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Immunology: Cancer & Psychoneuroimmunology

Study Questions:
1. Does having an immune response to a colon tumor preclude you from getting lung cancer? Why or why not?
2. What happens if you systemically and non-specifically turn on all of your T cells at once?
3. What are TSAs?
4. How does a DC vaccine for cancer work?
5. Why can people often fight off virally induced tumors but not spontaneous tumors?
6. Name one way that viruses that cause tumors evade the immune system.
7. Which cells of the immune system have receptors for neurotransmitters?
8. What effect do glucocorticoids have on the immune system?
9. Name 3 problems that make it difficult to do PNI studies.

1. No. Colon cancer and lung cancer have different antigens (Tumor A vs Tumor B)
2. Too many cytokines generated make your blood vessels leaky.
3. Tumor Specific Antigens
4. DCs present TSA with costimulation → activates person's T cells (innate ability to heal)
5. Virally induced tumors have a "danger" signal. Virus = TLR 4.
6. Downregulate MHC processing, also can cause secretion of immune suppressive cytokines (TGF beta), make their own MHC molecules
7. All of them. T cells, B cells, DCs, macrophages, NKs, etc.
8. Glucocorticoids are immunosuppressive.
9. Immune system is affected by nutrition, sleep, etc., most studies are done ex-vivo—taking the cells out of the system, assays are variable

Cancer Outline
I. Experimental Proof for Immune Response to Cancer
A. Experiments
B. IL-2
C. DC vaccines
D. Coley's Toxins

II. Tumor Specific Antigens

III. Tumors that Escape Immunosurveillance

IV. Normal Immune Response to tumor

V. Psychoneuroimmunology

I. Experiments
A. Experiment 1 (proves that you can induce a T-cell mediated immune response to a tumor by vaccinating with dead tumor cells from biopsy of that tumor)
--inject dead tumor A into two mice-->then inject live tumor A into one and live tumor B into other-->the mouse that got B tumor injected got tumor while mouse injected with tumor A didn’t
--repeat experiment in mice with no T cells-->both mice got cancer even after vaccination
--tumors have specific antigens which vary between tumors
--tumor A and tumor B have different antigens
--tumors can be targets for T-cell mediated immune response
--dead tumor gives us co-stimulation; with live tumor there is no co-stim so no immune response
--APCs can phagocytose dead tumors and present antigens with a danger signal

B. IL-2 (research proves that injecting this cytokine is a bad treatment)
--Steve Rosenberg figured out that T cells need 2nd signal and thought that 2nd signal was IL-2 (T cell growth factor) so he injected cancer patients with IL-2 systemically and they died from shock (leaky BV's, volume loss)
--IL-2 non-specifically stimulated T cells to divide and generated a response similar to superantigens

C. DC Vaccines
--biopsy tumor and put it into a dish-->kill it (freeze thaw twice)-->then draw blood and differentiate monocytes into dendritic cells-->feed the dead tumor cells to the DC's-->DC's present antigens in MHC II with CD86 (costim)-->inject DCs presenting tumor antigens back into patient-->DC’s activate tumor specific T cells!!!! -->Patient recovers!!!!
--injected DC’s gives us a Th1 response which is great for cancer
--DC's have 2000 more peptide presentation than macrophages
--DC's stimulate T cells (CD4 and CD8) which divide and go kill tumor
--highly effective, several different universities around the world are doing different types of tumors
--company in Seattle just won the NY Times "Innovation" award for this treatment this year
--still "experimental" so really expensive
--you can have your own blood drawn and stored in refrigeration in case you ever need DC treatment in the future

D. Coley's Toxins
--Coley was an MD pre-1920
--the procedure: mash up bacteria (any old kind, he had no way to know for sure what he had)-->kill it-->inject in into tumors-->watch the tumors go away
--inducing very strong Th1 response to bacteria-->bystander effect, immune system is sensitized to antigens on cancerous cells because it has costimulation
--some died from the fever, went into shock, so the FDA decided it was dangerous and banned it
--the ones that survived the fever no longer had cancer
--Ludwig institute is an international cancer research group figuring out mechanisms and trying to get it back
--Book about Coley called "Commotion in the Blood" (1997)

II. Tumor specific Antigens
--needed to develop immune response to tumors
--examples: proteins that are normally only expressed in embryo (tumors are not differentiated)
--examples: telomerase is a gene that extends life of cell-- expressed at high levels in stem cells (more in an embryo) and tumors,
--examples: mutant proteins such as Ras = oncogene usu presented as self-antigen, some tumors have a mutation in ras that makes it perpetually active, mutate ras is something new and "not me" so immune system responds
--examples: abnormal expression of protein, ie in wrong location
--examples: over-expressed protein
--TSAs are self antigens are often not immunogenic so therefore no danger signal
--Viral tumors are easier to fight off because there is a danger signal

C. Famous Tumor antigens
1. Melanoma has MAGE-1 & MAGE-3, antigen expressed in all melanoma tumors and nowhere else in adults except testis, currently used in both women and men
--also in melanoma: MART, antigen expressed by brain, inner ear, skin and all melanoma, if you target MARTs, you get brain damage, vertigo
2. Breast Cancer has BCA 1-3 and MUC-1
3. Prostate Cancer has PSA

