Transplantation Immunology Flashcards by Chris Rodarte

Tests before kidney transplantation

Compatibility

HLA (A, B, DR)
ABO (blood Ag’s)

Pathogens

HIV, HepB/C, AMV, HTLV, Syph, EBV

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Most common type of transplantation

allogenic

(from genetically different individuals)

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Allogenic immune responses after transplantation are caused by ______

Genetic differences (MHC, ABO) between donor and recipient

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What is a hyperacute reaction?

What two things can cause it?

An immediate response to either ABO or MHC expressed by endothelial cells

Preexisting AB’s to A/B antigen = acute rejection
Preexisting _AB’s to MHC_I or II from pregnancy, blood transfusion, or transplantation

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What needs to be tested before blood transfusion or organ donation

ABO blood antigens

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RBC’s dont express ____

They do express ______

Dont express MHC

Do express CHO antigens (ABO)

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Antibodies to blood antigens A or B can cause ______ or _______.

What kind of reaction is this?

Complement fixation/rapid RBC clearance or hyperacute rejection

Type 2 HS reaction

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All blood types/genotypes express __ enzyme

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A antigen ends in ____

GalNAC

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All ABO antigens are connected to _____ at its base

A ceramide

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Blood types are inherited from…

both parents

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Minor blood group antigens

The most important one is ____, due to…

Other minor blood group antigens such as ___, __, and ___ are less _____

Rhesus: C, D, E

RhD is morst important because it has high immunogenicity

Kell, Duffy, MN are less immunogenic

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TImeframe for acute rejection

Occurs within WEEKS

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Acute rejection caused by what?

This is similar to what kind of reaction?

How can this be prevented?

effector CD4+ T_H1 cells or CD8 Tcells responding to HLA differences between donor and recipient

Like a Type 4 HS reaction

Immunosuppressive drugs or anti-T-cell antibodies

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Accelerated acute rejection (AAR) ocurs within…

Mediated by what?

days

mediated by sensitized memory T cells from previous exposure or grafts

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What happens during acute rejection?

Alloreactive CD8 T cell responds to antigen on parenchymal cells = damage to parenchymal cell and interstitial inflammation

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Allorecognition occurs when (2 ways)

TCR recognizes an allogenic MHC whose structure resembles the MHC-foreign epitope complex
TCR recognizes structure formed from allogenic MHC + bound peptide

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Direct vs Indirect allorecognition

Direct = CD4 and CD8 bind directly to donor DC

Indirect = Donor DC death produces membrane vesicles that contain the allogenic complexes –> get internalized and presented by recipients DC to CD4/CD8 cells

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After transplantation, __________ migrate to the recipient’s _____ to activate T cells (which mediate rejection)

Donor’s dendritic cells

Spleen

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What is a Mixed lymphocyte reaction test?

It measures ____ and ______

How is it read?

Co-culture of donor + recipient blood cells, measures T-Cell proliferation and T-cell cytotoxicity

More proliferation = More mismatch

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Chronic rejection occurs ______ after transplantation

_______ occurs, leading to ______

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Months to years after transplantation

Thickening of vessel wall leadds to ischemia

Which HLA’s are most important in matching kidney transplant?

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A, B, DR

______ that differ in amino acid sequences give rise to ________________ between donor and recipient

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Polymorphic self proteins

minor histocompatibility antigen differences

2 types of alloreactions

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Transplant rejection = recipient’s T cells attack transplant
GVHD = When hematopoietic cells are transplanted the T cells in the transplant attack the recipient’s tissues (in Soviet Russia, graft attacks you!)

*there is also Graft-versus-Leukemia against leukemic or tumor cells (a type of GVHD)

Three conditions for GVHD to occur

1. Graft must have _immunocompetent_ T cells 2. There must be an _MHC mismatch_ 3. The recipient _must not be capable of rejecting_ the graft

* During GVHD, T cells circulate in blood to \_\_\_\_\_\_\_\_ * Alloreactive cells interact with _______ and proliferate * _______ and ______ enter tissues inflamed by the conditioning regimen and cause further tissue damage

Secondary lymphoid tissues Dendritic Cells Effector CD4 and CD8 T-cells

Pros and cons of BMT

* Pros * Can cure lots of diseases * Lots of donors * Simple procedure (marrow from iliac crests... local anesthesia, 30 minutes) * Cons * GVHD * Non-functional T cells due to MHC mismatch * Failed reconstitution (graft failure)

Alternative stem cell sources to minimize GVHD

* Autologous marrow (obtained before radiation) * Umbilical cord blood cells (lots of CD34+ hematopoietic cells) * Isolated stem cells free of T cells

Donor cells kill recipient tumor cells based on \_\_\_\_\_\_\_

MHC1 differences

Haploidentical transplant in which the recipient has only one of two ___________ of the donor. Donor hematopoietic cells inhibit \_\_\_\_\_ Recipient hematopoietic and leukemia cells inhibit \_\_\_\_\_\_

_inhibitory HLA-C_ Donor = inhibit _ALL_ donor NK cells Recipient = inhibits only _SOME_ donor NK cells

GVHD has ____ stages/grades These are based on what tissues?

