Organ Transplant Exam #3 notes

Pray for the best and hope you get ovr a 95

Q? What are anastomosis and what are some of the challenges that come with it?

anastomosis: Surgical procedure for connecting two tubes (blood vessles)

Challengs: Preventing leakage, infection, aneurysm, fibrosis, narrowing, and clotting

• at the time when they started no antigoagulatns were avaliable

  • what methods are used: finer silk and finer needles

What are some of the ways small blood vessels are repaired. What are teh different types of mechaniss and know what they look like

• Hollow stents or other inner tubes with 2 cut vessels pulled over and secured

  • used glass tubes

  • ivory tubes

  • and magnesium stents (couling device

In what ways are large blood vessels. What are the advatntages , what are lateral anatomosis method

1. generally more successful than reparing small vessels

   1. uss lateral anastomosis

      1. over and over silk stretches to join two larege abdominal vessels

   2. advantages

      1. more successful than repairing small vessels

Large blood vessels repair methods: invagnation? what is it, what makes it useful.

invagination technique: placing part of one vessel inside of another

• femoral artery damaged by a gunshot wound

Who is alexis carel and what is the triangulation method of reparing large bloodvessles

alexis carrel

• considred father of modern vascular and transplantation surgery

• used better needles with much finer sutoring material

Triangulation

• hold vessel open

• make three sutures and pull to create 3 flat lines = 3 separate sutures

• do not penetrate the wall

What are some of Alexis carrels contributions to transplantation history. What is actual life and latent life and how does it play into transplantation? What developments can be attributed to him

1. Standardizd the use of strict aseptic conditions of surgery

2. used fine straight silk

explored methods of prolonging tissue survival outside the body

1. “Actual life” - culture at normal body temperature allows for normal cellular functions

2. “latent life” - culture at colder temperatures = less risk of infection and reduced metabolisms

Demonstrates the organs die at different rates

1. colder temperatures

1. he standardized the use of strict aseptic conditions of surgery

2. used fine straight silk

3. flusing with saline regulary

4. lubricaiton of threads

5. full penetration of vascular wall

6. and holding of smal vessels with clamps

Developments

1. the triangulation methods

2. the carrel patch

What is the carrel patch and what does it do? what makes it so effective

• methods

  • removal of a patch of the aorta and vena cava containing renal arteries

    • used to prevent severying of the full artery

  • it is less problamatic to fully penetrate the vascular wall

    • stiches are futher from the renal artery and larger vessels = can toelrate more fibrosis or clotting without disrupting renal blood flow

What are some of Alexis Carre’s faliures and what did it result in(hint hint pumping)

1. he attempted to ake perfusion pumps but it often resulted in infection

   1. helped developed a closed sterile pumping system

Why were kidneys the first major solid organ transplatnt choice

1. they were easy to access and least challenging surgically

2. patients did not depend on only on

3. live donors

4. chronic diseases were common

What are the major advantages of Corneal (the eyes) grafts and what do they do

Corneal grafts

1. no blood circulation = no lymphocite infiltration or graph rejeection

   1. since it is avascular, no major blood vessles to the cornea

2. allows for suffiecient donor tissue

3. major resistance by the public bc corneal grafts come from passed people but it became routine early on

What are some of the early attepts at immunosuppression

Radiation

1. total body radiation reduced antibody responses

2. radiation prolonged life of rat tumonr grafts = reduced innate and lymphocite infiltraiton

Benzol

• benzene used as an early immuno s uppresiont but stopped bc it was dangerous

  • exposure lower blood coutns and damaged bone marrow

  • affects white cells (suppressed antibody function)

  • casued lukemia

  • suppressed antibody formation

Nitorgen mustard

• used during the ward, used to depress antibody formation

• used as a poision in world war 1

  • resuts in low white blood cell counts, significant bone marrow changes, very weak immune system, reduced antibody formation

What is histocompadibility and how does it play into organt ransplation

1. histocompatability = siilarity fo antigens between donor and recipient cells

   1. ex. tumor from strain a mouse bearing antigen 2 would thrive in other mise also carying antigen 2 but is rejected by th rest

What casued the reuptake of transplantation in the us

• war (again), burns, surgery ect

• expecially areial combat they suffered suvere burns

What is and what is the significance of the second set experiment

female pateint given a skin pinch from her brother

• second set of skin pinch was applied two weeks later

• both skin grafts were rejected at the sae time but the second set was rejected faster = example of adaptive immune response streingth

• allowed for the assumption that immue responses were antibody diriven

• reduced the idea of homografts and started a new field in tissue rejection

What are some of peter medawar’s contributions to cell rejection methods? what is the freemartin experiments

What did peter medawar discover

1. all tissue could immunize against future skin grafts

   1. responsible antigens present in most cell sof the body

2. supported that lymphmocites are required for graft rejection

Fremartin experiments (used twin cows lol)

