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Th1 cell_regulates CMI
- Secretes: IL-2, IFN-gamma
- IL-2 --> stimulates T cell growth and maturation
- Activates: macrophages and CD8 T cells
- Inhibited by IL-10 (from Th2 cell)
Th2 cell_regulates humoral immunity
- Secretes: IL-4, IL-5, IL-10
- IL-4, IL-5 --> stimulate B cells
- Helps B cell make antibody
- CD40L on Th cell binds CD40 on B cell
- Inhibited by IFN-gamma (from Th1 cell)
Activated lymphocytes (release IFN-?) and macrophages (release IL-1) to stimulate one another
What is the best way to suppress immune system?
Primary immune response is easier to suppress. Inhibition more likely if Tx begins before exposure to immunogen
What are the ultimate side effects of immune suppression?
Infections and malignancies
What is the temporal relationship of the effects of corticosteroids on the body?
Anti-inflammatory effects are rapid, immune suppression is slow to develop
What type of immune suppression is seen c corticosteroids?
Very broad: macrophages, lympholytic, cytokines, T-cells
What are the side effects of corticosteroids?
Cushing's syndrome, osteoporosis, peptic ulcers, mentrual/reproductive effects
What are the calcineurin inhibitors?
Cyclosporine, FK506 (Tacrolimus), Pimecrolimus
What part of the immune system do calcineurin inhibitors target?
What is the normal fxn of calcineurin in the T cell?
- Cell is signaled and it Inc. intracellular [Ca]
- Ca binds to calcineurin which dephosphorylates NFAT
- NFAT translocates to nucleus and binds DNA to stimulate transcription of IL-2
What is the MOA of cyclosporine?
Inhibits calcineurin and selectively inhibits T lymphocytes by Decrease IL-2
What advantage does it have over corticosteroids?
NO bone marrow suppression
What is its solubility and distribution?
- Very lipid soluble
- Accumulates in leukocytes and RBCs
How is cyclosporine metabolized?
- Narrow therapeutic range
- Many Rx interactions
- NO grapefruit juice
Boards: Inducers of P450
- St. John's wort
- Chronic EtOH use
Boards: Inhibitors of P450
- HIV protease inhibitors
- Grapefruit juice
- Acute EtOH use
What are the uses of cyclosporine?
- Prevent rejection (c corticosteroids/azathioprine)
- Maintenance following transplant
- Autoimmune dz, severe asthma, RA, bowel inflammation, DM
What are the major toxicities?
- Renal toxicity! [BOOM] --> don't combine c aminoglycosides
- Gingival hyperplasia
- Reminder: also seen c phenytoin and "-dipine" Ca channel blockers)
- Hyperlipidemia, hyperglycemia, hirsutism
When is Tacrolimus used?
- Prevention of transplant rejection, especially liver, kidney, and heart
- Rescue of transplant rejection-->better than cyclosporine
What are the side effects of tacrolimus?
- Better tolerated, less toxic than cyclosporine
- HTN, hyperglycemia
- Neurotoxic: tremor, HA, insomnia--> not seen c cyclosporine
What are the Rx interactions?
- Metabolized by CYP3A4 so same as cyclosporine
- Oral absorption affected by food
What is the MOA of sirolimus?
- Inhibits mammalian target of rapamycin
- Blocks T-cell proliferation in response to IL-2 (similar to previous Rxs)
- Inhibits B-cell proliferation
What are its pros and cons relative to the previous calcineurin inhibitors?
NO renal toxicity, but causes marrow suppression
What do the antiproliferative agents inhibit?
Inhibit DNA synthesis and decrease T and B lymphocytes
What are the antiproliferative agents?
- Mycophenylate mofetil
What is the mycophenylate mofetil MOA?
- Pro-Rx that inhibits monophosphate dehydrogenase that lymphocytes use for purine synthesis (others cells use HGPRT)
- Remember: HGPRT deficiency = Lesch-Nyhan --> Increase uric acid --> MR and self-mutilation
- X-linked recessive
What specific cells are inhibited by mycophenylate mofetil?
T cell proliferation and Ab formation by B cells
When is it used?
Prevention of transplant rejection (combined c tacrolimus)
What are the side effects?
- Generally mild: N/V/D, infections (sepsis, CMV)
- Rash --> as shitty one
- Teratogenic (so is cyclosporine and tacrolimus)
What is the azathiprine MOA?
- Converted to 6-mercaptopurine --> inhibits de novo purine synthesis
- Inhibits proliferation of lymphocytes
What are its uses besides transplant rejection prevention?
- Treat (diffuse proliferative) glomerulonephritis of SLE [Reminder: SLE has anti-nuclear Abs]
- Severe RA
What are the side effects of azathioprine?
- Bone marrow suppression
- Metabolized by xanthine oxidase (like 6-mercaptopurine)
- Reduce dose if used c allopurinol
What is the leflunomide MOA?
Inhibits pyrimidine synthesis --> inhibits T-cell proliferation and B-cell formation of Abs, decrease TNF-alpha
When is it used?
Rx of RA
What is the cyclophosphamide MOA?
- Alkylating agent that cross-links DNA inhibiting T and B-cells:
- Can destroy already active T-cells__one of the few Rx that can do this [BOOM]
- Blocks new antigens, and can inhibit established immune response
When is cyclophosphamide used?
- Organ transplant rescue (not general suppression)
- Marrow transplants
- Severe MS, RA, SLE
What are its side effects?
- Hemorrhagic cystitis [BOOM]
- Prevent c MESNA and hydration
- Bladder fibrosis, carcinoma
- Aspermia, infertility, marrow suppression, alopecia
What is the methotrexate MOA?
- Inhibits human DHF reductase --> decrease lymphocyte and macrophage fxn
- Also Decrease inflammation
When is it used?
