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41 Cards in this Set

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  • Back
What is immunomodulation?
Immunosuppression and Immunostimulation
What is the process of B and T lymptocytes?
Phagocytosis
Antigen presentation
Antigen recognition

Differentiation
Proliferation
Release of Ab, lymphotoxins
What are the systematics of immunosuppressants?
Glucocorticoids
Antiimetabolites - Azathioprin, Mycophenolate
Alkylants - Cyclophosphamid
Antifolate - Methotrextate
Signaltransduction inhibitors - cyclosporin A, Tacrolimus (FK506), sirolimus (Rapamycin), 15-Desoxy-spergualin (Gusperimus)
Receptor antagonists - IL-2 antagonists
Biologicals - Peptides, Antibodies
- Anti-lymphocyte gloculin, polyclonal (pAb)
- Murine monoclonal antibodies (mAb): Muromab CT3 (OKT3)
- Humanised/chimeric murine mAb
- Fusion proteins: Soluble ligands, soluble receptors
- IV immunoglobulins
- Peptides
- Antisense oligonucleotides
FDA approved mAb
Muromonab-CD3 - Orthoclone OKT 3 - CD3
Basiliximab - Simulect - IL-2-Rezeptor
Daclizumab - Zenapax - IL-2-Rezeptor
Infliximab - Remicade - TNF
Rituximab - MabThera - CD20
Trastuzumab - Herceptin - HER-2
Abciximab - ReoPro - GP Ilb/Illa
Palivixumab - Synagis - RS-virus
Antiinflammatory, immunosuppressive, antiproliferative actions of glucocorticoids
T lymphocytes decreased cytokines
Macrophages decreased cytokines
Eosinophils decreased apoptosis
Mast cells decreased number
Dendritic cells decreased number
What is the molecular mechanism at transcription levle?
- transcription inhibited - cytokines, COX-2, iNOS, endothelin-1, adhesion molecules
- Transcription enhanced - lipocortin-1, IL-1R antagonist
What are the unwanted side effects of glucocorticoids?
- Infections
- CNS - depression, euphoria, short-temperedness, psychosis
- Metabolism - reduced glucose tolerance, diabetes mellitus, gain in body weight
- Altered body mass distribution
- Skin atrophy
- GI ulcera
- Blood pressure, steroid hypertension
- Eye - glaucoma, cataracts
- Adrenal insufficiency
Femoral head necrosis
Total endoprosthesis (TEP) of right femoral head necrosis in young, kidney transplanted woman due to several immunosupressive therapies
Osteoporosis
Cod fish vertebra in thoracic and lumbar spine
Prophylaxis of glucocorticoid-induced osteoporosis
- lifestyle (body weight, sports, nicotine, alcohol)
- calcium (1-1.5 g/day)
- vitamin D (1000 IE)
- Estrogens (in menopause) plus/minus gestagens
- During therapy comedicated - Biophosphonates, calcitonin
Equivalent doses, Cushing's response.
- Potency/Cushing

Cortisol - 1
Prednison/Prednisolon - 4/10mg
Methylprednisolon - 5/8mg
Dexamethason - 25/2mg
Prednison/prednisolon dose ranges
- hohe Dosis > 100 mg/die
- mittlere Dosis 15-100 mg/die
- niedrige Dosis <15 mg/die
Cyclosporin A
Natural product from the fungus Tolypocladium inflatum, isolated from soil samples from Wisconsin (USA) and Norway
Mechanism of cyclosporin A and FK506 (Tacrolimus)
Act specifically on T helper cells
Transcriptionally inhibit IL-2 synthesis

CSA and FK505 binding proteins
Renal toxicity
glomerulm and vas afferens
Unwanted side effects of cyclosporin A
- Reduced infection-immunity
- Nephrotoxicity
- Hypertension
- Altered lipid metabolism
- Gingiva hyperplasia
- Neoplasia
- Tremor, epilepsy
Cyclosporin-induced gingiva hyperplasia
.
Cyclosporin handling.
- Highly lipophilic
- Higly variable bioavailability upon oral application
- Metabolised in liver in a cytochrom P450 dependent manner
- Therapeutic drug monitoring essential: Blood taken immediately before next application
Cyclosporin A drug interactions.
Plasma levels
- increased by: Erythromycin and Ca antagonists
- decreased by: Barbiturates, isoniazide, rifampicin, phenytoin

