how does hypoxia cause ischemic-reperfusion injury?
hypoxia-inducible factor
how does complement cause ischemic-reperfusion injury?
senses injury, activates endothelium and leukocytes
how do natural antibodies contribute to ischemic-reperfusion injury?
activate complement
how do oxidants contribute to ischemic-reperfusion injury?
activate endothelium, damage cells
how does apoptosis contribute to ischemic-reperfusion injury?
disrupts endothelium
how do toll-like receptors contribute to ischemic-reperfusion injury?
activate endothelium and leukocytes
how do cell-adhesion molecules contribute to ischemic-reperfusion injury?
facilitate leukocyte migrations
how do T-cells contribute to ischemic-reperfusion injury?
unknown
Name tow mechanisms of ishcemic-reperfusion injury that can occur during organ harvesting?
failed anastomosis can result in immediate transplant failure. Mild injury of the organ during the harvest can –> activated endothelium –> inflammation
what is the “no reflow” state in transplant?
severe injury to small blood vessels –> no reflow –> tissue necrosis
what three solid organs are more susceptible to ischemic-reperfusion injury than the kidney?
lungs, liver, heart
Define “histocompatibility”
The genetic relationship between donor and recipient
what does MHC stand for?
major histocmompatibility complex
can you still have rejection if MHC is matched?
yes, but its slower
do you have to match minor histocompatibility complexes between donors and recipients?
sometimes
Do antibodies have more effects on organ grafts or cell/tissue grafts?
organ grafts
what are the four fundamental characteristics of the antibody-mediated immune response?
1) systemic reaction. 2) specific reaction (second set reaction doesn’t affect third party grafts); 3) generalizable (same rxn aroused by tumor is aroused by skin); 4) exhibits memory
Briefly, how do T-cells and B-cells respond to transplantation
T-cells attack cells and tissues without Ab. B-cells and T-cells both attack organs, B-cells use Ab
What is TAP and which type of MHC is it associated with?
Transporter a/w Antigen Processing. Major transporter a/w MHC-I, determines immunogenicity of the peptide
What is the peptide loading complex and what type of MHC is it associated with?
MHC-I, promotes exchange of bound peptides, loaded in ER, further determines immunogenicity
What are the origins of TAP and peptide loading complex of MHC-I? (3)
endogenous proteins, virus-produced proteins, other intracellular origins
Define cross-presentation and what it is used for
Fusion of endosomes containing phagocytosed proteins / cell fragments to the ER. Cross-presentation is essential to develop cytotoxic responses to tumor cells, allogeniec treatment, and virus-infected cells
Which cells present MHC-I?
all nucleated cells
Which cells present MHC-II?
specialized, antigen-presenting cells. Macrophages, dendritic cells, endothelial cells.
Where do the peptides that bind to MHC-II originate from?
intact cells, cell debris, and proteins taken up by phagocytosis into phagosomes
are MHC-II lacking a bound peptide expressed on cell surfaces and why?
No they arent to ensure that extracellular peptides are not inadvertently presented
Describe the roles of positive and negative selection in development of T-cell receptors
ensure that TCRs recognize self-MHC but do not bind too tightly (positive selection –> negative selection)
What type of peptides do T-cells bind to (free or bound)?
Do not bind to free Ag, only bind peptides bound to MHC-I / II
What are the three coreceptor proteins for T-cell receptors?
CD3, CD4, CD8
how do Antigen-presenting cells (APCs) interact with T0cell receptors for immune response
APCs activate with cytokines –> APCs process and present antigens –> APCs migrate to LNs and activeate T-cells –> increased T-cell presentation + increased MHC-I/II expression + increased peptide stability
Name the two basic steps of T-cell activation
T-cell receptor bind to MHC, costimulatory receptors enhance binding to MHC (CD8 - MHC-I / CD4 - MHC-II)
what is the role of total level of signaling on T-cells
survival, activation, and apoptosis of T-cells depend on total level of signaling, therefore lotso low levels of signaling = big signals
what is the relative amount of T-cell stimulation required in blood vs. LNs
T-cells in blood require more stimulus than T-cells in LNs
how does immunologic memory compare to innate immunity?
immunologic memory is more rapid, specific, and effective than innate immunity
how long does immunologic memory take to be effective after first encounter with Antigen?
several weeks to respond
What type of cell retains cellular immunity?
Memory T-cells
Name the three characteristics of cellular immunity mediated by memory T-cells and how is this related to transplant immunology
migrate through the body, activated by little/no costimulation, hang around for a long time - therefore difficult to overcome in transplant pationetns. Basically, stronger, faster, more intense immune response
What part of the transplanted organ is the immunologic reaction directed at?
