tumor immunology
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- what are oncogenic viral antigens?
- RNa and DNA viruses that can induce tumors; Epstein-Barr virus, HPV, and Hep B, also HTLV-1 (assoc. with CD4+ cells)
- what causes downregulation of class I MHC??
- NK cells! they kill in an unrestricted MHC fashion
- what mechanisms fight against tumors?
- CTL's against carcinomas and sarcomas and virus-induced tumors; NK cells for hematopoietic origin; macrophages by ADCC or TNF-alpha
- How can TNF kill a tumor?
- directly lyse them by causing production of free radicals or by hemorrhagic necrosis
- What are ways the tumors can escape immune system?
- no expression of MHC proteins, may induce tolerance (tolerogenic or w/o costimulatory mol), "sneaking through", outgrow, anti-tumor antibodies may act as blocking factors, antigens shed by tumor cells may bind to cell surface receptors and prevent function tumor antigens may be modulated off surface of tumor cells, masked by mucopolysaccharides, immunosuppressive substances released by tumor cells, and finally, tumors can form their own immunoprivelaged sites by encasing themselves in collagen/fibrin
- what are non-immune cancer therapies?
- surgery, radiotherapy (x-rays or cobalt-60, this kills lymphocytes and may induce DNA mutations), hyperthermia, chemotherapy (drugs that inhibit DNA repl, RNA transcrp, or protein synthesis)-- investigations are still underway to find tumor cell processes that are not performed by normal cells
- what is special about immuneotherapy of tumors?
- it is a specifically tailored response to the tumor and may have fewer side effects
- what are tumor vaccines?
- tumor cells that have been treated to increase their immunogenicity (attaching haptenic groups or infecting them with virus), melanoma has used this approach, this also includes the Hep B vaccine to reduce hepatocellular carcinoma
- How are anti-idiotypic antibodies used?
- they bind to B-cell lymphomas since idiotype is only expressed on that tumor cell alone; problem with this is tumor mutant outgrowth
- Growth factor receptor antibodies?
- may slow down or kill tumors by modulating the receptors off the surface
- What is herceptin?
- targets HER-2/neu growth factor that is overexpressed in about 25% of breast cancers; it downregulates the expression of the receptor; overexpression is poor prognosis
- What are immunoconjugates?
- anti-tumor antibodies coupled to toxins that inhibit protein synthesis --- F(ab')2 fragments, devoid of Fc, must be used to avoid binding of toxic antibodies by Fc receptor-bearing cells such as macorphages and neutrophils
- what are bi-specific antibodies?
- genetically-engineered antibodies that can recognize both tumor antigens and immune system cells; this localizes immune system in vicinity of tumor cells
- What is adoptive cellular immunotherapy?
- LAK cell therapy and TIL therapy (LAK and CTL's are cultured and reinfused)
- What is cytokine therapy?
- IL-2 is infused to generate LAK and CTL's in vivo; tumor regression can be 20-40% of renal carcinoma and malignant melanoma; but there are severe side effects; TNF may be too toxic; IFN-alpha has antiproliferative effects on tumor cells, and induces class I MHC expression to make tumors more immunogenic -- this works best on hairy cell leukemia's and lymphomas
- what about transfection of cytokine genes?
- provides immunostimulation at tumor site while decreasing systemic side effects (they are trying IL-2 and TNF)
- x-linked agammaglobulinemia
- virtual absence of mature B-cells; so there is a block in maturation due to tyrosine kinase; x-linked so only males will get this; shows up around 6 mos when maternal antibodies disappear; susceptible to extracellular bacterial infections (pus) b/c antibody is primary way to rid them; tx is injection of gamma globulin and antibiotic thearpy; since T cells aren't attacked, patients don't get viral or fungal responses; they also don't get vaccines
- common variable immunodeficiency?
- b-cell defect; inability of mature b-cells to mature into plasma cells!; affects males and females; etiology may be due to B-cell inborn defect; high incidence of autoimmune diseases; get recurrent bacterial infections
- selective IgA deficiency?
- B-cell defect; MOST COMMON; generally asymptomatic b/c IgM can compensate since it can be transported across mucosal barriers; there can be transufion reactions b/c they might have an anti-IgA immune response; could be due to lack of IL-5 or TGF-beta to enhance IgA secretion
- Hyper IgM Syndrome?
- overabundance of IgM, lack of antibodies of other isotopes; x-linked!!; has inherited deficiency of CD40 ligand on T-cells, so CD40 is not engaged on B cells and no isotype switching occurs
- DiGeorge syndrome?
- T-cell defect; born with no thymus; problems with differentiation from 3 or 4th pharyngeal pouches; poor cell-mediated immunity against viral and fungal pathogens; linked to maternal alcoholism; exrathymic maturation compensates by about 5 yo
- SCID?
- B and T cell defect; neither develop from bone marrow stem cells; severely decreased or no humoral or cell-mediated immunity and will die from viral, b, or funal, or protozoan infection if not treated; due to deficiency of ADA or PNP- they will accumulate toxic byproducts in their cells (particularly lymphocytes); linked to gene mutation; tx is bone marrow transplantation or gene therapy
- chronic granulomatous disease? CGD
- phagocyte disease; congenital disorder characerized by recurrent bacterial infections, due to defect in NADPH oxidase in neutrophils so they can't produce superoxide anion; usually fatal in their 30's; INF-gamma may allow to produce normal NADPH oxidase may help some patients
- myeloperoxidase deficiency?
- phagocyte disorder- decreased enzyme; normally it produces HOCl as an antibacterial and antifungal; no increase in suscpetibility to infection, however they have a hard time getting rid of fungal infections
- LAD-1 deficiency?
- phagocyte disorder; defect in beta chain of LFA-1 and Mac-1 adhesion, so neutrophils can't adhere to endothelial cells for extravasation; wound healing problems; bonr marrow transplant is curative; there are moderate and/or severe versions of this disease; dx by extreme leukocytosis b/c neutrophils cannot marginate, so they collect in peripheral blood
- neutropenia?
- phagocyte disorder; inherited as dominant or recessive-- low levels of neutrophils; bone marrow transplant necessary; cyclinc neutropenia exists; due to mutation in neutrophil elastase enzyme that leads to buil-up of toxic intracellular protein which destoys neutrophils
- Wiskott-Aldrich syndrome?
- x-linked syndrome, also eczema and thrombocytopenia are also characteristic; can't respond to antigen even though they have normal T and B cells; genetic defect of actin cytoskeleton of bone marrow-derived cells; tx with gammaglobulin and antibiotics
- ataxia-telangactasia?
- autosomal recessive multi-system disease with loss of muscle coordination, vascular lesions, and hypersensitivity to ionizing radiation, and incidence of tumors; ATM protein defect which repairs DNA damage; reduced T-cells, B-cells are normal; lack of proper thymic development