• realized all tisssues could immunize against future skin grafts —> responsible antiges are present in most cells of the body

  • results = all twins accepted skin grafts from eachohter = shoed immunoligcal tolerance can be induced

  • later experiments showed that you can induce immunoligal tolerance to an allogenic graft

what is mosaicism and does it relate to graft rejection

• it was found that shared blood types = suggested that fetuses have an abiltity to recognize all tissue presnt during prenatle development as self

• he used blood. type expeiiments for early induction efforts = induction of immunological toerance to an allogenic graft

What is chimerism and what is adult to;erance

Typically when you insert biological dna or smt from one thing to another

• ex donor bone marrow from different people to incorperate into a recipient body

Adult tolerance: only skin grafts from strain of donor marrow could surivive (when donor bone marrow exists)

• a state where the recipient’s immune system accepts a donor organ without requiring lifelong immunosuppression, while maintaining the ability to fight infections.

Describe some of the early methos of histocobalitbility testing

1. normal lymphocyrte transfer set

2. irridated hampster test

3. third man test

1. normal lymphocyrte transfer set

   1. inject lymphocytes from donor into skin of recipent and monitor for minor hos vs graft response

2. irridated hampster test

   1. injectino of lymphocites and apcs from one bone doro and recipent into the skin of irridated hampsters and cehkf for an immune response

3. third man test (dangerou)

   1. graft heathly vounteer with recipient skin graft, next you take recipient family skin (donors) and graft it to the same volunteer, see if there is a second set style accelerated recetion = indication of similar antigens between the recipient and donor.

   2. Tissue (usually skin) from Donor A is grafted onto a Third Person (Person C).

   3. Later, tissue from Recipient B is also grafted onto Person C.

   4. If the second graft is rejected very quickly, it suggests Donor A and Recipient B share similar histocompatibility antigens (HLA).

      1. risky bc could make immune repsonse stronger or srpead disease

      2. sensitizes the imune sytem = exposure to frogien HLA antigens

         1. causes the production of memory t cells and antibodies against those antigens

      3. increase risk of future graft rejection

      4. accelerated hyperacute rejeciton

   5. unnecesary imune risk

      1. the third individual does not ned a transplantation so they are just at risk for nothing

What are some of the disadvantages of early appraoches to histocompatability

• Skin graft can sensitize patients to kidney transplant & accelerate rejection

• Potential to transfer disease (increasing transmission of hepatitis B in dialysis units at this time…)

• Tests were too slow relative to urgency of transplantation

• Couldn’t scale to large number of patients

What is the plastic revolution and how does it play into translant history

1. cell isolation, cell culture, and ability to stuyd cells in vitro = allowed for this

2. allowed ofor the developent of techniques for motering cell killing and mgiration throughtout the body

   1. alllowed for the ability to frieeze, store , and revive cells

What are the split thickness skin grafts and what were the nature of the first two skin grafts

1. developed by james barrett brown

   1. it is a skin graft invoving the epidermis and portion of the dermous

      1. thicker than previous grafts only including the pideris

      2. first successfull skin graft between identical twins (syngenic)

What is te bonnoer vs oran place and how did it pursh for mrore patoient rights and protections around surgery

1. boy was convinced to undergo procedure without his mothers concent and surgeyr ws a failerur

2. this estaglished legal precedences that infromed rconcent was required for surgyer and parental consent is required for childre

• Damages for assault and battery

• Boy was convinced to undergo procedure by his and his cousin’s aunt

Boy’s mother was home ill and never consulted → established legal precedent that informed consent is required for surgery & parental consent is required in the case of children

Outline the main accomplishments of the Boston Group and identify one or more unethical practices they engaged in.

1. team of 5 surgeions who undergo extensive underground transplant research at brigham and women’s hospital

Achievements

• sucessfully transplanted allogenic skin grafts to ww1 piolets

• First attepts of immunesppressive methods using

  • ACTH, cortisone, and testosterone

  • used blood type compatability too

• early immunosuppresive irridation and radiaition methods used

• breakthroughts in early experimental kidney transplantation in humans

• demonstrated temporary kideny graft was possible

• developed the used of pre-treatment dialisis to keep patients alive

• first successful kideny transplant between idientical twins = transplantation when imune rejection was avoided

• helped advanve bone marrow/hemapoetic stem cell transplantation and early immune tolearnce induction (human chimerism)

Unethical practices

• did experimental transplatation in secret without proper oersight or supervisors

• delayed reporting negative results due to fear of criticis

• used organs from cadaves or vulneraable children = no infomed consent

• high risk experimental procedures with many casulties

• they lacekd transparencey, oversigth, and ehtical safeguards

What allowed for the first succesfful kidney allograft

fraternal twin brothers

recived toatl body irridation but no other imunosuppresison

allowed for full recovery = more reserch into immunosuppressors

What do you nee dto know for allografts to succed, how do twins relate to transplants