Mainly directed at blood vessels that feed the transplant (recipient vessels)
How do T-cells interact with allograft MHC?
T-cells directly recognize allografts and MHC on foreing allograft cells, which can engage a large percentage of T-cells. Heightened immunogenicity of MHC-derived peptide can cause allografts MHC to load efficiently on host MHC.
How does the interaction of T-cells with allograft MHC affect immunologic memory?
the speed/intensity of the T-cell response to MHC is associated with the speed/intensity of immunologic memory
Describe the step of positive selection in development of central tolerance in T-cells
T-cells that bind to MHC survive, T-cells that bind to anything else die
Describe the step of negative selection in development of central tolerance in T-cells
T-cells that bind too tightly to MHC die
What do receptor-binding do B-cells require to be activated?
need activation with Antigen-receptor and second-receptor
How do antigen-presenting cells respond to tissue injury?
increase MHC and peptide expression with exposure to tissue injury
Name the four types of Peripheral Tolerance
peripheral deletion, anergy, regulatory T-cells, accommodation
What is the MOA of peripheral deletion?
shapes repertoire to eliminate reactive lymphocytes, part of peripheral tolerance
what is the MOA of Anergy?
conditional responses
what is the MOA of reglatory T-cells
suppression of immune response
what is the MOA of accommodation
prevents immune-mediated injury via resistance to complement and Ab
What histocompatibilty genes can be matched between transplant donors and recipients and how does this affect outcomes?
HLA A/B/DR can be matched, improved outcomes with match
why are MHC-compatible grafts sometimes rejected?
b/c MHC is not fully sequenced between donors and recipients, so there still may be a mismatch
how does donor viral infection affect recipient immune response?
if the donor has a virus (ex: CMV), this virus may be recognized as an alloantigen –> alloimmune response
Describe how crossmatch works in context of transplant immunology
recipient serum is applied to donor cells to test for C’-mediated lysis and binding by activated cell sorting
what does a positive crossmatch indicate in terms of transplant compatibility
positive crossmatch predicts hyperacute reaction therefore absolute CI to transplant
How does panel-reactive antibody test work in the context of transplant?
recipient serum is applied against a panel of cells/antigens that represents lots of donors –> tests for antibodies –> predicts degree of difficulty in finding a negative crossmatch donor
How does ABO blood type affect transplantation between donor and recipient
you match it when possible
what is the MOA of induction therapy for transplant and when is it administered?
administered at the time of transplant, its antibodies to deplete / block T-cells (thymoglobulin, anti-CD3, anti-CD25)
what does induction therapy for transplant accomplish?
reduces ischemic / reperfusion injury, increases susceptibility to bacteria / fungi
Name three agents used for maintenance therapy
glucocorticoids, calcineurin inhibitors, and antimetabolites
what is the MOA of glucocorticoids in maintenance immunosuppression for transplant and give an example
regulates gene transcription, ex: prednisone
what is the MOA of calcineurin inhibitors in maintenance immunosuppression for transplant and give an example
inhibit protein kinase / phosphatase. ex: cyclosporine (Gengraf), tacrolimus (Prograf, FK-506), rapamycin (Rapamune)
what is the MOA of antimetabolites in maintenance immunosuppression for transplant and give an example
reduced de nove nucleic acid synthesis. ex: azathioprine, mycophenolate mofetil (Cellcept), leflunomide (Arava)
How do you treat rejection?
treat with increased steroids and Ab
why don’t calcineurin inhibitors work to treat rejection?
b/c they prevent differentiation of naive T-cells, so not relevant in the case of rejection
What are the two effects of induction of tolerance in transplant patients (experimental)?
1) eliminates mature lymphocytes and other hematopoetic cells by providing stem cells from transplant source = no allogeneic immune response. Downside - you would knock out immunologic memory. 2) inhibit costimulatory molecules (CD80, CD86, CD40)
What are the locations of B-cell development in the fetus?
fetal liver
what is the location of B-cell development in the adult?
bone marrow
when does B-cell development occur in the human lifespan?
continually develops through life
what is the MOA of B0cell activation
B0cell receptors are immunoglobulins that activate by binding to target and then secreting antibodies –> somatic hypermutation and isotype class switch recombination
what are the two types of B-cells a naive B-cell can differentiate to?
memory B cell and plasma cell
how do memory B-cells interact with T-cells
T-cell dependent, interact with CD40/CD40L to increase IgM and IgG. Also interact with CD8 to reduce antipolysaccharide response.
How do plasma cells interact with T-cells?
Naive B cells can be activated by T-cells to differentiate into plasma cells. Otherwise they are T-cell independent and react to ABO Ag.
How is immune response in plasma cels activated?
