Immunology Transplantation: Solid Organ

Front 1

What is allogenic chimerism?

Back 1

The idea that the recipient of an organ becomes chimeric with the donor's dendritic cells in addition to the organ.

Front 2

Describe donor dendritic and stem cells in solid organ transplants

Back 2

-Incidental donor dendritic and stem cells are transplanted with grafts
-Mixed allogenic chimerism (particularly of donor dendritic cells)
-Long term surviving solid organ transplant recipients have donor dendritic cells throughout the body

-Pre-treatment with donor bone marrow cells
-Future of transplantation: tolerance without drugs
-Limited to living, related donor

Front 3

What is the goal of medical support in transplant?

Back 3

To temporize the system until it can reform around the organ.We are pretty much stabilizing while the immune system determines how to go forward.

Front 4

What does a successful transplantation exploit?

Back 4

-Plasticity of immune system
-Regenerative capacity of immune system

Front 5

Describe the origins of plasticity and regenerative capacity

Back 5

-Ontogeny
-Immune system develops anew in each individual
-Shaped by unique complement of paternal and maternal HLA and minor histocompatibility Ags

-Pregnancy
-Pregnancy is a tumor of mixed allo-haplotype
-Parturition breaks immune privilege of placenta

Front 6

Describe hyperacute rejection

Back 6

Cause: Pre-formed antibodies against ABO or HLA antigens (from pregnancy, blood transfusion or previous transplants)

Solution: Matching donor/recipient and screening for pre-formed antibodies

Front 7

Describe acute rejection

Back 7

Cause: Effector T cells responding to HLA differences between donor and recipient

Solution: Matching donor/recipient for HLA and treating recipient with immunosuppressive agents

Front 8

Describe chronic rejection

Back 8

Cause: multi-factorial

Solution: unsolved

Front 9

What is the mechanism of acute rejection?

Back 9

Dendritic cells are in the implanted organ. These travel to the recipient's lymph node where they activate effector T cells. These effector T cells migrate to graft via blood and destroy the graft

-Donor dendritic cells stimulate T effector cells to reject graft
-However, donor dendritic cells ultimately MAY help permit "detente" if not tolerance
-Delete or anergize donor's graft specific T cells
-Stimulate Treg

Front 10

How do you screen to prevent acute rejection?

Back 10

The mixed lymphocyte reaction.

The T cells of the recipient are mixed with the APCs of the donor

Measure T cell proliferation and measure T cell cytotoxicity

Front 11

What is the treatment philosophy in transplantation?

Back 11

-Immunosuppressive drugs presidpose to infection and neoplasia
-At the time of transplant, acute rejection is prevented by high doses of immunosuppressive drugs
-High doses of cyclosporin result in polyclonal B cell neoplasia

-As doses are decreased episodes of acute rejection (varying degrees of severity) occur periodically in transplant recipients
-Some find comparisons between episodes of rejection and flares (exacerbations) of autoimmune diseases
-To extent that metaphor, transplantation rejection is like a relapsing/remitting disease

Front 12

What can high doses of cyclosporin and tacrolamis cause?

Back 12

Polycllonal B cell stimulation called post transplant lymphoproliferative syndrome. It is a pre-neoplastic state. If one of those clones is infected with EBV then it can take off and become a full neoplasm. It also shows that the immune system is in constant balance and if you inhibit T cells then you get a polyclonal, non-cancerous, but neoplastic proliferation of B cells. In the early days when higher doses of cyclosporin were used, some patients developed B cell neoplasms, but not people dose cyclosporin better.

Front 13

What is the treatment for acute rejection

Back 13

-Corticosteroids
-Modulate gene expression
-Cytostatic drugs
-Mycophenolate mofetil
-Azathioprine
-Cytotoxic drugs
-Cyclophosphamide
-Anti-T cell antibodies
-polyclonal anti-thymocyte globulin
-mAb anti-CD3 (TCR complex)
-mAb anti-IL2R (CD25)
-mAb anti-CD52 (pan-lymph)
-Calcineurin inhibitors
-Cyclosporin A
-FK506/Tacrolimas
-mTor inhibitor
-Rapamycin

Front 14

What do cytostatic drugs do? Cytotoxic?

Back 14

Cytostatic drugs target dividing cells and stop them from dividing. Cytotoxic drugs kill dividing cells. Anti-T cell antibodies are an increasingly sophisticated and interesting group of drugs.

Front 15

What are the side effects of corticosteroids?

Back 15

They decrease the activity of a lot of cytokines, they decrease NOS, the decrease a lot of inflammatory enzymes. They have a wide variety of effects that are essential for transplant. Using corticosteroids for a long time, in addition to being immunosuppressive, have effects on weakening bones and weakening skin so you get stria and other complications of using them. There is no alternative, so high doses of steroids are used initially and then they are dialed down over time.

Front 16

How do cytostatic and cytotoxic drugs act?

Back 16

Targeting cell division (proliferating cells) targets lymphocytes, because proliferation (clonal expansion) is a specialized function of lymphocytes.

Front 17

What are some cytostatic and cytotoxic drugs?

Back 17

-Purine analogues
-Azathioprine and 6-mercaptopurine
-Not FDA approved for transplant

-Purine synthesis inhibitor
-Mycophenolate mofetil
-Mycophenolate sodium

-Alkylating agents
-Cyclophosphamide
-Not FDA approved for transplant

-Folic acid analogue
-Methotrexate
-Not FDA approved for transplant

Front 18

What are the side effects of cytostatic and cytotoxic drugs?

Back 18

These drugs inhibit the activity and function of other cells that divide, such as cells in the GI tract and hair cells.

