Autoimmune Flashcards
What is an autograft?
Cells taken from a patient and then put onto a different part of the same patient
Leukemia, skin graft
What is an allograft?
Cells or tissue transplanted from another person
What is a xenograft?
Cells or tissue transplanted among species (human tumor into a mouse)
What are the different types of graft rejection?
Hyperacute: Occurs in minutes
Acute: 7-21 days
Chronic: 3 months
How does specific immunity against organ transplantation (GVHD) occur?
Foreign organ proteins are engulfed and presented by macrophages or other antigen presenting cells which stimulates Th cells to activate B cells form antibodies against the foreign proteins. The antibodies will then cause neutralization, opsonization and phagocytosis to help rejection
How does the helper T cell activate the B cells?
Interacts with the B cell and releases cytokines, which activate the B cells
Interleukins
How are antibodies formed?
The activated B cell proliferates into clones which then proliferate and differentiate into antibody secreting cells and memory cells
How does cyclosporine work?
Binds to the protein cyclophilin and their complex inhibits calcineurin/NF-AT activation (phosphorylation of NF-AT) and blocks IL-2 gene transcription (inhibits IL-2 release and expression of their receptors)
Decreases activation of T cells
Induction phase
What are the pharmacokinetics of cyclosporine?
Oral, IV
Oral absorption is slow and incomplete
T1/2 is about 24 hours
Concentrated in peripheral tissue (lymphomyeloid, adipose tissue)
What are the adverse effects of cyclosporine?
Nephrotoxicity, hypertension, increased risk of infection, liver dysfunction (monitor)
What are the drug interactions with cyclosporine?
Inhibit metabolism: Ca channel blockers, azoles, mycin, grapefruit juice
Induce metabolism: Phenytoin, anti-TB drugs (isoniazid, rifampin)
How does tacrolimus work?
Binds to FK binding protein (FKBP) which inhibits calcineurin phosphatase which decreases activation of transcription factor (NF-AT) and decreases IL-2 gene transcription
Induction phase
How does sirolimus work?
Binds to intracellular immunophilins but does not block IL-2 gene transcription, but instead interferes with IL-2 signal transduction pathway to activate cell proliferation in activated T cells
How does mycophenolate mofetil work?
Inhibits inosine 5’-monophosphate dehydrogenase (crucial enzyme in purine synthesis) which inhibits T and B cell proliferation
What are the pharmacokinetics of mycophenolate mofetil?
Converted to mycophenolic acid
Mg and Al impair absorption
Metabolites undergoes enterohepatic circulation
What is mycophenolate mofil indicated for?
Transplant recipients with cyclosporine and steroids
How does azathioprine work?
Metabolized to 6-MP (anticancer)
Inhibits the HGPRT enzyme which is important in purine synthesis
Cytotoxic to dividing cells
What is azathioprine indicated for?
IV loading dose on day of transplant
Oral for maintenance
Used in combo with other immunosuppressant drugs for kidney, liver transplants and RA
What is the major side effect of azathioprine?
Bone marrow depression
How does cyclophosphamide work?
A nitrogen mustard (alkylating agent) prodrug whose alkyl groups cross react with 2 DNA nucleophilic sites (guanine) to inhibit DNA replication
What is cyclophosphamide used for?
Lupus and RA
What are the adverse effects of cyclophosphamide?
Bone marrow depression, GI disturbance
Toxic metabolite can cause hemorrhagic cystitis
What are some examples of glucocorticoids?
Prednisone, methylprednisolone, dexamethasone
How do glucocorticoids work?
Both induction and effector phases
Inhibits macrophage activation and release of IL
Decrease clonal expansion of T and B cells and IL-2 secreting T cells
Decrease production and action of cytokines (interleukins, TNF)
Decrease generation of IgG
What are glucocorticoids used for?
Asthma, allergic rhinitis, eczema, RA, organ transplant Neoplastic disease (Hodgkins disease, leukemia) Replacement therapy (Addison's syndrome)
What are the adverse effects of glucocorticoids?
Insomnia, mood changes (take in morning), increased appetite and weight gain, suppressed response to injury or infection, fluid retention, osteoporosis, GI bleeding, hyperglycemia
How do polyclonal antibodies work?
Bind to proteins on the surface of lymphocytes, triggering the complement response which causes lysis of lymphocytes
Works against all T cells
What are the adverse effects of polyclonal antibodies?
Newly synthesized antibodies against these polyclonal antibodies could produce anaphylactic reactions
How do monoclonal antibodies work?
Works directly against a specific surface component of T cells
Targets CD3 proteins with antigen receptors, CD4 coreceptors, IL-2 receptors and TNF
Affects induction and effector phases
What is used for prevention of acute rejection?