Nephrotoxicity
- with aminoglycoside, smphotericin B, NSAIDs

Rhabdomyolysis
- with HMG-CoA reductase innhibitors (statins)
Mechanism of action
- Anti-proliferative effects on all cells with high proliferation rate
- Inhibition of the cellular and humoral immune response
- Azathioprine & mycophenolat interfere with purin synthesis
- Cyclophosphamide covalently links DNA strands
- Methotrexate blocks conversion of folic acid in tetrahydro folic acid
What are the unwanted side effects of azathioprine, cyclophosamide & methotrexate?
- On all tissues/organs with high cell turnover
- Bone marrow - cytopenia
- Skin, mucosa - hair loss, stomatitis
- GI - diarrhoea, barrier dysfunction
- Gonads - genotoxicity
Special side-effects of cyclophosphamid
Haemorrhagic cystitis in 7-15%
- via urinary excretion of its metabolite acrolein
- mesna antidote has high risk of allergic reactions

Uroepithelioma risk 10-20 increased
Rare but life-threatening
Venoocclusive liver damage
- Azathioprin
- Cyclophosphamide

Interstitial pneumonia,lung fibrosis
- Methotrexate
Some different side effects.
CMV pneumonia and giant cells
Pneumocystis carinii pneumonia
Pneumocystis carinii
Aspergillus fumigatus
Cavernous lung tuberculosis
Mycobacterium tuberculosis
- Ziehl-Neelsen stain
- Acid resistant rod-shaped
Miliary/disseminated tuberculosis
Pneumococcal pneumonia
Wishful thinking in immunosuppressive therapy.
Aims
- Clearly defined disease
- Validated diagnosis
- Evidence-based therapeutic protocol
- Cooperative patient
- Regular therapeutic monitoring
- Contraindications acknowledged

Reality
- rare, diffusely defined diseases
- diagnosis not validated
- little experience, no clinical studies
- non-compliance
- irregular control examinations
Control check ups
- Inspect skin & mucosa
- Complete physcial examination
- Body weight
- Blood pressure
- Blood count
- Kidney function, liver function
- Blood sugar, blood lipids
- Eye examination
- Gynecologic examination
Three stages of immunosuppressive therapy
Emergency
- life threatening
- Prevention of a terminal organ failure

Long term
- symptom relief
- lowered mortality
- stable transplante function

Intermittent
- Disease episode with aggravated symptoms
IS Emergency: Wegener's granulomatosis
Untreated: 82% mortality within 1 y, 90% in 2 y
Treated: 93% complete remission, 7% non-responder
Fauci scheme:
- prednison or prednisolon (0.25-1g/d, 1mg/kg/d)
- and cyclophosphamid (2mg/kg/d)
Goodpasture syndrome
Pulmonary hemorrhage
Bronchial hemorrhage
IS Emergency: Good pasture syndrome
Preservation of kidney function
Critical level 6.5mg/dl S-creatinine
Scheme
- prednison/Prednisolon (0.5-1g for 5d)
- and plasmaseparation
IS long-term therapy - rheumatoid arthritis
Destruction of finger joints

Symptom relief
Disease modification
Alternating schemes e.g.
- low dose prednison/prednisolon (<15mg/d)
- daily alternating with Azathioprin (50-150mg/d)
- or methotrexate (7.5-20mg/week)
New: Etanercept (Enbrel)
- fusion protein, blocks TNF receptor
Pecking order of anti-rheumatics
Immunosuppressants

Gold, D-penicillamine, chloroquin, sulfasalazin, MTX, CSA, Aza

NSAIDs

Physical therapy, ergotherapy, patient training rest
Intermittent IS therapy: Chron's disease, colitis ulcerosa
Oredison/Prednisolon during an acute exacerbation

Scheme
1st week - 60mg
2nd week - 40mg
3-7 week - 5mg/week
8-14 week - 10mg
3-6 months 10mg every 2nd day

Distal Colitis ulcerosa: Budesonide foam externally
Intermittent IS therapy: Crohn's disease
Ileitis terminalis in Chron's disease
Colitis ulcerosa
.
IS therapy after organ tranplantation
Perioperative induction
- Glucocorticoids high/medium dose

Baseline/Long-term therapy
- glucocorticoids low dose
- Cyclosporin A or Tacrolimus
- Azathioprin or Mycophenolat

Rejection therapy
- glucocorticoids high dose
- Muromonab-CD2 (OKT-3) and antithymocyte gloculin (ATG)
IS therapy after organ transplantation: Unwanted side effects
- Tumour risk
- 3-4x increased versus normal population
Immunostimulants
Interferons
Growth factors
Immunoglobins
Others
Interferons
Usually recombinant material
Mostly interferon alpha
- mix of up to 20 subtypes
- mostly 2a, 2b
Interferon beta and gamma
- single compounds
Applications of Interferons
INF alpha (Roferon, Intron)
- hepatitis B+C
Hairy cell leukemia
- Kaposi sarcome, specific lymphomas

INF beta (betaferon, Avonex, Rebif)
- multiple sclerosis

INF gamma (Imukin, Polyferon)
- septic granulomatosis
- Rheumatoid arthritis