Front 19

Describe polyclonal anti-thymocyte globulin

Back 19

-Used to Tx acute rejection
-Rabbit (thymoglobulin)
-Horse (atgam); (lymphoglobulin) - off market

Front 20

Describe mAb anti-CD3 (TCR complex)

Back 20

-Expressed on resting and activated T cells
-Murine mAb (muromonab; orthoclone)
-First mAb approved by FDA
-Used for acute rejection

Front 21

Describe mAb anti-IL2R (anti-tac, anti-CD25)

Back 21

-Expressed on activated T cells; block IL2 signaling
-Chimeric mu/hu mAbs against the alpha chain of IL2R
-Basiliximab (simulect)
-Daclizaumab (zenapax)

Front 22

Describe anti-CD52

Back 22

-Expressed on most lymphocytes
-Alemtuzumab (campath) is a depleting murine mAb
-Not FDA approved for transplant

Front 23

Describe cyclosporin and tacrolimas

Back 23

-Cyclosporin and tacrolimas (FK506) bind different targets but have similar downstream effects
-Calcineurin inhibitors (CNIs)
-Inhibit T cell activation

-Targets
-cyclosporin: cyclophilin (CyP)
-Tacrolimas: FK binding protein (FKBP)

-Cyclosporin-CyP and Tacrolimas-FKBP both bind to and inhibit calcineurin
-Neither CyP nor FKBP normally bind calcineurin, but are believed to be peptide isomerases
-Cyclosporin is a cyclic peptide; Tacrolimas is a macrolide

Front 24

What does rapamycin bind? What does it interact with?

Back 24

Rapamycin binds FKBP
-Rapamycin:KMBP complex binds "mammalian target of Rapamycin" (mTOR)
-Rapa binds the same FKBP as tacrolimas, but induces interaction with a different molecular target (mTOR instead of calcineurin)
-Rapa:FKBP inhibits mTor complex and pathway
-Rapa:FKBP:mTOR inhibits the productin of IL-2 receptor

Front 25

Where is rapamycin used?

Back 25

Used in kidney transplant and has safety advantage in patients iwth uremia. It is also used to coat coronary stents.

Front 26

What are the side effects of rapamycin?

Back 26

It has an effect on wound healing.

Front 27

What drugs were used in kidney transplant before CNIs?

Back 27

Prednisone/Azathioprine

Front 28

Describe chronic rejection

Back 28

-Primary lesions
-Vascular endothelium (intimal proliferation)
-Craft parenchyma (fibrosis) with loss of normal structure
-Treatment phenomena
-More likely following acute rejection
-More intesnsive T-cell depletion doesn't prevent CR
-MMF, Rapa delay but don't prevent CR

Front 29

Describe direct allorecognition in chronic rejection

Back 29

The donor DC cells present peptides to the recipient CD8 and CD4 cells that activate them and cause them to go attack the graft

Front 30

Describe indirect allorecognition in chronic rejection

Back 30

The donor DC cells travel to the lymph node where they die and are taken up by the recipient's DCs. The MHC class I and class II molecules of the donor are broken down and presented to the recipients CD4 cells. This ultimately leads to a counterattack against the cells of the graft through the production of anti-Class I antibodies.

Front 31

Describe CD40-L helper function's role in new approaches to chronic rejection

Back 31

-mAb anti-CD40L has unique activity (heart, islets) but may have been associated with thrombosis in human SLE trial.
-concept is to target activated T helper cells "in flagrante delicto" to spare resting cells
-Second generation, single chain anti-CD40L designed to reduce toxicity

Front 32

What are some of the new targets/new approaches to chronic rejection?

Back 32

-Promote T-reg cells to protect the graft (peripheral tolerance)
-CD8+CD28- T suppresor (Ts) cells: ILT3 and ILT4 on dendritic cells and other APC may stimulate CD8+ Ts cells
-CD4+CD25+FoxP3+
-B cells (source of allo-antibodies)
-Deplete B-cells (with mAbs) for induction therapy
-Chemokine receptor inhibition
-Block chemokines (CCR5) associated with macrophages
-Fibroblasts?
-Block proliferation of fibroblasts

Front 33

Is graft chimerism good or bad? why?

Back 33

This is hard to know
-Grafts are repopulated to some extent by host bone-marrow derived stem cells
-Normal process by which organs are replenished
-Normally organs also replenished by tissue-derived stem cells (which may operate in grafts)
-Inflammation is a trigger for bone-marrow derived stem cells to home and differentiate
-Inflammation recruits stem cells to stomach that have the potential to become epithelial cancers
-Some evidence suggests graft chimerism is associated with chronic rejection

Front 34

What are concordant xenografts?

Back 34

Transplant between species with no hyperacute rejection
-Primate-to-man
-Problems: ethics, supply, infection (SIV)

Front 35

What are discordant xenografts?

Back 35

Transplant between species with hyperacute rejection
-Pig-to-man
-Problems: scientific (infection, PERV)

Front 36

What are some problems and potential solutions to pig xenografts?

Back 36

-Pig cells express Gal 1,3 alphaGal sugars to which humans have preformed antibodies
-Solution: Generate Gal-transferase knockout pigs

-Human complement is activated by other pig proteins
-Solution: Generate human CRP (human complement regulatory protein) - transgenic pigs

-Work on Gal-transferase[KO]; CRP[tg] pigs is ongoing

Front 37

What devices/temporizing measures or potential solutions are available?

Back 37

-Kidney dialysis
-Can be a long term solution
-Hemodialysis
-Peritoneal dialysis
-Left ventricular assist device (LVAD)
-Supports heart failure patients waiting transplant

-Ex-vivo liver assist devices (for FDA approved)
-Temporize patients waiting transplant; allows some fulminant hepatic necrosis patients to recover
-Bio-artificial liver