- Organ transplants (not 1st line)
- RA, psoriasis, anti-neoplastic, severe asthma
What is the thalidomide MOA?
decrease TNF-alpha and IL-6
What are its uses?
- May decrease immunity through T-cells and neutrophils
- Prevents GVH
- Used in multiple myeloma, leprosy, HIV (to gain wt)
What are the side effects?
Teratogenesis, sedation, neutropenia
When are lymphocyte Ig or antithymocyte globulin used?
Antibodies to T-cells used during acute rejection episodes and bone marrow induction to prevent rejection
What are the adverse rxns?
- Severe rxn against foreign protein, chills, fever, hypotension, rash
- Give corticosteroids and cytotoxic Rx to decrease rxns
What is Muromonab and its MOA?
- Monoclonal Ab to CD3 on T-cells
- Binds near antigen recognition complex and prevents binding of antigen --> T cells removed from circulation
When is it used?
- For steroid resistant rejection, kidney rejection
- Deplete T cells from donor marrow
What is the toxicity?
Cytokine release syndrome: range from flu-like Sx to anaphylactoid rxn (pre-treat c corticosteroids)
What is the MOA of Daclizumab and Basilixumab?
Binds IL-2 receptor on activated T-cells to prevent further activation
What are their benefits?
- Prophylaxis decease renal rejection by 50%, minimal adverse effects
- No general immunosuppression
What is a typical organ transplant protocol?
- Induction: daclizumab, basilixumab
- Initial then maintenance: tacrolimus or cyclosporine, coriticosteroids, mycophenylate mofetil, azathioprine
- Rejection episodes: high dose corticosteroids, anti-lymphocyte Abs, cyclophosphamide, tacrolimus, muomonab, mycophenolate mofetil
What is the Efalizumab MOA?
- CD-11 Ab that prevents binding to ICAM that is ? in psoriasis
- Prevents T-cell activation, but doesn't destroy them
What is the Alefacept MOA?
- Binds to CD-2 on cell surface to block T-cell activation
- Fusion protein ("-cept") used in psoriasis
What is the Omalizumab MOA?
Anti-IgE blocks binding of mast cells, basophils ? used in severe allergic rxns
Targets B-cells, used in non-Hodgkin's lymphoma
What is the Infliximab MOA?
Neutralizes TNF?, used in Tx of RA
What is the Rh (D) Ig MOA?
Antibodies to Rh(D) antigen that binds the fetal antigen to prevent mother from mounting a response and developing Abs
What are uses of immunomodulators?
AIDS, chronic Heb B and C, CA Tx
When is IL-2 used?
RCC, malignant melanoma
What is the role of IL-2?
Increase proliferation of T-cells, B-cells, macrophages, and Increase toxicity of NK cells
What are its adverse effects?
Pulmonary edema, severe hypotension, hematologic (anemia, thrombocytopenia)
What is Oprelvekin and how is it used?
- Recombinant IL-11
- Prevents chemo-induced thrombocytopenia
How is G-CSF used?
Tx of neutropenia from stem cell transplant, chemo, HIV Tx, or interferon
How is it given and what are the adverse rxns?
- SC injection
- May cause bone pain, injection site rxn
What is the use of epoetin alfa?
Recombinant EPO used for anemia from chemo, interferon, HIV Tx, kidney dz
What are the adverse effects?
Blood clots, stroke, HTN
What are the uses of alpha and Beta interferons?
Inc response to viruses
What does gamma interferon stimulate?
- T-cells, NK cells, and macrophages
- Inc expression of MHCs
What are the uses of interferon alfa 2b?
- Hep B and C c ribavirin
- Hairy cell leukemia, Kaposi's sarcoma, condylomata accuminata, NHL
- Antiviral, antiproliferative, Dec viral transmission
- Hairy cell leukemia, Kaposi's sarcoma, Hep C
What is the use of interferion beta-1b?
Multiple sclerosis: suppress class II MHCs to dec antigen to nervous system
What is the glatiramer MOA?
Decoy for myelin basic protein__Abs bind to it instead of myelin
What is the MOA and uses of gamma-1b?
- Activation of macrophages, neutrophils, NK cells
- Inc Class I and II MHCs
- Dec infections in CGD and Tx of pulmonary/hepatic fibrosis
What are the interferon side effects?
- Depression and suicide!
- "flu-like" Sx
- Marrow suppression, alopecia
In class clicker Qs:
Rx causing tremor, insomnia, hyperglycemia ?
Immunosuppressant causing rash ?
decrease macrophage rxn, destroys lymphocytes, inhibits cytokine synthesis ?
Causes fever, chills, lymphoma, hypotension ?
Activates T cells and NK cells ?
Can't be taken c grapefruit ?
Tx of neutropenia ?
- Ingestion of cysts that hatch into trophozoites in the gut
- Cyst: 4 nuclei
- Troph: centrally located endosome
- Sx: RUQ pain, bouts of bloody diarrhea, may persist for months
- Can cause extra-intestinal cyst (especially liver)
- Found in tropical areas worldwide
- Troph: teardrop shape, 2 nuclei, adhesive disc, multiple flagella
- Attach to small intestine cause malabsorption and steatorrhea
- Does NOT invade tissue
- Protozoal Micro Review
- Flagellated protozoan causing STD
- Sx: malodorous vaginal discharge, associated c cellular atypia (clue cells)
- Dx via wet mount
- Cyst in meat or cat feces, teratogenic
- Brain abscess in HIV
- Triad: chorioretinitis, hydrocephalus, intracranial calcifications (ring-enhancing brain lesion on CT)
- Not a protozoa__it is a yeast-like fungus
- Major cause of pneumonia and death in HIV pt