1. surgical techniques were succesful but imune rejection was a hard hurdle to pass

2. transplants by twins were generaly the only succsffull ones without immuno suppression

3. you need ot know the follwoign things to considre imuno suppresssion

   1. mechanims of rejction

   2. how to match patients and donors

   3. and effective imuno suppression efforts

Tolerance mechanisms: Central tolerance vs peripheral mechanis. What is invovled? what are th

Central tolerance: negative selection “Clonal deletino” of self reactive lymphocites in central lyphoid organs

• T cells: thalamus

• B cels: bone marrow

Peripheral toelrance; Various mechanism for deleting or inacivating self-reactive lmphocites outside of central lymphoid organs

How do you break Central Tolerance mechanisms?\

1. T cell negative selection is a sepctru = not all alutorective t cells are deleted

2. developing B cells do not se all self antigesn (bc in the bone marow you are not exposed to evrything)

   1. not all self reactive B cells are deleted

What are some of the tolerance mechanisms? how are t cells used (special type)? What mechanims and signals are needed? What are the results if this happens or doesnt happen

T cells

• self reactive T cells become regulatory t cells in developent

  • iTregs = t cells specifc to self or healthy antigens differentiate into regulatory t cells thorughout the lifespan

  • Tregs: bystandur suppresion, infections tolerance, and IL-2 consumption

Ntregs = natural t regs

• develop in the thalamus

Itregs = indcued t regs

• derrived from native CD4+tcells in the periphery

Three signals are need for tolerance

1. antigen

2. costimulation

   1. without this = anergy = inactivation

3. cytokines

innate immue system determines self/nonself and healthy and dangerous cells

What are tthe checkpoint molecuels for tolerance mechanisms

• Activated T cells express inhibitory molecules

• CTLA-4: agonist of B7 molecules (blocks CD28 signalling)

• PD-1: binds to PD-L1 and PD-L2

  • Pd stands for program death ligand

  • two distinct ligands that bind to PD-1, transmitting a signal that inhibits T-cell activity, allowing tumor cells to evade immune destruction

  • good for maintaining immune homeostasis by preventing autoimmunity, but bad in the context of cancer and chronic infections

    • PD-L1: expressed by wide variety of cells

      • used by tumor cells to inhibit T cell responses

    • PD-L2: expressed by antigen presenting cells during inflammation

      • Involved in immune reg

• Negative feedback to prevent overactivation of T cells

  • Exploited by pathogens & cancer cells → checkpoint inhibitors are a common and effective cancer treatment!

  • Stimulate expression to prevent organ transplant rejection?

What are other ways tolerance is broken? molecular mimicaray? antigen presentation? Damps

• Molecular Mimicry (cross reactivity): dangerous antigen looks like self antigen

• Antigen presentation of healthy self and dangerous non-self (viral envelope) → response against healthy self

• DAMPs can come from sterile tissue damage → activate innate response against self

What are the 3 stages of graft rejection

1. Hyperacute Rejection (Minutes to Hours)

2. Acute Rejection (Weeks to Months)

3. Chronic Rejection (Months to Years)

Describe hyper accute rejeciton and use the blood vesssel as an example. What happens? what are the mechanims involved

1. occurs when blood does not match the host body

   1. allontigens and blood group antigens cause mismatch = rejection by natural antibodies (MHC)

   2. antibodies bind to the endotheilum and triegger complent, clotting cascade and immune cell recruitment

      1. causes plaque build up and artherosculrosis in the blood vessle

   3. mostly problematic folliwng other blood trasfusions, transplants, or xenografs

How are damps related to accute graft rejection? what happens? what is the overall mechanism

during surgery blood and lymphatic vessels are severed = very traumatic

• tissue is breifly starved of oxyggen = decrease in ph

• sudden reprofusion = additionalinjry

results in the relase of DAMPs = prr activation = inate activation = adaptive immune response to damage

What is the human leukocyte antigen? what is the major histocompatability complex? what dos it incod? whats the difference between MHCS

• Major histocompatibility complex (MHC): that thing that presents antigens!

  • “H2 region” in mice encodes MHC-I and MHC-II

• Human leukocyte antigen (HLA): the human MHC

  • most polymporphic genes of human genome

  • HLAs are the human MHCS

MHCs

• 1 has 3 alphas 1 beta

  • HLA a-c

• 2 has one half beta and one half alpha

  • HLA-DR, DQ, and DP

What are the different types of allorecognition? direct, indirect, and semi direct pathways. what does it involv, what are the receptors? what are they responsibl for

Direct pathay

• Donor APcs connect and prosent dornor antigens to host t cell

  • uses hla/peptide complex

  • results in activation of large polyclonal T cell response

  • responsible for acute rejection

• indirect =

  • recipient apc presents donor antigen using its own presention receptor to recipent t cell

  • Recipient apcs present donor antiges (both MHC and minor self antigens) on self to t cells = responsible for chronic graft rejection

• semidrect pathway

  • recipent apc obtains donor MHCs from plasma membrane trasfer

  • Semi-direct allorecognition relates to acute rejection because recipient antigen-presenting cells (APCs) acquire and display intact donor MHC molecules, activating T cells that damage the graft.

