Shared Flashcard Set

Details

Therapeutics Immuno Hecht
Exam 2 Solid Organ Transplantations
50
Chemistry
Graduate
04/06/2010

Additional Chemistry Flashcards

 


 

Cards

Term
Most important cells in Allograft Rejection
Definition
  • T-cells (CD4+ and CD8+)
  • Activity largely mediated by IL-2 (see Witt's lecture)

 

Term
Minor Histocompatibility Antigens
Definition
  • Not used for matching
  • Can lead to rejection -- this is the reason MHC-matched, non-identical individuals require immunosuppression
Term
Matching Organ Donors
Definition
  • HLA matching (increases "cold ishcemia time", primarily done in kidney transplants, not routinely done for other organs)
  • Blood type match is required for all transplants
Term
Panel Reactive Antibodies
Definition
  • A panel of common random antibodies
  • Recipients are tested for reactivity
  • If they have > 10-20% reactivity, HLA typing must be done for that recipient
Term
Risks for elevated Panel Reactive Antibodies
Definition
  • Previous transplant(s)
  • Pregnancy
  • Multiple blood transfusions
Term
Hyperacute Rejection
Definition
  • Preformed donor antibodies present and complement-fixing antibodies (blood ABO and/or MHC antigens) bind to vascular epithelium
  • Occurs w/in 48 hrs
  • NO TREATMENT
Term
Humoral Rejection
Definition
  • Activation of memory cells formed in utero
  • Binding of complement or non-complement antibodies leading to antibody dependent cellular cytotoxicity
  • Occurs w/in hrs to days after transplant, within 3 months
  • Anti-lymphocyte agents have limited efficacy
Term
Acute Rejection
Definition
  • T-lymphocyte mediated (delayed type IV hypersensitivity reaction)
  • Usually occurs w/in first 90 days, but may occur anytime
  • Biopsy is done to confirm
  • Prevention is main goal of immunosuppressive therapy

Reasons for acute rejection:

  • failure of regimen
  • non-adherence
Term
Chronic Rejection
Definition
  • Immunologic (humoral) role
  • Non-immunologic (drug toxicity, comorbidities, donor disease, infectious diseases) role
  • Ultimately results in obliterative disease via allograft fibrosis
  • Occurs greater than 90 days after transplant (slow, indolent pathological changes)
  • No known effective therapy (change from calcineurin inhibitors to sirolimus or MMF may help prevent further damage)
  • Treat comorbid diseases to prevent further damage

 

Term
Organ Damage as a result of Chronic Rejection
Definition
  • Liver -- vanishing bile ducts, fibrous tissue
  • Kidney -- glomerular sclerosis, interstitial inflammation, fibrosis
  • Heart -- accelerated atherosclerosis
  • Lung -- bronchiolitis obliterans
Term
Diagnosis of Rejection
Definition

Biopsy must be done!

