BL.2.14: Hematologic Malignancy cases, Immunology: the big picture: Flashcards
Describe an experiment that shows that immune responses might be “conditioned” in a Pavlovian sense.
Robert Ader showed that you could condition immunosuppression, the way Pavlov conditioned gastric secretion. He gave mice an injection of the immunosuppressive drug cyclophosphamide, and coupled it with a novel stimulus, saccharin, in their drinking water. Of course, such mice make a poor (suppressed) response to antigen given shortly after the cyclophosphamide. If rested a month, and then given another antigen injection and saccharin to drink, the mice made a poor antibody response, even though no further cyclophosphamide had been given. Mice given cyclophosphamide alone, and then a month later given antigen and saccharine, made a normal response (this is the necessary control for residual cyclophosphamide effect)3.
Define superantigens, and show diagrammatically how they work to stimulate T cells.
In the past few years, a number of substances have been found in nature that, when added to T cells isolated from blood, cause proliferation and differentiation of many cells. The difference between these and mitogens was that not all T cells responded; the percentage was variable, from about 3% to maybe 20%. That’s way too high for antigens, but low for mitogens. These molecules have the extraordinary, in fact mind-boggling, ability to bind both to MHC Class II molecules, and to the variable domain of the β chain of only certain Vβ families (the particular families involved being different for each different superantigen).
Define “cytokine storm.”
Suppose that a bacterium, say Staph. aureus, made a superantigen that it released into the blood stream during infection, and that that superantigen bound to TCRs that used Vβ8 and Vβ14, and also suppose that together those two families comprise 20% of your T cells. Therefore 20% of your T cells might suddenly become activated, divide, and release lymphokines. This is much more than would ever happen in a “normal” immune response. What does, say, too much IL-2 in the system do? It causes a dreadful vascular leakiness syndrome, and shock. The syndrome is also called cytokine storm.
Describe a therapeutic application of bovine IgA in humans.
Their first drug, available over the counter in Australia since 2005, is Travelan, from cows immunized with enterotoxigenic E. coli, endotoxin, and flagellin; it has been shown to prevent and treat traveler’s diarrhea. They are planning an anti-anthrax product, and talk, a little wildly, about products that could be slimed onto surfaces to neutralize microorganisms after a bioterrorism attack.
Describe some of the late effects of cancer treatment, related both to chemotherapy and radiation therapy.
Radiation: endocrine complications, infertility, effects on growth, dental abnormalities, cardiac, lung toxicities, gi tract effects, liver fibrosis, kidney and bladder trouble, cns effects, 2o malignancyChemo: trouble relating to a given system: Endocrine, Fertility, Growth, Cardiac, Pulmonary, Renal, Bladder, Liver, Hearing, Vision, Nervous system, Vascular system, Secondary malignancies
Discuss risk of secondary malignancy following cancer treatment and list factors that increase that risk.
Use of radiationUse of certain chemotherapy agents â—_ Alkylating agents (e.g., cyclophosphamide) â—_ Topoisomerase II inhibitors (e.g., etoposide)Genetic predisposition â—_ Li-Fraumeni syndrome (p53 mutation) â—_ Bilateral retinoblastoma (germline Rb mutation) â—_ Neurofibromatosis â—_ DNA repair defect syndromes
Describe some of the psychosocial difficulties that cancer survivors face.
obtaining medical insurance coverage, family issues, employment issues, depression and others.
Estimate the percentage of the population who are cancer survivors.
Currently close to 10 million cancer survivors in the US (3.3% of the population).
List important aspects of the patient history to ask when evaluating a patient with a suspected hematologic malignancy.
Weight loss? Fatigue? Headaches? SOB? Time frame? Epistaxis? Fever? Chills? Night sweats? Bruising? Family history? Dizziness? Blood in GI system? Regular menstruation? Exposure to harmful chemicals? History of present disease? Appetite/Dieting?
List important aspects of the physical exam when evaluating a patient with a suspected hematologic malignancy.
Fever. Overall appearance. Thin, pale, murmurs. Splenomegaly. Bleeding findings. Hepatomegaly. RR. BP. Lymphadenopathy. Tachycardia. Masses. Breath sounds. Distended abdomen.
List some of the important laboratory studies to obtain when evaluating a patient with a suspected hematologic malignancy.
CBC w/diff, retics, smearBone marrow biopsyCoagulation parametersGuiac testingChest Xray/ CT scan of involved areasMetabolic panelBiopsy the masses
What are B symptoms?
Night sweats, fever, weight loss.
What signs and blood results do you think of when you think of CML?What treatment?What cytogenetic abnormality?
All the white cells increased, left shift, splenomegaly, B symptoms, eosinophilia, basophiliaGleevact 9,22 BCR-ABL
Distinguish the chronic phase from the accelerated and blast phases of CML, and correlate the phase at presentation with prognosis.
Accelerated: after approx 3 years in chronic phase. marked by increasing anemia and thrombocytopenia, sometimes have a rise in basophils in blood. Additional cytogenetic abnormalities (e.g. +8, dup of Ph chromosome)blast phase: evolves from accelerated phase or skips accelerated. actually acute leukemia arising from CML. >20% blasts in peripheral blood or bone marrow. 10-80/20-30 myeloid / pre-B cell blasts suggesting cell origin of CFU-LM.Robbins: The outlook is much more dire once the accelerated phase or blast crisis supervenes. Transplantation is not as effective
Explain the mechanism of action of Gleevac in treating patients with CML.
It is a small molecule inhibitor of ABL tyrosine kinase. Inhibits proliferation and induces apoptosis of Bcr-Abl-positive cell lines as well as fresh leukemic cells from Ph+ CML. Inhibits tumor growth of Bcr-Abl transfected murine myeloid cells as well as Bcr-Abl-positive leukemia lines derived from CML patients in blast crisis in vivo.