  • they present forgien MHC: antigen to T cells = assive polyclonal response

    • robust, rapid, polyclonal response

  • responsible for acute rejection

What is the mechagnism of direct allorecogition? how does it relate to cross reactivity

1. TCRS are specific to MHC: antigen complex not just the antigen

   1. self and nonself mhcs are pretty similar but mosty differ in antigen binding rations

2. Cross reactivity:

   1. the same TCR can reconize different antigesn on different MHCs (ie slf or donor mhc)

   2. Lots of foreign MHCs & minor alloantigens = lots of distinct MHC:antigen complexes

ex: TCR can bind to the antigen presenting MHCs of both self and donor apcs for recogntion

• 1-10% of T cells in an individual can directly engage intact foreign MHC

• Highly diverse polyclonal adaptive immune response is immediately activated

What is the binding affinity of direct allorecognition

Foreign MHC may bind TCR with higher affinity → more efficient activation

What is cross matching, ABO incompatable transplants, and Xenografing in relation to hyperacute graft rejection? What mehtods are used to help with ABO inompatable transplants

• Cross-matching: test whether donor & recipient have antibodies reactive to the other

• ABO Incompatible Transplants: now possible with preconditioning 

  • Plasmapheresis: Remove plasma (contains antibodies) from blood

  • Immunosuppressive drugs

  • Especially possible in livers, which seem less sensitive to hyperacute rejection (for some unknown reason)

Major problem for xenografting

• Host cells express complement protein competitors & proteases to protect themselves

• Complement-regulatory proteins work less effectively across species barriers

• Current attempts to genetically modify pigs to be less susceptible to hyperacute rejection from human recipients!

What is an example of direct and semidrect allorecognition in the kidnesy? how does this activate iune repsonses? how does this play out longtrm? what are passenger leukocytes

1. passenter leulocites = donor dendritic cells that travel to lymph

   1. passenger leuokocytes eventual die off = lower direct and smidrect allorecognition risk and acute rejection risk (direct)

   2. some long lived tissue residnt cells (tr macrophages, innate lymphoid cells, memory cells, ect) can still persists (Semidirect)

What is chronic graf rejection? how doesi schemia reperfusion injuries relae to this

chornic graft rejection

• specific immune alloreactivity and/or non-immune injuies

• viral infecitosn resulting from immunosuppression can contribute to this (similar to autoimmunity)

recurrence of teh same disese that destroyed the og organs - note there are different responses in different organs

Ischemia reperfusion injuries; provid dampsat tie or transplant to start innate repsonses —> Adaptive immune response) induces crhronic response

What is chronic allograft vasculopothy? donor specific antibodies (DSA’s) and how does it relate to chronic graft rejectionq

Chronic allograft vasculopathy: chronic arteriosclerosis of graft vasculature resulting in reduced blood flow, fibrosis, and atrophy

• major component of chronic graft rejection, especially in the kidney and heart transplant

develops DSA’s = aloreactive t cell to graft vascular endothelium (alloreacive = reacting to forgein bodies)

• endotheilial injury = immune infiltraiton into allograft

• some immunosupresive drugs cause vascular injury

What is graft vs host disease? what is the mechanism? how do you resolve this

Bone marrow transplant is generally used to treat leukemias and lymphomas

• rejection of recipient tissues by donor immune cells followign bone marrow

  • 1impacts the skin, intestines, and liver (alrady damaged by chemotherapy and raidation)

  • thats why attempts at inducing adult tolerance didnt go well

mechanism

1.. allogenic hmatopoetic cell transplant contains mature and memory t cells

t cells circulate in blood to secondary lymphoid tissues = alloreactie cells interact with dendritic cells and proliferate

effector cd4 and cd8 t cells enter host tissues and cause injuy

What are the different types of T cells 8 and 4. what are their differentations

• CD8+ Cytotoxic: mediate cell killing during rejection

  • May promote Th1 response

• Th1 CD4+: generally promote rejection

  • Increases CD8+ function, activates macrophages, recruits T cells

• Th2 CD4+: generally protective

  • Antagonizes Th1 responses, stimulates wound healing

• Th17 CD4+: generally promote rejection

  • Antagonizes Treg responses, recruit neutrophils

  • inflammaiton, attachsk mucosal sites

Tregs: critical for establishing graft tolerance

What are b cells and what type of graft rejection are they typically responsible for? what do they produce? what can be done to help promote tolerance