  • Acute rejection -- lymphocytic infiltrates
  • Acute humoral rejection -- C4d staining positive
  • Chronic rejection -- fibrosis
Term
High Immunological Risk of Rejection
Definition
  • Previous Transplant(s)
  • Acute Tubular Necrosis
  • African-American
  • Pancreas, lung, or small bowel transplant
  • High PRA titer
  • Poor match
  • Cadaveric donor
Term
Low Immunological Risk of Rejection
Definition
  • Primary Transplant
  • Caucasian
  • Low PRA titer
  • Living transplant
Term
Immunosuppressive Approach: Induction
Definition
  • ALL patients get perioperative high dose IV steroids (dexamethasone or methylprednisolone 1 gm)
  • High risk patients also receive aggressive immunosuppressants
  • Therapies are started intraoperatively or immediately post-op
  • Calcineurin inhibitors are typically NOT used in induction
  • Therapies target IL-2 or T-cells
Term
Corticosteroids: Place in Therapy
Definition
  • Induction
  • Maintenance
  • Treatment of Rejection
Term
Corticosteroids: MOA
Definition
  • Interferes with macrophage function
  • Inhibit synthesis and release of IL-1
  • Inhibit IL-2 secretion of T-cells
  • Non-specific anti-inflammatory effects
Term
Corticosteroids: Toxicity
Definition
  • Acne
  • CNS effects
  • GI ulcerations
  • HTN
  • Increased appetite
  • Hyperlipidemia
  • Osteoporosis
  • Impaired growth
  • Myopathy
  • DM
  • Na+ and H2O retention
  • Cataracts
  • Impaired wound healing
  • Risk of infection
Term
Antithymocyte Globulin: Agents
Definition
  • Thymoglobulin (rabbit)
  • Atgam (equine)
  • Polyclonal antibodies
Term
Antithymocyte Globulin: Place in Therapy
Definition
  • Induction
  • Reverse steroid-resistant acute rejection
Term
Antithymocyte Globulin: MOA
Definition
  • Binds to activated T-cells (multiple sites)
  • May alter ability of T-cells to cause rejection
Term
Antithymocyte Globulin: Toxicity
Definition
  • Mainly cytokine release
  • Fever, chills, erythema, pruritis, infection, anaphylaxis
  • Leukopenia, Thrombocytopenia
  • Arthralgias, Myalgias
  • Serum sickness
  • Malignancy
Term
Muromonab-CD3: Place in therapy
Definition
  • Induction
  • Reverse steroid-resistant acute rejection
Term
Muromonab-CD3: MOA
Definition
  • Murine monoclonal antibody
  • Potent anti-T-cell immunosuppressant
  • Targets mature T-cells expressing CD3 antigen in TCRs
Term
Muromonab-CD3: Toxicity
Definition
  • Headache
  • Photophobia
  • Chest pain
  • HTN
  • Pulmonary edema
  • Dyspnea
  • Rigor
  • Tremor
  • Flu-like symptoms
Term
Basiliximab: MOA
Definition
  • Monoclonal Antibody
  • Targets IL-2 receptors on CD25 (low on resting T-cell, induced on activated T-cell)
  • Chimeric/Humanized:

Highly specifc binding

Long serum half life

Minimal immunogenicity

 

Term
Daclizumab: MOA
Definition
  • Monoclonal Antibody
  • Targets IL-2 receptors on CD25 (low on resting T-cell, induced on activated T-cell)
  • Chimeric/Humanized:

Highly specifc binding

Long serum half life

Minimal immunogenicity

 

Term
Daclizumab: Place in therapy
Definition
Induciton only
Term
Basiliximab: Place in therapy
Definition
Induction only
Term
Cyclosporine: MOA
Definition
  • Calcineurin Inhibitor
  • Inhibits transcription of IL-2 early in the T-cell activation pathway
Term
Tacrolimus: MOA
Definition
  • Calcineurin Inhibitor
  • Inhibits transcription of IL-2 early in the T-cell activation pathway
Term
Calcineurin Inhibitors: Place in therapy
Definition
  • Maintenance
  • Calcineurin Inhibitors are the backbone of therapy
Term
Cyclosporine: Adverse Effects
Definition
  • CNS (confusion, hallucinations, seizures)
  • HEENT (gingival hyperplasia)
  • CV (HTN, hyperlipidemia)
  • GI (nausea, diarrhea, hepatotoxicity)
  • Endocrine (glucose intolerance)
  • Renal (nephrotoxicity, hypomagnesemia, hyperkalemia, hyperuricemia)
  • Dermatologic (acne, hirsutism)
Term
Tacrolimus: Adverse Effects
Definition
  • CNS (neurotoxicity, insomnias, headache, tremor, seizures)
  • HEENT (alopecia)
  • CV (HTN, hyperlipidemia)
  • GI (nausea, diarrhea)
  • Endocrine (glucose intolerance)
  • Renal (nephrotoxicity, hypomagnesemia, hyperkalemia)
Term
Adverse Effects of Tacrolimus vs. Cyclosporine
Definition

