Therapeutics Immuno Hecht – Flashcards

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

;

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

• 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

• 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

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

• 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

• 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

• 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

• 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

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

Biopsy must be done!

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

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

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

• 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

• Induction
• Maintenance
• Treatment of Rejection

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

• 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

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

• Induction
• Reverse steroid-resistant acute rejection

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

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

• Induction
• Reverse steroid-resistant acute rejection

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

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

• 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

• 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

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

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

• Maintenance
• Calcineurin Inhibitors are the backbone of therapy

• 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)

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

HTN: CSA ↑

Hyperlipidemia: CSA ↑

Renal: Same

GI: Tac ↑

Endocrine: Tac ↑

CNS: Tac ↑

• 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

• 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

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

• 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

• GI
• Bone marrow suppression

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

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

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

• 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

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

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

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

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

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