Transplant immunology Flashcards
Hyperacute rejection happens within minutes to hours following reperfusion of the transplanted organ. What kind of HSR is this associated to ?
Type 2 HSR
What is the technique used to prevent hyperacute rejection of graft ?
Cross-matching
You are looking for pre-existing Ab.
Acute graft rejection happens in what time frame post transplant ?
Weeks to months
What is the mechanism behind acute graft rejection ?
Adaptative immune response mediated by T cells that respond to non-self HLA.
Direct pathway : Donor APCs in the graft present donor peptides of to CD4+ T cells via MHC class II or via cross-presentation, to CD8+T cells. CD4+ T cells activate Th1 & Th17 responses as well as activation of B cells for Ab production. CD8+ T cell target endothelial cells of graft, leading to injury.
Indirect pathway : Recipient APC present peptides from graft via MHC class II to CD4+ T cells leading to CD4+ pathways described.
T cells that react to HLA other than self are usually refered to as :
Alloreactive T cells
The recipient’s T cells have become sensitized to donor.
The frequency of activated T lymphocytes for an allo-response is 100-1000x as strong as for a normal antigen.
Recipient’s plasma cells secreting anti-donor HLA antibodies refers to what type of reaction ?
Hyperacute graft rejection (immediate)
Acute graft rejection would be what type of HSR ?
Type IV HSR (If CTL mediated)
Type II (if Ab mediated)
e.g. **C4d **breakdown product of complement is now î used as evidence for mediated acute graft rejection).
What is a pannel for reactive antibodies ?
Taking most common HLAs in the population and mixing it with pt’s serum to see if he/she mounts an immune response.
Screening test for recipients to see what types of Ab they have floating around. The result gives you a CPRA value.
E.g. A CPRA value of 95 would mean pt’s serum reacts with 95% of donors. He/she would move up on the list.
Ischemia/reperfusion injury (more important in dead donors) is a main driver of activation of autoreactive B & T cells resulting in chronic allograft inflammation. What organs is known to be better preserved and has a rate of acceptance of 95% ?
Kidney
However all pts that get a SOT will have chronic low grade inflammation that will require anti-rejection regimen for the rest of their lives.
The condition in which a SOT recipient exhibits a well-functioning graft and lacks histological findings of rejection after receiving no immunosuppresion for at least 1 year while also being able to mount effective immune response against pathogens is referred to as :
Clinical operational tolerance
Indications for bone marrow transplant ?
Lack B/T cells (e.g. SCID)
Blood CA
Autologuous-HSCT (e.g. after chemo/rx)
Allo-HSCT (will induce graft vs host disease)
Thought to be mediated mostly by mature donor T cells in the graft ;
Can be acute (35-80% of recipents) or chronic (80% of recipient) ;
Current first line trx = glucocortico & calcinurin inh.
Graft vs host disease (GvHD)
Donor T cells recognize the recipient’s cells as foreign and attack the epithelial cells in the skin, liver and gut causing acute graft versus host disease (GVHD).
Basically, donor T cells are responding to recipient’s HLA.
Cancer is described as :
Uncontrolled growth within normal tissue
We have immune surveillance i.e. our immune cells can recognize and destroy (CD8+ T cells) transformed cells before they grow into tumors, but tumors can evade these mechanisms or down-regulate host response. Also tumors grow really fast.
What are neoantigens?
Antigens of oncogenic viruses
E.g. EBV & HPV
In lymphomas and leukemias, you have icreased expression of what CD marker ?
CD20
Th1 cell response may enhance CD8+ T cell killing via :
TNFa & INFy
What is ADCC ?
Antibody-dependent cellular cytotoxicity is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific antibodies.
1. Binding of antibodies produced by B-cells to antigens (mostly IgG)
2. Recognition of the constant fragment (Fc) by effector cells
3. Release of damaging substances by effector cells
4. Destruction of the pathogenic organism
ADCC is an interaction between innate and adaptive immunity that is important because?
It allows innate immune effectors to recognize pathogens that
do not express PAMPs;
hide these patterns from innate immune detection
otherwise subvert innate immune function
it composes a big part of the immune response to parasites
ADCC is an adaptation of innate immune functions by the adaptive immune system.
Cells involved in ADCC of tumors that have their activity increased by presence of IL-2, IL-12 and IL-15 ?
NK cells
Specific activating receptor on the NK cell : NKG2D –> killing
Dendritic cell conditioning by tumor leads to :
Differentiation of antiinflammatory T cells –> Th2 response–> M2 macrophages –> differentiation of myeloid derived supressor cells and inhibition of tumor-specific effector T cells. Tumor associated M2 macrophages are also involved in stimulation of tumor growth.
Myeloid-derived supressor cells accumulate in tissu of tumor patients.
Role of PD-L1 ?
Inhibitory ligand on tumor cell surface which binds with PD-1 on surface of T cells, and leads to inactivation of T cells.
This process is referred to as checkpoint inhibition
Expression of inhibitory tumor cell surface proteins.
Immunosupressive cytokine made by the tumor cells ?
TGF-B
Pressure of ongoing immune response results in survival of less immunogenic cells in the tumor and thus failure of the tumor to produce tumor antigen. This leads to ?
Lack of T cell recognition
What would be the result of adding anti-CTLA to serum ?
Restoration of T cell proliferation
CTL4 is a regulator, inhibits proliferation of T cells.
What is the concept of checkpoint blockade ?
Giving monoclonal Ab specific for inhibitory receptors such as PD-1 & CTLA-4 on T cells.
Enhancer of active immunity.
T cells removed from pts and expanded in culture OR monoclonal Ab specific to tumor Ag injected into patient would be examples of :
Passive immunity
What is the concept of CART therapy ?
Chimeric Antigen Receptor T cells
T cells are not MHC restricted anymore.
They can directly bind tumor cells that express CD19.
