Therapeutics Immuno Hecht Flashcard

Most important cells in Allograft Rejection

  • T-cells (CD4+ and CD8+)
  • Activity largely mediated by IL-2 (see Witt’s lecture)

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Minor Histocompatibility Antigens

  • Not used for matching
  • Can lead to rejection — this is the reason MHC-matched, non-identical individuals require immunosuppression

Matching Organ Donors

  • 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

Panel Reactive Antibodies

  • 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

Risks for elevated Panel Reactive Antibodies

  • Previous transplant(s)
  • Pregnancy
  • Multiple blood transfusions

Hyperacute Rejection

  • 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

Humoral Rejection

  • 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

Acute Rejection

  • 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

Chronic Rejection

  • 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

 

Organ Damage as a result of Chronic Rejection

  • Liver — vanishing bile ducts, fibrous tissue
  • Kidney — glomerular sclerosis, interstitial inflammation, fibrosis
  • Heart — accelerated atherosclerosis
  • Lung — bronchiolitis obliterans

Diagnosis of Rejection

Biopsy must be done!

  • Acute rejection — lymphocytic infiltrates
  • Acute humoral rejection — C4d staining positive
  • Chronic rejection — fibrosis

High Immunological Risk of Rejection

  • Previous Transplant(s)
  • Acute Tubular Necrosis
  • African-American
  • Pancreas, lung, or small bowel transplant
  • High PRA titer
  • Poor match
  • Cadaveric donor

Low Immunological Risk of Rejection

  • Primary Transplant
  • Caucasian
  • Low PRA titer
  • Living transplant

Immunosuppressive Approach: Induction

  • 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

Corticosteroids: Place in Therapy

  • Induction
  • Maintenance
  • Treatment of Rejection

Corticosteroids: MOA

  • Interferes with macrophage function
  • Inhibit synthesis and release of IL-1
  • Inhibit IL-2 secretion of T-cells
  • Non-specific anti-inflammatory effects

Corticosteroids: Toxicity

  • 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

Antithymocyte Globulin: Agents

  • Thymoglobulin (rabbit)
  • Atgam (equine)
  • Polyclonal antibodies

Antithymocyte Globulin: Place in Therapy

  • Induction
  • Reverse steroid-resistant acute rejection

Antithymocyte Globulin: MOA

  • Binds to activated T-cells (multiple sites)
  • May alter ability of T-cells to cause rejection

Antithymocyte Globulin: Toxicity

  • Mainly cytokine release
  • Fever, chills, erythema, pruritis, infection, anaphylaxis
  • Leukopenia, Thrombocytopenia
  • Arthralgias, Myalgias
  • Serum sickness
  • Malignancy

Muromonab-CD3: Place in therapy

  • Induction
  • Reverse steroid-resistant acute rejection

Muromonab-CD3: MOA

  • Murine monoclonal antibody
  • Potent anti-T-cell immunosuppressant
  • Targets mature T-cells expressing CD3 antigen in TCRs

Muromonab-CD3: Toxicity

  • Headache
  • Photophobia
  • Chest pain
  • HTN
  • Pulmonary edema
  • Dyspnea
  • Rigor
  • Tremor
  • Flu-like symptoms

Basiliximab: MOA

  • 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

 

Daclizumab: MOA

  • 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

 

Daclizumab: Place in therapy
Induciton only
Basiliximab: Place in therapy
Induction only
Cyclosporine: MOA

  • Calcineurin Inhibitor
  • Inhibits transcription of IL-2 early in the T-cell activation pathway

Tacrolimus: MOA

  • Calcineurin Inhibitor
  • Inhibits transcription of IL-2 early in the T-cell activation pathway

Calcineurin Inhibitors: Place in therapy

  • Maintenance
  • Calcineurin Inhibitors are the backbone of therapy

Cyclosporine: Adverse Effects

  • 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)

Tacrolimus: Adverse Effects

  • CNS (neurotoxicity, insomnias, headache, tremor, seizures)
  • HEENT (alopecia)
  • CV (HTN, hyperlipidemia)
  • GI (nausea, diarrhea)
  • Endocrine (glucose intolerance)
  • Renal (nephrotoxicity, hypomagnesemia, hyperkalemia)

Adverse Effects of Tacrolimus vs. Cyclosporine

HTN: CSA ↑


Hyperlipidemia: CSA ↑


Renal: Same


GI: Tac ↑


Endocrine: Tac ↑


CNS: Tac ↑

 

 

Comparative Efficacy between Cyclosporine vs Tacrolimus

  • 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

Azathioprine: MOA

  • 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

Azathioprine: Adverse Effects

  • Bone marrow suppression
  • Alopecia
  • Pancreatitis, Hepatotoxicity
  • Increased risk of skin cancer

Mycophenolic Acid: MOA

  • 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

Mycophenolic Acid: Toxicity

  • GI
  • Bone marrow suppression

Sirolimus: MOA

  • mTOR inhibitor
  • Binds to FK binding protein
  • Interferes with the signaling of IL-2
  • Markedly suppresses T cell proliferation

Sirolimus: Toxicity

  • Leukopenia, anemia, thrombocytopenia
  • Hyperlipidemia (esp. triglycerides)
  • Impaired wound healing, mouth ulcers, interstitial pneumonitis

Sirolimus: Drug Interactions
Give at least 4 hrs after cyclosporine — can potentiate nephrotoxicity
Sirolimus: Place in therapy

  • May decrease CMV disease
  • Useful in calcineurin free regimens
  • May decrease risk of malignancy

Acute Treatment of Rejection

  • 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

Belatacept: MOA
Selectively binds to costimulatory ligand (CD80 and CD86) on the surface of APCs — blocks T cell activation
Alemtuzumab: MOA

  • Recombinant humanized CD52-specific monoclonal antibody (expressed on T and B cells, eosinophils, monocytes, dendritic cells)
  • Used for corticosteroid sparing protocols

Rituximab: MOA

  • Binds to CD20 marker in B cell
  • Used in prophylaxis and treatment of humoral vascular rejection

Post-Transplant Problems

  • Risk of rejection
  • Infection
  • Risk of ulcers (w/ chronic corticosteroid use)
  • Cardiovascular complications
  • Malignancy

Pathogens associated with Post-Transplant Infections

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

Anti-Infective Medications for Post-Transplant Infections

  • Bacterial Prophylaxis
  • Fungal Prophylaxis (nystatin suspension or clotrimazole troche)
  • CMV/HSV (donor/recipient status, acyclovir or valganciclovir)
  • PCP Prophylaxis (TMP/SMX or Dapsone, Atovaquone)

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