1. they produce DSA’s -Donor specific antiboidies = prootes graft rejection

   1. genearlly hyepracute and chronic

2. they support t cell differentation and memory formation

3. indirect antigen presentation = indirect allorecogntion

4. accommodation: physiological changes that allow regeneratino of tissue function after grafting

   1. 30 persent of pateitns generate DSAs without other signs of rejection

      1. ex class switching from IgG3 to IgG2 for less efficeint complement activation

5. subset of regulatory B cells (bregs) help promote tolerance

What are neutrophils and how do they realte to graft rejection? what do they do what activates the

= damps (ischmia-reperfusion injury) relase = tissue resident myeloid cell actiaiton = recruitent of neutorphils

1. generally pro-inflammatory (promotes rejection)

   1. inflammatory cytokien production skews APCs to induce Th1 and Th17 t cell phenotypes

      1. th 17 recute neutrophils chronically (positive feeback loop)

2. may provide costiulatory signals to T cells in graft

3. one neutrophil su bset may be later involvd in revascularization

Phagocytes. What are they and how to they relate to rates of graft rejection. What is the mechanism behind that? what signaling molecule is beign used

1. Damps may not be sufficeint for activating the innate immune system during graft rejection

   1. allogenic, but not syngeneic grafts in mice induce monocyte maturation or innate cell activation

   2. innate cells must be recognizing non self rn (how? phagocytosis eat me eat me)

1. CD47 = dont eat me signal = signals that prevents phagocytosis of healthy self cells

2. Sirpa on phagocytes bind to CD47 on other ells = inhibits phagocytosis x

   1. one is missing = its eaten

What is the function of cd47 and sirpa? how do differneces alter binding affinity

1. used to recognize CD47 signaling to preent phatgocytosis

   1. highly polymorphic between individuasls

   2. differences in SIRPa between individuals = differencs in binding intensity = differences in myeloid cell activation

      1. not alwasy functional due to bidning affinity

   3. myloid cells may mature, traffic to lymph nodes, and activate t cells even if activated

What are the function of macrophages? do they help or prevent graph rejection

1. they are pro inflamatory, pro-wound healing, pro-resolving

   1. pro inflamatory: phagocytose bacteria and dead cells to attract immune cells

      1. bad for grafts

   2. pro wound healing: have roles in ECM formation and wound closure

      1. mediu, for grafts

   3. pro-resoliving: they secrete mmps for atrix reoeling

      1. pro graft rejection

2. type 2 machrophages promote wound healing = necessary for neovasucalirzation and graft repair

What are some of the characthersitcs of innate lymphoid cells

1. lyphoid cells with innate charachteristics

2. they are generally tissue resident

   1. nk cells circulate with them as well

   2. they are involed in tissue homeostasis and have specific function dependent on the tissue

   3. they are often protective but not alwasy

   4. can be donor or recipient derrive = some donor dervied cells may stay longterm

What are some of the innat lymphoid cells and what are their function. different types of nk cells, gama cells, ilcs, nkt cells

• NK cells → analogous to cytotoxic CD8+ T cells

  • activated independent of antigen

  • integrates many activating and inhibitory signals = quantity and quality of donor cell signals

  • is donor and tissue stressed = morea ctivation

  • the target cell, whether the MHC1 is signaled or not tells the nk cell to kill it or not to kill it

• ILC1/ILC2/ILC3 → analogous to helper CD4+ T cell subsets

  • il2 = th1, il2 = th2, il3 =th17

  • they are activated independent of antigen

• NKT & 𝛾ẟ T cells: CD1-restricted lipid antigen recognition

• Type 1 NKTs → analogous to CD4+ T cell subsets

  • often activated independant of antigen but can be activated by lipid antigens

• Type 2 NKTs: mostly immunoregulatory

  • generally activated by lipid antigens

how are NK cells educated? describe both of their roles in graft protection and rejection

Protective mechanisms

Nk cells learn waht self is via MHC an inhibitory olecules during development

• Recipeitn NK cells recognize missing self on donor apcs = hinders direct allorecognition (protective)

  • non-self MHC may act as an activating lignad for NK cells

rejection mechanisms

1. non-immune cells in the graft dont express recipeint-MHC

Mechanisms that mediate rejection

• non-imune cells in the graft also doesnt express recipient-MHC

• Donor-specific antibodies (DSAs) against vasculatore can trigger ADCC

  • other mechanisms may also be involved = imbalance and activating and inhibitory receptors

What are the different types of NKT cells and are tehy protective or adverse for grafts

• NKT cells are generally protectiv

  • they are beneficial in pancreatic islet, cardiac, the liver, and the kidney

• apcs and injured cells upregulate CD1d= damp production + lipid antigen presentation = nkt cell activation = anti inflammatory cytokine production = immunosuppresion

Type 1 NKT cells

1. nkt1s = proinflammatory and promote ischemia-reperfusion injury, can induce cell death