4 stages Skin, Liver, and GI tract

\_\_\_\_ are the xenoplantation donor of choice 3 problems with this procedure? Solutions?

Pigs _Problems_: 1. humans have **antibodies** to pig endothelial CHO 2. human **complement** attacks pig cells 3. **Zoonoses** _Solutions_ * Transgenic pigs expressing DAF * Transgenic pigs that dont express the reactive antigens * Germ free pigs

What is the advantage of xenotransplantation?

**MHC molecules differ** between species = human T cells dont recognize Therefore T cell response is *mild*

\_\_\_\_\_\_\_\_\_\_\_ make allogenic transplantation possible, and also treat \_\_\_\_\_\_\_\_\_\_ Four Examples?

Immunosuppressants, Autoimmune diseases * Corticosteroids * anti-lymphocyte proliferation drugs * microbial immunosuppressives * Immunosuppressive antibodies

Short and long term sides from immunosuppressive drugs

Short = susceptibility to infection Long = higher incidence of cancer

Immunosuppressive targets for: * Belatacept * Alemtuzumab * rATG * Basiliximab * Anti-CD3 mAB

Belatacept = **CD28** Alemtuzumab = **CD52** rATG= **immunodepletion** Basiliximab = **IL-2** Anti-CD3 mAB = **TCR/CD3** complex

Target for: * Tacrolimus, Cyclosporin * Methotrexate, Mycophenolate, Cyclophosphamide, Azathioprine

* Ca--\> calcineurin * DNA replication

Anti-CD52 is efficient at...

depleting leukocytes before organ transplantation

Prednisolone mechanism Side effects?

induces _IkB-alpha_ = **inhibits NFkb activation** Side effects = cortisol sides

Corticosteroid effects (5)

* Reduces cytokine-mediated inflammation * Reduces NO * Reduces PG's/LT's * Reduces emigration of leukocytes from vessels * Induces apoptosis in lymphocytes and eosinophils

Annexin/Lipocortins suppress

PLA2

Cyclosporine A derived from \_\_\_\_\_ Targets \_\_\_\_ Blocks \_\_\_\_\_

a cyclic decapeptide from soil fungus Targets calcineurin blocks NFAT activation

Fk506 (a.k.a.\_\_\_) definition Targets \_\_\_\_ blocks \_\_\_\_\_

macrolide from soil actinomycete Targets calcineurin blocks NFAT activation

Rapamycin definition Blocks \_\_\_, which is required for \_\_\_\_\_\_

macrolide from soil bacterium Blocks _mTOR_, required for _cell proliferation_ (inhibits IL-2 signaling)

Mechanism of Anti-CD3 monoclonal antibody (2 effects) it is used to treat what?

* depletes T cells * Promotes phagocytosis or complement-mediated lysis \*used to treat acute rejection

Calcineurin is a ________ that activates ______ and is inhibited by \_\_\_\_\_/\_\_\_\_\_

ST kinase activates NFAT inhibited by CsA or tacrolimus (FKBP)

calcineurin is a ______ protein, required for \_\_\_\_\_\_\_

_calcium-binding protein_ required for _T, B, and granulocyte activation_

effect of CsA or FK506 in granulocytes

reduced calcium-dependent exocytosis of granules

Nonspecific cytotoxic drugs target _______ cells Examples? (with mechanisms)

dividing cells **Azathioprine** = _inhibits DNA replication_ (all dividing cells) **Cyclophosphamide** = _cross links DNA_ (bladder damage sides) **Methotrexate** = Inhibit _Thymidine synthesis_ (prevents DNA rep)

Uses and limitations for antibodies specific to human T cells

Used to deplete T cells or to suppress their functions Limitation = the non-human antibodies can induce formation of antibodies to the anti-Tcell antibodies (yo dawg) This reduces the effectiveness of the anti-Tcell Ab's

Transplantation Immunology Flashcards

(50 cards)