mod 2 slide 2 (solid organ transplantation & HSCT)

what are the 3 components of organ transplantation?

• organ, tissue, or cell

• transplant (nonself, self)

• rejection

solid organ transplantation (SOT)

• new advancements in surgical techniques have allowed for more efficient and refined multi-organ procurements with minimal complications and decreased ____ ____ ____

• immunosuppression therapy has also seen advancements with the expansion of immunosuppressive protocols to dampen the host immune response and improve _____ and ____ ___ ____ ____

• the field of SOT faces new barriers, most importantly the expanding demand for SOT that is outpacing the current supply

• ______ protocols have been developed in an attempt to address these concerns

• ischemic injury events

• short and long-term graft survival

• allocation

solid organ transplantation

• the transplant of an organ or tissue from one individual to another (graft) of the same species with a different genotype is called a(n) _____

• the transplant between individuals of different species is called a(n) ______

• where do allografts come from?

• allograft

• xenograft

• cadavers, living-related, and living-unrelated donors

organ transplantation and rejection

• kidney transplantation is the optimal treatment for patients with what? — who would otherwise require dialysis

• people who require a new kidney have ______ and/or _____ as a cause of chronic renal failure and ESRD

• patients with ESRD are at dramatically increased ______ risk compared with the general population

• ESRD

• HTN and/or diabetes

• CVD

organ transplantation and rejection

• worldwide, CVD remains the leading cause of what?

  • what are also major causes?

• the new kidney is transplanted into a _________ neighborhood

• transplanting an organ/tissue from donor or recipient results in immune system responding in the normal fashion… attempts to _____ _____

• death with a functioning graft (DWFG)

  • infection and cancer

• pro-atherosclerotic

• destroy non-self

organ transplantation and rejection

• solution: _____ the immune system — this must be done for a lifetime

• many immunosuppressive agents increase risk for ____

• ____ and _____ are 2 major barriers to successful organ transplantation

• suppress

• CVD

• infection and rejection

MHC = HLA — huan leukocyte antigen

• ____ represents a gene product that allows T cells to interact with cells presenting antigens (APCs)

• MHC is the most ______ system in the body, which makes it very unlikely that 2 individuals will express identical sets of MHC molecules (graft/transplant rejection)

• what type of cells have MHC?

• what is it also referred to as?

• > 41,000 HLA alleles

• most polymorphic are the -A, -B, -C (class I) and -DP, -DQ, and -DR (class II)

• these 6 HLA alleles commonly used for what in transplantation?

• on what chromosome?

• MHC

• polymorphic

• all nucleated cells

• HLA (human leukocyte antigen)

• matching

• human chromosome 6

haplotypes and HLA

each set of HLAs is referred to as a ____ — where do we get these?

• due to the inheritance patterns, it is possible to determine the probability of sharing HLA types with a ____

  • you have a 25% chance of being HLA identical, a 25% chance of being completely non-identical, and a 50% chance of inheriting ½ haplotype with your siblings

• odds go ____ exponentially with everyone else in the world

• HLA matching generally uses HLA-___, -___, and -___ alleles (6 match system)

• some agencies use 10 match system — ore difficult

haplotypes — one form each parent

• sibling

• down

• A, B, DR

what is a balancing act between capturing the benefits of a well-matched transplant and diminishing the problems associated with achieving that transplant

transplantation

C34+

• what is used to treat patients with hematological malignancies, such as non-hodgkin’s lymphoma and multiple myeloma, and to reconstitute hematopoiesis following high-dose chemotherapy — usually autologous (stem cells form own patient) or allogenic (donor)

• what is the ultimate goal?

• although a small number of hematopoietic cells circulate the peripheral blood at all times, _____ is necessary to drive sufficient numbers of hematopoietic stem cells from the bone marrow to peripheral circulation, where the can be harvested (collected) by ______

• what eradicated the cancerous patient immune cells using a combination of high-dose radiotherapy and immunosuppressive drugs such as cyclophosphomide after stem cells have been harvested?