2. NKT2s and NKT10s = immunosuppresive cytokin production = tolergenic

Type 2 NKT cells

• they inhibit type 1 = reduced macrophage and neutorphil accuulation = reduced ishceia-reperfusion injury

  • Similar to CD4+ subsets

γδ T Cells. What do they do and do they promote rejection or torance

• can mediate both depending on the tissue and circumstances

• can behave like a Treg or a Th17 cell depending on the situation

• Th-17 like pheonotype = inflammatory cytokine produciton and neutrophil recruitment (promotes rejection)

• treg-like phenotype = antiinflammatory cytokine produciton and T cell inhibition = promotes tolerance

What makes liver transplants so succesful

1. they are constantly being exposed to environmental antigens from GI tract and spleen via the portal vein = generally tolerogenic area

2. imunosuppresive masures can be seased for some and some may be able to achive spontanious operational tollerance

3. they are highly regnerative = you can recive a partial liver from a living donor or a total liver from deceased donor

What immune cells allow for liver transplant protection or rejcection

Donor-derivd NK cells can persist for over a decade and are generally protective

• reduced pro-inflammatory and increased anti-inflammatory cytokine production

• inhibits T cells via PD-D1/PD-L1 axis

infiltrating recipeint NK cells may promote ischemia-reperfusion injury rejective

What are teh effects of the ILCs on lier transplants? protection or rejectin?

• ILC1s

  • Worsen ischemia-reperfusion injury (IRI)

• ILC2s

  • Induce type 2 (wound healing) macrophage activity

  • May contribute to chronic fibrosis - can lead to chornic graft rejection

• ILC3s

  • Protective against ischemia-reperfusion injury

  • May promote regeneration

• Most data comes IRI model of steatotic liver, limited allogeneic data

What are the effects of γδ 1 and 2 cells on liver transplants

• γδ 1 cells: generally immunosuppressive

• γδ 2 cells: generally inflammatory

• Spontaneous tolerance observed in recipients where γδ 1 > γδ 2

What are some of the charachteristics of bone marrow transplatns (HSC)

• you dont really ahve to take the bone marrow anymore

• G-CSF (granulocyte colony stimulating factors) produced by cells throughout the body to induce HSCs to movilize during homeostasis and inflammation

• 80% of bone marrow donationsa re now given thorugh a peripheral blood stem cell transplantation

What are the function of nk cells, gamma cells, and ILCS in bone marrow transplant. What is the mechanism

NK cells

• protect from graft vs host disease and promote graft vs host leukemia

• impare APC and T cell funciton

• ILC2s

  • Barrier maintenance

  • Induce anti-inflammatory myeloid cells (myeloid-derived suppressor cells, MDSCs)

• ILC3s

  • Recipient-derived ILC3s protect gut tissue from GVHD

  • Barrier & stem cell protection

  • Inhibit T cells

• γδ T cells may help engraftment & be protective against GVHD (conflicting data)

What are the stats for kidney transplants. What are the effects of NK cells, ILC2s and gamma cells

• About one third of transplants are from living donors

  • Better immediate kidney function & less risk of rejection from living donor

• Circulating recipient NK cells

  • Recruit neutrophils & kill renal tubule cells → exacerbates ischemia-reperfusion injury

  • Kill graft vascular cells via ADCC (donor-specific antibodies)

• ILC2s

  • Stimulate cell growth & survival → minimizes ischemia-reperfusion injury

  • Promote type 2 (wound healing) macrophage activity 

• γδ T cells

  • Recruit αꞵ T cells & cause renal tubule damage

What are the stats for intestial transplants? What are the efeects of NK cells and ILcs

• intestines house large an complex lymphoid tissue

• there is a substancial number of donor derived ILCs sustaind for years = gradually transitions to recipient derived ILCS

Most donor-derived ILCs are NKCls, ILC1s, ILC33s,

ILC1s may facilitate rejection

ILC3 and gama t cells seem protective

What are the stats for Lung Transplatns? What are teh effects of NK cels and ILCS

• Nk cells exacerbate iscehmai reperfusion injury but may also kill donor APCs

• ILC3 = tolrance

• ILC1 = protective

• ILC2 - recrut eosinophils = tolernace

• gama t cells = niflammatory (rejective)

Heart transplants what are the effects of ILC2, nk cells, and gamma bea cells

• Difficult to study → limited samples, mostly mouse

• Most helper ILCs are donor-derived ILC2s → little infiltration of other recipient helper ILC subsets or precursors

• NK cells

  • Accelerate both cellular- and antibody-dependent graft rejection

  • Contribute to vasculopathy

• γδ T cells generally inflammatory

What are islet transplants (pancreatic) vs whole pancreus transplants? what are teh differences in procedure and risks? What are teh effects of nk cells, ilc2s and gama theta t cells

