Organ Graft Rejection

Question 1

Describe transplantation.

Answer 1

-transplantation via taking cells, tissues, organs called ‘graft’ from one individual & placing into a diff individual
-individual who provides graft is called donor & receiver is called recipient
-if graft is placed into normal anatomic location = orthotopic transplantation
>diff site = heterotropic transplantation
-transfusion = transfer circ blood cells/plasma from one individual to another

Question 2

Describe rejection.

Answer 2

-transplantation of cells/tissue from one individual to a non identical individual = rejection bc adaptive immune resp (inflam reaction)

Question 3

Describe the adaptive immune resp to graft rejections.

Answer 3

-memory & specifics mediated by lymphocytes
-individuals that reject grafts from one donor show faster rejection of another graft from the same donor BUT not from a diff donor = rejection process is immunologically specific

Question 4

Describe autologous, syngeneic, allogeneic, xenogeneic, grafts.

Answer 4

-autologous = graft transplanted from one individual to the same individual
-syngeneic = graft transplanted between two genetically identical individuals
-allogeneic/allograft = graft transplanted between 2 genetically diff individuals of same species
-xenogeneic/xenograft = graft transplanted between individuals of diff species
*molecules recog as foreign in allografts = ‘alloantigens’ & in xenografts ‘xenoantigens’

Question 5

Describe MHC in allografts.

Answer 5

-antigens that stim adaptive IR against allografts are proteins encoded by polymorphic genes (MHC proteins)
-all animals of inbred strain = genetically identical
-inbred animals of diff strains & individuals in outbred species differ in genes they inherit

Question 6

Describe the rules of transplantation immunology.

Answer 6

1. Cells/organs transplanted between genetically identical individuals are not rejected
2. Cells/organs transplanted between genetically non identical people OR 2 diff inbred strains of a species = always rejected
3. Offspring of mating between 2 diff inbred strains wont reject grafts from either parent
4. Graft from offspring of mating between 2 diff inbred strains = rejected by either parent

Question 7

Describe the 2 ways allogeneic MHC molecules of a graft can be presented.

Answer 7

1. Unprocessed MHC in graft = direct presentation of alloantigens
2. Indirect = recog foreign protein antigen APC -> draining lymph nodes

Question 8

Describe activation & effector functions of alloreactive T lymphocytes.

Answer 8

-transplanted organs carry with them APCs that express donor MHC
-donor APCs can migrate to LN & present on surface unprocessed allogeneic class I or II MHC to recipient CD4 & CD8 T cells

Question 9

Describe the activation of alloreactive B cells & production & functions of alloantibodies.

Answer 9

-antibodies against graft antigens = donor specific antibodies contribute to rejection
-high affinity alloantibodies made by helper T cell = dependent activation of alloreactive B cells
-antigens recog by alloantibodies are donor MHC I & II
-alloreactive antibodies made in graft recipients engage same effector mechanism like Fc receptor mediated binding & activation of neutrophils, macrophages, & NK cells

Question 10

Describe the innate immune resp to allografts.

Answer 10

-interruption of blood supply to tissue/organs from removal to placement = ischemic damage -> expression of DAMPs in graft -> stim innate immune resp by graft & recipient -> graft injury & enhance adaptive immune resp by increase migration of alloreactive circ memory T cells into graft & activating APCs
-host NK cells resp to absence of self MHC on donor graft cell

Question 11

Describe the mechanisms of allograft rejection.

Answer 11

-CD4, CD8 T cells & alloantibodies = mediate allograft rejection
-hyperacute -> acute -> chronic

Question 12

Describe hyper acute.

Answer 12

-thrombotic occlusion of graft vasculature
-min/hrs after host blood vessels anastomosed to graft vessels -> mediated by preexisting antibodies in host circ that bind to donor endothelial antigens

Question 13

Describe acute reaction.

Answer 13

-injury to graft parenchyma & blood vessels mediated by alloreactive T cells (cellular) & antibodies (humoral)
>cellular = both CD4 helper T cells & CD8 CTLs specific for graft alloantigens -> parenchymal & endothelial injury
>humoral = alloantibodies -> complement activation -> Fc neutrophils, NK = destruction

Question 14

Describe acute antibody mediated (humoral) rejection.

Answer 14

-alloantibodies bind to alloantigens (HLA) on vascular endothelial cells -> endothelial injury & intravascular thrombosis = graft destruction
-binding of alloantibodies to endothelial cell surface = trigger complement activation -> lysis of cells, activate neutrophils, thrombus formation
-Fc receptors on neutrophils & NK cells = kill endothelial cells

Question 15

Describe chronic rejection.

Answer 15

-kidney & heart -> vascular occlusion & interstitial fibrosis
-lung -> thickened small airways
-liver transplants -> fibrotic/nonfunctional bile ducts
-dominant lesion of rejection in vascularized grafts = arterial occupation bc prolif of sm m cells & graft eventually fail bc ischemic damage

Question 16

Describe the methods to reduce immunogenicity of allograft.

Answer 16

-min alloantigenic diff between donor & recipient
-avoid hyperacute rejection = ABO blood group antigens of graft donor must be compatible with recipient
-patients that need allografts tested for presence of performed antibodies against donor MHC or other cell surface antigens

Question 17

Describe immunosuppression to prevent or treat allograft rejection.

Answer 17

1. Inhibitors of T cell signaling pathway
2. Antimetabolites
3. Function-blocking or depleting anti lymphocyte antibodies
4. Costim blockade
5. Treatment to reduce alloantibodies & alloreactive B cells
6. Anti inflammatory drugs
7. Xenogeneic transplantation

Question 18

Describe inhibitors of T cell signaling pathways.

Answer 18

-calcineurin inhibitors: cyclosporine & tacrolimus = inhibit transcription of certain genes in T cells like IL2
-immunosuppressive drugs: rapamycin = inhibits growth of factor mediated T cell prolif

Question 19

Describe antimetabolites.

Answer 19

-metabolic toxins = kill prolif T cells
-azathioprine = inhibit prolif of lymphocyte precursors during maturation & kill prolif mature T cells stim by alloantigens

Question 20

Describe function blocking / depleting anti lymphocyte antibodies.

Answer 20

-antibodies that react w T cell surface & deplete/inhibit T cells used to treat acute rejection

Question 21

Describe costim blockade.

Answer 21

-drugs that block T cell costim pathways to reduce acute allograft rejection
-antibody binds to T cell CD40L & prevents interactions w CD40 on APCs

Question 22

Describe treatments to reduce alloantibodies & alloreactive B cells.

Answer 22

-plasmapheresis
-bortezomib = kill plasma cells & treat antibody mediated allograft rejection

Question 23

Describe anti inflammatory drugs.

Answer 23

-corticosteroids = reduce inflam reaction to organ allografts
-block syn & secretion of cytokines like TNF & IL1 -> reduced leukocyte recruitment
-immunosuppressive therapy = increased susceptibility to infection & tumor -> antiviral therapy
-opportunistic infections = fungal & protozoan

Question 24

Describe xenogeneic transplantation.

Answer 24

-transplantation of organs from other mammals like pig into human recipient
-immunologic barrier bc natural antibodies in human = hyper acute rejection
>prevention = xenografts damaged by form of acute vascular rejection occurs 2-3d after transplantation ‘delayed xenographic rejection’