• hematopoietic stem cell transplantation (HSCT)

• to repopulate the bone marrow with a complete lineage of hematopoietic stem cells with minimal burden to the patient

• mobilization; apheresis

• myeloablative conditioning

hematopoietic stem cell transplantation (HSCT)

what are the steps in order?

1. injections

2. mobilization

3. collection

4. storage

5. freezing

6. chemotherapy and/or radiation

7. stem cell transplant

8. engraftment and recovery

name the drug: first in class antagonist of the CXCR4 receptor — it blocks binding of SDF1a, thereby mobilizing CD34+ cells to peripheral blood

plerixafor (mozobil)

plerixafor (mozobil)

• indicated for use in combination with _____ to mobilize hematopoietic stem cells to the peripheral blood for collection

• CD34 is a cell surface protein cluster of differentiation found on surface of ____ ___ — it’s an adhesion molecule which keeps stem cells attached to bone marrow — one of many cell markers

• G-CSF

• stem cells

transplantation: IL-2 is the key

• the most important mediator of the immune response are what?

  • activation of these is accomplished largely by the cytokine interleukin ____

• what follows a sequence of events that involves detection of donor histocompatibility differences by the recipient’s immune system, recruitment of activated T cells, activation of immune effector mechanisms, and ultimately, leading to this?

• rejections are categorized as what?

• T cells

  • IL-2

• graft rejection

• hyperacute, acute, chronic

occurs within minutes to days of transplantation, is due to performed IgG antibodies in the recipient that react against antigens in the transplanted organ — B cell issue

hyperacute

occurs most frequently in the first 6 mos after transplantation and is mainly mediated by T cells, which infiltrate the allograft and cause tissue destruction — immunosuppressive induction therapy is mot effective in preventing this type of rejection

acute

graft function slow deteriorates and there is histologic evidence of fibrosis — for all organs, the pathophysiology of this rejection is similar: progressive hypertrophy of the arteries and fibrosis and eventual failure of the organ transplant — immunosuppressive maintenance therapy is effective → lifetime

chronic

induction vs. maintenance therapy

• what is the goal of induction therapy?

achieve immediate, profound immunosuppression for approx. 2 wks post-transplant to reduce the likelihood of hyperacute and acute rejection

induction vs. maintenance therapy

• what is the goal of maintenance therapy?

reduce the immune system’s ability to recognize and reject the foreign organ or tissue, while limiting toxicity — as the patient progresses further post-transplant the risk of rejection is reduced and the immunosuppressive regimen is tailored to the individual patient to provide lifelong suppression of the immune system with minimal toxicity

what is the best maintenance immunosuppressive regimen?

• although an adequate level of immunosuppression is required to dampen the immune response to the allograft, the level of chronic immunosuppression is slowly decreased over time (as the risk of acute rejection decreases) to help lower the overall risk of ____ and _____ — these risks directly correlate with the degree of overall immunosuppression

• the type of immunosuppression may also be varied to decrease the risk of developing _____ _____ ____, the most common underlying long-term cause of allograft loss

• immunosuppressive regimens vary among transplantation centers — selection is _____ specific

• what is required for all patients?

• infection and malignancy

• chronic allograft nephropathy (CAN)

• patient

• therapeutic drug monitoring

induction agents

• primary reason for the use of induction therapy, or intense immunosuppressive therapy at the time of transplant, is to avoid what?

• 2 classes — what are they?

• acute rejection

• T cell depleting agents

• IL2 receptor blockers

thymoglobulin

• is a purified ____ ____ ____ obtained by immunization of rabbits with human thymocytes (T cells)

• is indicated for the treatment of what in conjunction with immunosuppresion?

• in patients, profound T cell depletion is usually observed within how many days from initiating thymoglobulin therapy?

• should be used under ____ medical supervision in a hospital setting, and patients should be carefully monitored during the infusion

• most commonly used induction agent in the US

• IgG based polyclonals

• renal transplant acute rejections

• 2 days

• strict

basiliximab (simulect)

• binds specifically to IL2 receptor on surface of activated T cells — it’s a(n) _____ ____ ____

• competitively inhibits IL2 activation of T cells — what is it a critical pathway in?