1. used to treat patients with type 1 diabetes

Can be either a major surgery or just islets

• Islet transplant: lower surgical risk, successful at eliminating severe hypoglycemia & glucose changes but may require multiple donors to achieve insulin independence

Whole pancreas: higher surgical risk, but higher likelihood of insulin independence after single transplant

• NK cells generally promote tolerance, likely by killing donor APCs

• ILC2s generally protective & can induce myeloid cells to secrete retinoic acid, which activates insulin secretion

• γδ T cells may be protective

How does microbione impact transplatnation

1. micorbionme at mucosal sites (lungs, gut, skin eyes, ect) are ky to tissue homeostatsis both locally or systematically

2. recipeint receives donor microbiome of mucosal organs

   1. changes dynamically following transplatnation = local and sytemic physiologicy can be impacted

      1. microbial communities and metabolites produced = behavior of tissue and sytemic cells (both immune and nonimmune)

      2. ability and metabolism of immunosuppresive drugs

   2. can affect transplanatation outcome (tolerance and rejection

MHC and HLA diversity - What makes them polymorphic, what parts changes,

1. MHC proteins bind a restricted number of antigens based on their structure

2. HLA alleles are the most polymorphic genes of a person (humans are 99.9% identical to eachother)

   1. its a 3 domain protein with 3 alpha helixes and beta sheets

3. Broad antigen coverage within the population to poulation-level protection

What are the different types of HLAs and which part differentiates them

• HLA class I: HLA-A, HLA-B, HLA-C

  • >28,000 known alleles

    • they differentiate in their alpha chains but constant beta domain

• HLA class II: HLA-DR, HLA-DQ, HLA-DP

  • >12,000 known alleles

  • Separate genes for alpha (A) and beta (B) chains

• Non-classical HLAs: HLA-E, HLA-F, HLA-G

  • >500 known alleles

How does HLA match? What are the most importaint chains of hlas? Where are the Gene locuses, the serological group, designated allele, and genetically distinct area: HLA-a*01:01:01:01

Most important = HLA-A, HLA-B, HLA-C, HLA-DRB1 (Beta cahin 1 of HLA-DR)

1. rapid in depth sequencing of HLA genes at nucletide level

2. hla genes with similar reactivity to certen sera were grouped

3. Genetically dsing area

   1. they are genetically distinct but phenotypically identical alleles

      1. noncoding dna changes or those that dont result in differnt amino acids

How are HLA genes distributed from parents? How are HLA matching happen per parents? what are the ratios between siblings

1. 1 hla from each parent is distrubuted both HLA 2 and HLA 1

Parents and children

• Half-atch

Full siblings

1. 25 chance of perfect match

2. 50 haploidentical

3. 25 chance of no match

Crossing over happens (1%) —> reare to get new haplotypes within family

Chance of an exact match with unrelated donor: <1 in 100,000

What is linkage disequilibiru? What does it mean with HLA matching

1. Linkage disequilibrium: Some combinations of HLA alleles are more common than others because of mechanism of inheritance

   1. not necessarily matching 8 genes independently

   2. Linkage disequilibrium means that certain genetic variants tend to be inherited together more often than expected by chance.

      Why this happens

      Genes or genetic markers that are physically close together on a chromosome are less likely to be separated during recombination (crossing over) in meiosis. Because of this, they often travel together from parent to child.

2. some haplotypes are more common = easer for some recipients to find donors thatn others

note that databses skew towards white people of european descent

What are the different types of HLA matching in different organs: Bone marrow, kidney, heart and lungs, liver, and cornea

Bone marrow: requires strict matching to prevent graft-vs host disease

Kidney: HLA matching is used becuase patients can remain on dialisis for long periods of time

Heart and Lungs: frequently ismatcehed; would benefit from bettter HLA matching, but trnasplatns are. urgent and organs are limid

Liver: not currently clinically considered because liver is more tolerogenic but research suggest HLA matching could be beneficial

Cornea: not requried (no vascularization so its not needed)

• improved immunosuppresion protocas are bridging the gap between matched and mismatched graft survival

What are the effects of minor Histocompatability antivens on HLA matching? when are HLA matchs 100%? When is immunosuppression ecessary

• no perfect matching unless identical twins

  • you ned immunosuppresion is essentail for everyone else

Minor histocompatability antigens: antigens that are different between recipeint and donor are not HLA

• Y chromosome genes transplanted into an XX recipient are foreign

• Mostly autosomal & mostly unknown

• Reject more slowly than HLA mismatches

What are some challengs to HLA matching

• Some haplotypes are more common than onters = there may not be many mathces avaliable

• some transplants are too. urgent = no time to wait for a perfect match

• even perfect HLA match is allogenic (aside from identical twins) immunosupprefsion is essential regardless

What are the results of early high does radiation studies

• high level radiation exposured resulted in repressed bone marryow, low white and red blood cell counts, increased chance of infection