HTN: CSA ↑


Hyperlipidemia: CSA ↑


Renal: Same


GI: Tac ↑


Endocrine: Tac ↑


CNS: Tac ↑

 

 

Term
Comparative Efficacy between Cyclosporine vs Tacrolimus
Definition
  • Earlier studies suggest Tac showed decreased rates of rejection vs CSA
  • Tac is dominant in US
  • Pts with HTN, hyperlipidemia, and increased risk of rejection may do better on Tac
Term
Azathioprine: MOA
Definition
  • Metabolized to 6-mercaptopruine (6-MP)
  • 6-MP inhibits DNA and RNA synthesis by preventing the formation of adenylic and quanylic acids from inosinic acid
  • Interferes with proliferation of T and B cells
Term
Azathioprine: Adverse Effects
Definition
  • Bone marrow suppression
  • Alopecia
  • Pancreatitis, Hepatotoxicity
  • Increased risk of skin cancer
Term
Mycophenolic Acid: MOA
Definition
  • Similar MOA to azathioprine, but more specific to T cells
  • Selectively inhibits lymphocyte proliferation and functions, including antibody formation, cellular adhesion and migration resulting in immunosuppression
Term
Mycophenolic Acid: Toxicity
Definition
  • GI
  • Bone marrow suppression
Term
Sirolimus: MOA
Definition
  • mTOR inhibitor
  • Binds to FK binding protein
  • Interferes with the signaling of IL-2
  • Markedly suppresses T cell proliferation
Term
Sirolimus: Toxicity
Definition
  • Leukopenia, anemia, thrombocytopenia
  • Hyperlipidemia (esp. triglycerides)
  • Impaired wound healing, mouth ulcers, interstitial pneumonitis
Term
Sirolimus: Drug Interactions
Definition
Give at least 4 hrs after cyclosporine -- can potentiate nephrotoxicity
Term
Sirolimus: Place in therapy
Definition
  • May decrease CMV disease
  • Useful in calcineurin free regimens
  • May decrease risk of malignancy
Term
Acute Treatment of Rejection
Definition
  • Each episode of rejection shortens the life of the graft
  • High doses of steroids initiated and subsequently tapered when rejection has resolved
  • Anti-leukocyte antibodies used when steroids are not enough
  • After rejection, increase doses of maintenance medications (esp. calcineurin inhibitors) and add another immunosuppressant in a different class
Term
Belatacept: MOA
Definition
Selectively binds to costimulatory ligand (CD80 and CD86) on the surface of APCs -- blocks T cell activation
Term
Alemtuzumab: MOA
Definition
  • Recombinant humanized CD52-specific monoclonal antibody (expressed on T and B cells, eosinophils, monocytes, dendritic cells)
  • Used for corticosteroid sparing protocols
Term
Rituximab: MOA
Definition
  • Binds to CD20 marker in B cell
  • Used in prophylaxis and treatment of humoral vascular rejection
Term
Post-Transplant Problems
Definition
  • Risk of rejection
  • Infection
  • Risk of ulcers (w/ chronic corticosteroid use)
  • Cardiovascular complications
  • Malignancy
Term
Pathogens associated with Post-Transplant Infections
Definition

1.  Bacterial

  • wound
  • catheter-related
  • pulmonary
  • urinary tract

2.  Fungal

  • candida
  • aspergillus

3.  Viral

  • BKV (not seen in healthy ppl)
  • CMV
  • HSV
  • EBV

4.  Protozoan

  • PCP
  • Toxoplasmosis
Term
Anti-Infective Medications for Post-Transplant Infections
Definition
  • Bacterial Prophylaxis
  • Fungal Prophylaxis (nystatin suspension or clotrimazole troche)
  • CMV/HSV (donor/recipient status, acyclovir or valganciclovir)
  • PCP Prophylaxis (TMP/SMX or Dapsone, Atovaquone)
Supporting users have an ad free experience!