopurine in the body to prevent T cell activation. Is given in combination with corticosteroids.

Mycophenolic acid (MPA)

An antiproliferative drug that inhibits inosine monophosphate dehydrogenase to prevent purine synthesis.

cyclosprine, tacrolimus, sirolimus

three Inhibitors of T Cell Activation used in the prevention of transplant rejection

Cyclosporine

a fungal metabolite that inhibits the production of IL2 which is required for T cell proliferation.

Cyclophilin

an intracellular receptor which can be blocked by cyclosporine to cause the inhibition of calcineurin.

Calcineurin

a factor which catalyzes dephosphorylation of the NFAT complex leading to IL 2 gene transcription. It is inhibited by cyclosporine to prevent T cell proliferation.

Tacrolimus

drug having a similar mode of action, but greater potency than cyclosporine. It is also less nephrotoxic, but is diabetogenic in some patients.

Less nephrotoxic

the benefit of using tacrolimus over cyclosporine to inhibit T cell activation

FKbinding protein 12

an intracellular receptor which can be blocked by tacrolimus to cause the inhibition of calcineurin.

Sirolimus

drug that inhibits the response to IL2 by inhibiting the signals transmitted due to IL 2 binding to its receptor. Has widespread antiproliferative effects of T cells.

Corticosteroids

anti-inflammatory drugs used for transplant immunosuppression. They bind to intracellular steroidal receptors which will then bind to a glucocorticoid response element to alter gene transcription.

Negative glucocorticoid response element

when this transcription element is bound by glucocorticoid receptor complexes, other transcription factors are displaced and there is a inhibition of transcription resulting in anti-inflammatory effects.

Inhibition of proinflammatory cytokine secretion, Inhibition of nitric oxide synthase (results in vasoconstriction), Inhibition of adhesion molecule expression, Induction of endonucleases (prevents apoptosis)

four effects of steroids

Muromonab CD3t

he first monoclonal antibody approved in the prevention of transplant rejection. Binds to CD3 on T cells suppressing T cell responses

Daclizumab and basiliximabt

two IL2 receptor antagonists widely used in preventing transplant rejection. Act by the blocking of IL2 resulting in T cell depletion.

Ametuzumab

antibody used for the treatment of patients with relapsing forms of MS. It binds to CD52 found on T and B cells. This lowers circulating T and B cells through anti-body dependent cellular cytolysis and complement mediated lysis.

Abatacept

antibody used for the treatment of rheumatoid arthritis. It is composed of CTLA4 fused with the Fc portion of IgG1. It interferes with activation of T cells by binding to CD80 and CD86 molecules needed for T cell stimulation

Belatacept

antibody used to prevent rejections in patients having kidney transplant It binds to CD8 and CD86 antigens present on cells and blocks CD28 mediated stimulation of T cells.

Shortage of organ donors and Chronic rejection

two Limitations of Transplantation

Immune privilege

property of a tissue or site of transplant describing their ability to tolerate a transplant. Ie) corneal graft are rejected less vigorously than other grafts

Ignorance of the immune system, Poor lymphatic drainage, Low numbers of dendritic cells, Tgf beta, Melanocyte stimulating hormone, Fas ligand

six Mechanisms of Immune Privilege in the Cornea

vascularization Cornea may undergo rapid rejection when there is ______ of the graft bed