They are initiated by polyclonal activators (LPS) which stimulate B-cells through toll-like receptors
what patients have anti-ABO Ab and what is their presumed origin?
anti-ABO Ab are “natural” and universally present possibly 2/2 exposure to commensal bx with polysaccharide walls
what type of sequential B-cell activation takes longer - T-cell dependent or independent?
T-cell dependent takes longer b/c of sequential activation, therefore cant usu treat primary infection but creastes long-lasting Ab and memory
What are two mechanisms of B-cell memory?
relies on long-lived plasma cells in bone marrow or de novo generation of short-lived plasma cells from long-lived memory cells.
name four postulated mechanisms of long-lived humoral immunity
2/2 plasma cell differentiation from memory B-cells responding to: 1) persistent Ag; 2) polyclonal stimuli; 3) noncognate T-cells; 4) cross-reactivity to self
Define B-cell tolerance
absence of humoral immune response following adequate stimulus
What is the role of clonal deletion in development of B-cell tolerance?
eliminates self-reactive B-cells
What is the role of clonal deletion in development of B-cell tolerance?
eliminates self-reactive B-cells
What is the role of receptor editing in development of B-cell tolerance
low affinity self-Ag binding on immature B-cells, induces rearrangement of Ig genes from self to nonself
what is the host immune response directed at cellular transplants?
fed by recipient blood vessels therefore there is reduced Ab/C’-mediated injury
what is the host immune response directed at tissue transplants?
recipient Ab bind to donor blood vessels. Recipient vascularization can help shield graft. Ischemia can occur.
what is the host immune response directed at organ trasnplants
recipient Ab bind to donor vessels to a much greater extent than cell/tissue transplants
what is the timeline of hyperacute rejection?
occurs within 24 hours of transplant
how does hyperacute rejection present and what is its MOA?
p/w inflammation, interstitial hemorrhage, and thrombosis secondary to preformed antidonor antibodies binding to blood vessels and complement activation
what role do anti-ABO Ab have in hyperacute rejection
hyperacute rejection with ABO-Ab can depend on Ab-level and affinity/susceptibility to injury
how do livers, kidneys, and heart transplants compare in terms of susceptibility to hyperacute rejection and why?
livers are less susceptible than kidneys and hearts, possibly 2/2 differences in the sizes of vascular beds
what is the role of complement in hyperacute rejection?
complement activation mediates it, can sometimes be 2/2 unidentified lectin/alternative pathways reacting to endothelial antigens
how can you get hyperacute rejection WITHOUT preformed antibodies?
classic/lectin/alternative complement reacting to endothelial antigens
Describe the steps of crossmatch prior to transplant
1) combine donor lymphocytes with recipient serum; 2) if donor specific lymphocytoxic Ab present in recipient, will attack donor cells; 3) damage to donor cells will cause uptake of dye = positive crossmatch
what is the timeline of Ab-mediated rejection?
without immunosuppresion, can begin within 24 hours of transplant
how can Ab-mediated rejection occur in the abscence of Ab?
does not exclude Ab-mediated rejection b/c donor organ can absorb lotso Ab
how do pathologiests identify Ab-mediated rejection in transplant?
rely on C4d deposition in peritubular capillaries as evidence of Ab-mediated rejection
what is the pathophys a/w Ab-mediated rejection?
activated endothelial cells shed thrombomodulin and heparin sulfate –> express tissue factor and plasminogen activator inhibitor –> coagulation –> focal ischemia, endothelial cell injury, intravascular coagulation
how do you treat Ab-mediated rejection?
plasmapheresis, sometimes anti B-cel Ab
What is the MOA of chronic rejection?
2/2 repeated immune and non-immune injury and inflammation of graft
What is the name of chronic rejection in the kidney?
chronic allograft nephropathy
What is the name of chronic rejection in the liver?
vanishing bile duct syndrome
What is the name of chronic rejection in the lungs?
bronchiolitis obliterans
What is the name of chronic rejection in the heart?
accelerated arteriosclerosis
what should you suspect as the MOA of chronic rejection if you see C4d deposition?
humoral immunity
what is the treatment of chronic rejection?
no tx
Define accommodation in terms of transplant immunology
acquired resistance of an organ graft to humoral immunity
what is the MOA of accommodation in transplant?
healthy organs can absorb anti-donor Ab. Xenografts/allografts with accomodation have protective/anti apoptotic agents
What types of transplants are susceptible to cellular rejection?
all allografts are susceptible therefore need to reduce cell immune responses
what is cellular rejection directed against and what cells mediate it?
directed against small blood vessels –> thrombosis. Mediated by cytotoxic T-cells (CD8), helper T cells, and delayed-type hypersensitivity (CD4)
what effect do CD4 cells have on blood vessels in the transplant?
causes edema in relatively uninjured blood vessels