Transplantation Immunology Flashcards
Prior to transplantation, tests for (1) compatibility (2) pathogens?
- HLA (HLA-A, HLA-B, HLA-DR) and ABO
- HIV, Hep B, Hep C, CMV, syphilis, EBV, HTLV 1 and 2
Allogeneic immune responses are caused by what?
Differences in MHC and ABO between donor/recipient
- donor T-cells aren’t used to recipient MHC
- antibodies from recipient bind to donor molecules (as in ABO)
What is a hyperacute (immediate) reaction?
Type II hypersensitivity
Response to ABO (and/or MHC) expressed by endothelial cells
- PRE-EXISTING antibodies to A/B antigen in recipients bind to the antigens on donated organs
- also pre-existing Ab to MHC, which can come from pregnancy, blood transfusion, or previous transplantation
**Can’t be controlled
Antigens / Antibodies in: A B AB O
A: A,O / anti-B
B: B,O / anti-A
AB: A,B,O / none
O: O / anti-A, anti-B
What does H enzyme do?
Convert precursor to ABO antigen to the H or O antigen (same thing)
- everyone has this enzyme
What does the A enzyme do? The B enzyme?
A enzyme converts O antigen to A antigen
B enzyme converts O antigen to B antigen
Universal donor? Recipient?
Donor: O RhD-
Recipient: AB RhD+
Which is dominant, D+ or D-?
D+
What is acute rejection?
Type IV hypersensitivity
Occurs within weeks; caused by effector CD4 Th1 or CD8
- response to HLA differences
- always some mismatch in allografts
**Can be controlled with immunosuppressive drugs / anti-T-cell antibodies
What is accelerated acute rejection?
Within days; sensitized memory T cells by previous grafts or exposure (still type IV)
Direct allorecognition:
Indirect allorecognition:
- Donor DC presents its MHC structure / its MHC with a peptide that is recognized by recipient CD4 / CD8
- Recipient DC presents MHC from dead donor DC
Direct pathway example:
Donor DCs to LN, recognized by T-cells, activated effector T-cells, go to target tissue (donated) and destroy
(kidney example)
Examine potential for graft rejection:
Mixed Lymphocyte Reaction test (MLR)
- Lymphocytes, monocytes, DCs isolated from donor / recipient
- Donor cells irradiated so they act only as stimulators, not responders
- Mixed
- Measure magnitude (proliferation of host cells) and killing of donor cells (capacity for graft rejection)
What is chronic rejection?
Months or years later
- May be due to chronic DTH response?
- T cells produce cytokines, lead to thickening of vessel due to growth of smooth muscle
- localized tissue anemia
What causes (minor) MHC antigen differences in donor and recipient?
Polymorphic self proteins that differ in amino acid sequence between individuals
What is graft-versus-host disease?
Hematopoietic cells from transplant (T-cells) attack recipient tissues
- mostly skin, liver, intestines (tissues most damaged by chemo and radiation - most inflamed already and more susceptible)
What is graft-versus-leukemia response? (patient with acute myelogenous leukemia)
Good! Donor NK cells kill recipient tumor cells based on MHC I differences
- Haploidentical transplant (recipient has one of two inhibitory HLA-C ligands of donor)
- Selectively kill host hematopoietic cancerous cells
- Graft is depleted of T-cells to prevent GvHD
For GvHD to occur:
- Graft contains immunocompetent T-cells
- MHC mismatch
- Recipient incapable of rejecting graft
Alternatives to minimize GvHD:
- Autologous BMT (taken prior to radiation treatment)
- Umbilical cord blood cells (less GvHD)
- Isolated stem cells free of T-cells
Why is T-mediated reaction often mild in xenotransplantation?
MHC molecules of different species are so different that human T-cells can’t recognize them; rejection is mild
**NOT always the case (Ab to pig endothelial carbohydrates, attacks by human complement, presence of a zoonosis)
What do corticosteroids do?
Induce expression of anti-inflammatory genes (IkB-alpha, for example) that inhibit NF-kB activation and production of inflammatory cytokines
- So, inhibit macrophage cytokine secretion
Side effects: fluid retention, weight gain, diabetes, loss of bone mineral, thinning of skin
What do Annexin / Lipocortins do?
Suppress phospholipase A2
What does cyclosporine do?
Target calcineurin and block NFAT (make IL-2 for immune cell activation)
Cyclosporin : cyclophilin binding targets calcineurin
What does tacrolimus (FK506) do?
Target calcineurin and block NFAT (a macrolide)
–> no cytokine production
Tacrolimus : FKBP targets calcineurin
What does Rapamycin do?
Macrolide that blocks mTOR signal transduction required for lymphocyte cell proliferation (Sirolimus does this too)
What does anti-CD3 monoclonal antibody do?
Deplete T cells by binding to CD3 and promoting phagocytosis or complement-mediated lysis
(Treat acute rejection)
Cyclosporin A and Tacrolimus effects in T cells:
- Less IL-2, IL-3, IL-4, GM-CSF, TNF-alpha
- Less cell division (IL-2)
- Less Ca-dependent exocytosis of granules
- Inhibition of antigen-driven apoptosis
Cyclosporin A and Tacrolimus effects in B cells:
- Inhibit cell division (T-cell cytokines absent)
- Inhibit antigen-driven cell division
- Induce apoptosis after activation
Cyclosporin A and Tacrolimus effects in Granulocytes:
Reduced Ca-dependent exocytosis of cytotoxic granules
What does Azathioprine do?
Chemo drug
Inhibit DNA replication. Kill not only lymphocytes, but also all dividing cells in body: BM, intestinal epithelium, hair follicle
What does Cyclophosphamide do?
Chemo drug
Cross-link DNA; side effects include damage to bladder
What does Methotrexate do?
Chemo drug
Prevent DNA replication by inhibiting thymidine synthesis
How do anti-CD3 antibodies work?
Derived from sheep/goats and humanized. Block signal to increase Ca in cell and downstream IL-2.
- Can induce formation of antibodies to themselves and reduce effectiveness
Effects of corticosteroids:
- Reduce IL-1, IL-3, IL-4, IL-5, GM-CSF, TNF-alpha, CSCL8 (IL-2?)
- Reduce NOS (therefore NO)
- Reduce Phospholipase A2 and Cyclooxygenase 2; Increase Lipcortin-1
- Reduce cell adhesion molecules (poorer migration)
- Induce exonucleases (apoptosis in lymphocytes and eosinophils)