I. Tumors that Escape Immunosurveillance
--if you don’t have immune system tumors start arising
--most tumors area virally induced and therefore will have a danger signal
--we constantly have little tumors starting and stopping
--no danger signal
--no co-stimulation (if not viral), therefore can't activate T cells
--look like self
--lack distinct Ag peptides
--stop expressing some of their MHC molecules (down regulate 2 of 3 MHC molecules) so they have enough MHC not to attract NK attention, but not enough to activate T cells
--some viruses make their own MHC that T cells don't recognize
--not known why you don't get an alloresponse to these-- may be xeno
--viruses can make immunosuppressive cytokines (TGF-β)

II. Normal Immune Response to a Tumor
--Virus infects cell and mutates an oncogene/disrupts a tumor supressor gene-->viral antigen and/or mutant protein is presented by MHC class I molecule without co-stimulation (not professional APC)-->cell dies-->DC or Macrophage eats dead cell with virus particles-->DC or Mac presents virus and TSA with Co-stimulation-->CD8 T cells activated (probably CD4s too)-->CD8 T cells kill DC or Mac along with all other infected cells (tumor)
--need CD8 T cells to kill because most tumor antigens are endogenous: presented by MHC class I
--viruses have developed ways to block presentation or immune responses
--Herpes makes ICP47-- a protein that blocks TAP
--Cytomegalovirus makes US6-- a protein that blocks ATP binding site of TAP
--EBV causes production of IL-10 and blocks B cell signalling

Psychoneuroimmunology (sometimes referred to as Neuroimmunomodulation)
--science that connects mind and body, brain and immune system
--Pyschoneuroimmunology or neuroimmunomodulation? not the same thing because psychoneuro considers subjective states of mind, emotions etc, whereas neuro just looks at objective measures, neurotransmitters etc
--Hippocrates, entwined body and soul in the 4th century BC
--Descarte, reductionist of the 16th century
--LPS induces fever and releases endogenous "pyrogen" that induces fever via hypothalamus
--fever correlates with increase in plasma cortisol, suggesting activation of HPA axis
--IL-1 is endogenous pyrogen, also makes you sleepy (ie it influences brain)
--lymph nodes are innervated
--lymphocytes express receptors for neurotransmitters, incl glucocorticoids, catecholamines

F. More than 150 studies have shown that stress has an effect on the immune system
--studies with Med students-->exams and social support effect Hepatitis vaccine response
--Isolate PBLs, treat with catecholamines-->shuts down IL-12 production-->Th2 response
--Inflammation = IL-1, IL-6, TNF-a
--Th1 = IFNg, TNFa
--Th2 = IL-4, IL-5, IL-10
--HPA axis and Glucocorticoids: Paraventricular nucleus (PVN) in the hypothalamus releases CRH (Coricotropin Releasing Hormone) and AVP (Arginine Vasopressin)-->pituitary makes ACTH (AdrenoCoricoTropic Hormone)-->adrenal cortex to make cortisol-->various effects on the nervous system, endocrine system, and immune system
--Glucocorticoids suppress the immune system, are prescribed clinically as anti-inflam med
--Nobel Prize awarded to Kendall, Reichstein, and Hench for their characterization of hormones of the adrenal cortex
--Glucocorticoid Effects on the immune system
a. Cytokines
b. Chemokines
c. Adhesion Molecules
d. Trafficking
e. Proliferation
f. Effector Functions
--GC receptors are transcription receptors, and cytokine genes have GC response elements
--GC could also effect NF-kB, could prevent NF-kB from migrating to the nucleus

C. Chronic Immune Activation
--if you block cortisol in Rheumatoid arthritis-->immediate flare in disease activity
--decreased CRF has been noted in several chronic inflammatory disease animal models
--EAE, SLE, Arthritis
--MS-- elevated resting levels of cortisol in plasma suggests that cortisol keeps things from getting over activated
--1/2 of RA and MS pts have altered HPA axis

IV. Sympathetic Adrenal Medullary Axis (SAM)
--Works in concert with the HPA axis
--medulla produces epinephrine and norepinephrine
--"flight or fight response"
--macrophages express alpha and beta adrenergic receptors, concentration dependent
--low concentration of Epi/NE, alpha adrenergic (high affinity)
--high concentration of Epi/NE, beta adrenergic (low affinity)
--alpha increases phagocytosis, increases TNFa, increases IL-6
--beta decreases phagocytoisis, decreases antigen processing and presentation, decreases production of IL-12.

--morphine significantly decreases the production of IL-12 in macrophages in vitro-->decreases Th1 response-->skew toward Th2 response
--enhanced immune function associated with psychiatric intervention in patients with malignant melanoma (Fawzy et al): increased CD8 cells, NK cells, and NK cell activity, lower mortality after 5-6 years
--similar studies with breast cancer
--breast cancer patients may have higher levels of depression
--neuropeptides associated with depression (complicated pattern)
--HIV patients have higher levels of anxiety (therefore higher levels of Epi/NE?)

IX. Problems with studies in PNI
--Immune function is affected by age, sex, alcohol, tobacco, other drugs, nutrition, sleep
--Assays are variable, most studies use PBMCs, yet these cells comprise less than 5% of total pool of WBCs
--For many of these studies, the interest is in what the "whole system" (mind and body) are doing. Yet, to do the experiments, we take the lymphocytes out of the system and manipulate them in vitro
--Drugs used rather than natural neurotransmitters



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