High dose of glucocorticoids, purine synthesis inhibitors, immunosuppressive antibodies 1-2 weeks prior to transplant
What is used for prevention of chronic rejection?
Triple drug therapy consisting of calcenurin inhibitor, inhibitor of purine synthesis and glucocorticoid
What is used for breakthrough episodes in chronic rejection?
Cyclophosphamide, polyclonal and monoclonal antibodies and anti TNF therapy
How does self-tolerance work?
Immune system protects itself against autoreactive B and T cells via clonal deletion of immature lymphocytes in the B and T cells that recognize self-antigens with high affinity and mature autoreactive lymphocytes are inactivated by anergy, immunolgical ignorance, antigen sequestration, programmed cell death or suppression by regulatory T cells
What occurs when there is a loss of self-tolerance?
Autoreactive T helper 1 cells release interferon and interleukin to activate macrophages that secrete cytokines (TNF, IL) to cause local inflammation
Autoreactive Tc cells cause tissue damage
T cells cause B cells to form autoantibodies which activate the complement system to cause inflammation, block hormone signals or form complexes
What can cause a loss of self-tolerance?
Viral infection, molecular mimicry, immune cells targeting tumors, damage associated molecular patterns (DAMPs)
What drugs are used in RA therapy?
NSAIDs, glucocorticoids, disease modifying antirheumatic drugs (DMARDs)-methotrexate, sulfasalazine, leflunomide, anti-TNFa therapies, anti-IL therapies
What are the different phases of rheumatoid arthritis?
Initiation phase: Inflammation within the joint
Amplification phase: T cell activation
Chronic inflammatory phase: Tissue injury due to destruction of the bone and remodeling of the joint
What are some examples of anti-TNF based therapeutics?
Entanercept, infliximab, adalimumab, certolizumab, golimumab
How does entanercept work?
The only solube receptor TNF antagonist that binds all TNF
No neutralizing antibodies, low immunogenicity
Does not bind complement, no cell lysis
What are some examples of anti-IL based therapeutics?
Anakinra, canakinumab, tocilizumab
What is ulcerative colitis?
Inflammation of the submucosa with ulcerations that may cover the entire surface of the colon
Diarrhea, bleeding, severe pain, loss of nutrition, anemia
Colon can become stiff from scarring and burst
What is Crohn’s disease?
Seperate, isolated regions of inflammation which can cover the entire digestive system
Fistulas may form, the intestinal wall may be breached
May also have severe inflammation
How can the inflammatory bowel diseases be treated?
Typically relapsing. remitting inflammatory diseases
No cure, 5-ASA (1st line)
Surgical removal of the colon can eliminate ulcerative colitis, but surgery cannot always elminate Crohn’s
What are the 3 goals of treatment of inflammatory bowel diseases?
Treat the acute outbreak
Induce and retain remission
Treat complications
How does 5-ASA (mesalamine) work?
1st line treatment in mild to moderate ulcerative colitis
Does not work by COX inhibition (NSAIDs exacerbate)
5ASA is only released in the large intestine in sulfasalzine by bacteria
What are the different types of patient responses to glucocorticoids?
Steroid-responsive: Symptoms improve over 1-2 weeks and the disease remains in remission as the steroids are tapered off
Steroid-dependent: Respond to steroids but experience relapse with tapering
Steroid unresponsive
How are glucocorticoids used in inflammatory bowel diseases?
Used for acute treatment of moderate to severe, not useful in maintaining remission
What are the side effects of glucocorticoids?
Weight gain, moon face, stress and emotional reponse, steroid-dependent diabetes, increased risk of infection
How is thopurine used in inflammatory bowel diseases?
Used in steroid-resistant or dependent patients, useful in remission and reduction of relapse
Not for acute attacks due to long onset time
Small risk of major infection
How does methotrexate work?
Dihydrofolate reductase inhibitor (blocks DNA synthesis)
Also reserved for steroid resistant or dependent patients
How is cyclosporine used in inflammatory bowel diseases?
Only used for the most serious cases and right before surgery
Serious side effects, levels must be constantly monitored
How are TNF alpha inhibitors used in inflammatory bowel diseases?
Inhibits the proinflammatory ligand
Infliximab is an engineered antibody (may kill the cell to which it attaches) and has very prolonged effects due to long half life, repopulation of submucosa is required
Etanercept also reduces TNF but is not an effective treatment
How is thalidomide used in inflammatory bowel diseases?
It is an inhibitor of NF-kB, a transcription factor involved in inflammation
How are anti and probiotics used in inflammatory bowel diseases?
They may be due to changes in intestinal bacteria
These may change the proportions of different bacteria