• indicated for induction therapy in patients receiving what kind of transplants? — used in conjunction with immunosuppressants

• IV admin

• not considered as potent an immunosuppressive agent as thymoglobulin but has a much more _____ adverse-effect profile and is most commonly used in patients at ____ risk for acute rejection

• IL2 receptor antagonist (IL2 RA)

• the cellular immune response in transplant rejection

• kidney

• favorable; low

maintenance agents

• maintenance immunosuppressive therapy is administered to who?

  • why?

• adverse event profiles vary among drugs

• all transplant recipients

  • to help prevent acute-chronic rejection and the loss of the renal allograft

mTOR inhibitors (mTORi): sirolimus (rapamune) and everolimus (zortress)

• small molecules, oral admin

• clinical trials have demonstrated that everolimus, in combination with reduced-dose calcineurin inhibitors (CNI) like cyclosporine A or tacrolimus, is effective in preventing what?

  • the combined use of sirolimus and CNIs should be _____, because these agents potentiate nephrotoxicity, particularly when used in the early post-transplant period

• ______ has improved solubility, 60% greater bioavailability, a shorter half-life (28 vs 60 hours), and more rapid achievement of steady-state levels (4 vs 6 days) than sirolimus

• both metabolized by what? DDIs?

• what do they both require?

• when used as _____ maintenance, everolimus has been used in reduced dosages in different regimens in combination with CNIs

• rejection episodes and graft loss

  • avoided

• everolimus

• CYP450 3A4 — yes, DDIs

• therapeutic drug monitoring — narrow TI

• long term

calcineurin inhibitors (CNI)

• CNI suppress the immune system by doing what?

• long term CNI use may induce _____ _____, resulting in progressive graft dysfunction

• CNIs can also promote what? — which are the leading causes of premature death with a functioning graft

• preventing IL2 production in T cells

• irreversible nephrotoxicity

• cardiovascular events, infections, and malignancies

cyclosporine

• hirsutism

• gingival hyperplasia

• hypercholesterolemia

tacrolimus

• alopecia

• neurotoxicity

• pancreatic islet cell toxicity leading to glucose intolerance

• GI disturbances

both cyclosporine and tacrolimus

• nephrotoxicity

• HTN

• gout

• hyperkalemia

• hypomagnesemia

tacrolimus (prograf)

• the calcineurin inhibitor prograf is contraindicated with ____ ____

• should limit the amount of time spent in what and avoid what?

• are tacrolimus extended release tablets the same as prograf capsules or granules?

  • can they be substituted for each other?

• tacrolimus dosed in mg/kg body weight/day and based on adult/pediatric patient and type of organ transplanted.

• live vaccines

• sunlight and avoid exposure to UV light (tanning machines)

• no

  • no

tacrolimus (prograf) - box wanring

• what is there increased risk of?

malignancies and serious infections

mycopnenolate mofiil (MMF)

• prodrug that gets converted by _____ to mycophenolic acid (MPA)

• what type of drug is this?

• MPA is inhibitor of inosine monophosphate dehydrogenase (IMPDH) — what does it inhibit?

• what is it indicated for?

• box warning?

• esterases

• anti-proliferative drug

• de novo pathway of guanosine nucleotide synthesis

• prophylaxis of organ rejection (allogenic renal, cardiac or hepatic transplants)

• embryofetal toxicity, malignancies, serious infections

belatacept (nulojix)

• a ____ ____ composed of the Fc fragment of a human IgG linked to the extracellular domain of CTLA-4 (decoy receptor) which is a molecule crucial for T cell co stimulation

• it’s a T cell co stimulation blocker that interferes with what?