• bone marrow transpalants from any strain (chimerism) could restroe functioning, but only skin grafts from the donor strain would be tolerated

  • thre were attempts to induce adult tolerance but that resulted in graft vs host diease

What were the conditions for the first succesfful kidney allograft

• fraternal twins, oner eicived total body irridation but no other immuno suppresion

  • most likey benefitted from HLA matching

What is high does readiation used for an dnot used for

NOT used for…

• General immunosuppression

• Inducing chimerism or adult tolerance

Used for…

• Treating blood disorders (especially leukemias & lymphomas)

  • Ablating recipient bone marrow prior to receiving a bone marrow transplant

What is tolerance vs immunosuppression

The Ultimate Goal:

• Tolerance: immune system recognizes graft as healthy/self and does not attack it

But beggars can’t be choosers…

• Immunosuppression: immune system recognizes graft as dangerous/non-self but is unable to effectively reject it

  • Also less able to reject things like pathogens and cancer cells…

What are some of the early immunosuppression methods and what are their drwabacks? Benzol? Nitorgen mustard

1. benzol.

   1. usd as an industrial sol;ivent in the late 19th centrury

   2. stopped when learning it casues leukimia

2. Nitorgen mustard

   1. used as a poison during WW1

   2. used experientally to treat mous and human lymphomas and leukimia but difficult to used

What is 6-mercaptopurine (6-MP)- early immunosuppresision methods

1. used as a potential suppressant

2. chemotheropy drug that cuases bone marrow suppression

3. more predictable effects tahn random conntinous ise = could extend survival of skin grafts survival

4. iniital use were a faleure b/c the patients it were used on all died

What steriods were used during WW2 and what did they do: Cortisol

1. Cortisone was initaually used to counteract. hypoxia so pilots could fly higher at altitudes

   1. war use was doubtful btu seen to have other theraputic benifits

      1. Used to treat arthuritis

      2. it reduces antibody functions and allows grafts to last onger even afther withdrawl

      3. results wer inconsistent and not dramatic enough for continued research

What is thomas starzl’s contribution to organ transplantation resaerch. what steroids did he use

Azaathioprine and Prednisone

• used together improved graft survival in dogs (especially in the liver)

• he used studies in the liver = less powerful rejection and occasional spontaneous reversal of rejection

• rejection seen only with azathiroprine but uses of predisone fixies that

• reccomended flusing and cooling of donor organ

His contributions

• he is considered the father of rogan trasnplantations and his protocaol became standard for the liver kindey and heart for 32 decades

• new transplantation centers

What was the order of the first transplantations. waht came first waht is most recent

look at diagram

How do you treat chronic graft rejection? what is usually seen

• steroids

  • need for new protocols for chronic care

• Chronic issues:ucommon infections (

• Chronic issues: uncommon infections (usually controlled in immunocompetent patients), reactivation of infections (tuberculosis, herpes, CMV, etc.), vascular stenosis at sites of anastomosis

• Chronic side effects of steroids: poor wound healing, diabetes, pancreatitis, gastrointestinal hemorrhage, muscle loss

• Need to balance risk of graft rejection with risks associated with treatment

What are the steps to. modern day intervention

• Induction

  • Immediately after transplantation to prevent acute rejection

  • Not for long-term use

  • Includes: OKT3, Basiliximab, and others

• Maintenance

  • Before, during, and/or after transplantation for long-term maintenance

  • Includes: Prednisone, Cyclosporine, Tacrolimus, Azathioprine, Rapamycin, and others

• Anti-Rejection

  • Treating acute rejection episodes during initial post-transplant period or later follow-up periods

  • Same as induction drugs

What are the steps to modern immunosuppression. Nechanisms - draw it out

1. they inhibit broad general inflammatory gene transciirption

   1. sterridos (prednstone)

2. target T cells for destruction

   1. anti CD3

   2. Alemtuzumab

3. Prevent T cell activation and proliferation

   1. Belatacept (synthetic CTLA-4)

   2. Basiliximab (IL-2R antagonist)

   3. Mycophenolate & azathioprine (cell cycle inhibitors)

   4. Cyclosporin A & tacrolimus (Ca2+ signalling inhibitors)

   5. Sirolimus (“rapamycin”) reduces IL-2 signalling

1. Provide at least two examples of how World War II impacted transplantation research. Consider impacts during and immediately following WWII (the Cold War Era).

• 1939 - 1945

• Increased mechanization of warfare → aerial combat

• Fighter pilots often suffered burns from engine fires located in front of cockpit

• ~4,000 aerial burn cases alone in France & Britain

• Large number of burns during naval ship sinkings

• Required emergency care & plastic surgery

• Britain prioritized the study of burns

Cold war

• competition between soviets and the us

• fear of nucelar war = increased reserach into the effects of radiation and radiation exposure

• increased intrerest in surgical techniques and developkent