• indicated for prophylaxis of organ rejection in adult patients receiving a _____ transplant

• what is there increased risk of developing (predominantly involving the CNS)

• recipients without immunity to epstein barr virus (EBV) are at a particularly increased risk; use in EBV ______ patients only

• do not use nulojix in transplant recipients who are EBV ____ or with unknown status

• fusion protein

• APC CD 80/86 interactions

• kidney

• post transplant lymphoproliferative disorder (PTLD)

• seropositive

• seronegative

induction and maintenance data

• in the US, approx 85% of transplant recipients were discharged on ______ and _____ either with (58%) or without (42%) steriods

tacrolimus and MMF

trends in immunosuppression

• what does the picture show?

maintenance

trends in immunosuppression

• what does the picture show?

induction

deeper dive into tacrolimus

• most common regimen combines tacrolimus with _____ (with or without steroids)

• the principle challenge in immunosuppression is achieving a balance between under-immunosuppression and over-immunosuppression

• the task of optimizing tacrolimus dosing in immunosuppression therapy extends beyond mere monitoring of drug levels; requires consideration of a multitude of clinical factors, including patient age, cardiovascular health, infection status, renal function, DDIs, interpatient variability, and recent graft injections

MMF

what can under-immunosuppression lead to?

graft rejections

what can over-immunosuppression lead to?

off-target toxicities and infection

deeper dive into tacrolimus

• clinical use of TAC is associated with the risk of what?

  • has a _____ TI and is metabolized by CYP3A4 (DDIs)

• tacrolimus trough level targets a range from what?

• 2019 — range from what?

• nephrotoxicity, neurotoxicity, HTN, dyslipidemia, and posttransplant DM

  • narrow

• 5 - 20

• 7 - 12

tacrolimus trough

• maintaining tacrolimus levels within 5 - 7.9 for the first yr and 5 - 6.9 for years 2 - 6 correlates with what?

high graft survival and optimal safety outcomes

ischemia/reperfusion (I/R) injury

• harvested organs (stored on ice) are subjected to injury during cold preservation due to a _____ and _____ condition

  • further damage is induced at ______ when warm oxygenated blood is reintroduced into the graft

• the lack of oxygen during cold preservation induces depletion of ATP and shifts to _____ metabolism by glycolysis pathway, followed by deterioration and activation of cytotoxic enzymes

• subsequent warm reperfusion of grafts causes what promoting further cell damage?

• hypoxic and hypothermic

  • reperfusion (warm reperfusion)

• anaerobic

• excess of oxygen and generates reactive oxygen species

ischemia/reperfusion (I/R) injury

• as a result, damage or loss of vascular endothelial cells (VECs), disturbance of microcirculation, activation of potent inflammatory mediators, and inflammatory infiltration are known to be _____ features associated with I/R injuries

• initially, I/R injury contributes to ____ ____ ____ — the need for dialysis within one week after renal rtansplantation

• characteristic

• delayed graft function (DGF)

carbon monoxide (CO)

• what does it reduce?

  • how does it do this?

• I/R injury in organ transplantation

  • protecting vascular endothelial cells (VEC)

  • acting as an anti-coagulation factor

  • exhibiting anti-inflammatory effects

  • inhibiting apoptosis

carbon monoxide (CO)

• CO and allograft rejection

  • what does it prevent?

• T cell proliferation

• allograft rejection

• fibrosis

what is the landmark transplant?

xenograft

schematic of MOAs of immunosuppressive drugs

• T cell proliferation results from activation after presentation of ____ ____ by antigen presenting cells in conjunction with the MHC class II and B7 co-stimulation complex

• this mechanism results in activation of _____

  • which leads to production of ____

• autocrine stimulation by IL2 results in cell proliferation by a pathway involving _____ and ____ ____ ____

• donor antigen

• calcineurin

  • IL2

• m-TOR and cyclin-dependent kinase

schematic of MOAs of immunosuppressive drugs

• immunosuppressive agents exert their effects at a number of different targets to prevent _____ _____

• drugs act at all phases of T cell activation processes

• always used in combination for what?

• T cell proliferation

• optimal therapeutic outcomes

carbon monoxide releasing molecules (CORMS) for IRI

• small molecule “____“ of CO

  • ruthenium carbonyl complexes

  • boron carbonyl complexes

  • water soluble, delivery of exact amounts to tissues

  • useful in studying the effects of CO in cells/tissues in a therapeutically relevant setting

prodrug