what is pleitropy and how does this affect cytokines' use therapeutically?

a single cytokine may act on many different cell types, mediating diverse biological effects

poses a problem therapeutically because interrupting one cytokine would disturb its other biological effects, resulting in unwanted side effects

what is redundacy and what impact does it have on cytokine-directed therapeutics?

multiple cytokines have same functional effects

antagonizing one cytokine due to one of its particular functions may not fully eliminate that particular response...since other cytokines are mediating the same response

bind with high affinities at very low concentrations

low percent receptor occupancy required to mediate response

receptor expression mediated by external signals (+/- feedback)

what cytokine sustains interaction between innate and adaptive immunity?

IL 12 is secreted by macrophage and stimulates CD4+ and CD8+maturation, differentiation, and proliferation

• IgE production via B cell stimulation
• Th2 differentiation
• Macrophage inhibition

these all demonstrate the varied roles of IL4

increased expression of class I MHC molecules on many cell types

this is an example of SYNERGY

name a cytokine that antagonizes the macrophage stimulating effect of IFNγ.

• IL 1
• IL 6
• TNF

most cytokines induce gene expression. the jak/stat pathway is a common one for cytokine signaling. describe the key steps.

1. cytokine binds dimerized receptor
2. binding triggers JAK mediated phosphorylation of tyrosines located on the intracellular portion of the receptor dimers
3. phosphorylated tyrosines enable association of 2 STAT proteins to the receptor
4. STATs are phosphorylated by JAK and then dimerize away from receptor
5. STAT-dimer translocation to nucleus, where it acts as a transcription factor via promoter binding on a cytokine responsive gene
6. transcription

• IL 4
• IL 10

• IL 1
• TNF α

• source: fibroblasts, bone marrow, stromal cells
• targets:immature lymphoid progenitors
• cell populations induced: B and T lymphocytes

• source: T cells
• targets: immature progenitors
• cell pops induced: ALL

• source: T cells, macrophages, endothelial cells, fibroblasts
• target:immature and committed progenitors, mature macrophages
• cell pops induced: granulocytes, monocytes, macrophage activity

• source: macrophages, endothelial cells, bone marrow cells, fibroblasts
• targets:committed progenitors
• cell pops induced: monocytes

• source: macrophages, fibroblasts, endothelial cells
• targets: committed progenitors
• cell pops induced: granulocytes

what does the Ig super family of receptors primarily bind?

low quantities

• local inflammation via leukocyte activation, endothelial cell IL 1 secretion

moderate quantities

• systemic effects like fever (CNS), liver production of acute phase proteins, bone marrow leukocyte production

high quantities

• septic shock: low cardiac output, thrombus and low resistance in blood vessels, hypoglycemia

TNF antagonizes glucocorticoid induction of PEPK (a key enzyme involved in gluconeogenesis)

what cells primarily produce TNF and what stimulates these cells?

LPS is a potent stimulator of macrophage secretion of TNF-a

other bacterial products are also effective stimuli

what does etanercept treat and what is its mechanism?

etanercept is a treatment for RA

soluble TNF receptor-Ig Fc region fusion protein dimer that competes with cell-associated receptor for free TNF

anti-TNFa mAb

also treats RA

what are some of the major characteristics of RA and, when appropriate, what cells are involved?

• inflamed synovial membrane
• pannus (membrane of granulomatous tissue derived from mesenchyme and bone marrow cells) formation in the afflicted joint
• synovial fluid full of PMNs
• cartilage thinning resulting in bone on bone

TNF is all over these processes via macrophage; also fibroblasts and T cells involved

what two cell types that degrade the joint are stimulated by IL 1 and TNF?

• chondrocytes
• synoviocytes

both cell types produce collagenases and other neutral proteases

what are the downstream effects of TNF/IL1 stimulations in joints?

• increased inflammation via macrophage secreted pro-inflammatory cytokines
• increased cell infiltration via increase in adhesion molecules (endothelium)
• increased angiogenesis via endothelium released VEGF
• articular cartilage damage via synoviocyte metalloproteinase synthesis
• bone erosions via osteoclast increase in RANKL expression

IL 1 is a proinflammatory cytokine.  What are some of its major functions, esp thinking about its role in RA?

• activates macrophages --> inflammation
• induces fibroblast prolif--> synovial pannus
• activates chondrocytes--> cartilage breakdown
• activates osteoclasts --> bone resorption

what are the components of IL 1-mediated signaling?

IL 1 R + IL 1R AcP (accessory protein) form a heterodimer to bind IL 1

Myd88 is the adapter signal that aids in intracellular signaling, ending in activation of NFkB (transcription factor)

recombinant anti-inflammatory protein that acts as a IL-1 receptor antagonist

attempts to bind IL1R so that IL-1 cannot; when anakinra is bound to IL-1R, it does not transmit any intracellular signals because IL-1R and IL-1R AcP are blocked from association...

source: primarily LPS-activated macrophages, DCs

primary mediator of innate response to intracellular microbes

key inducer of CMI via its ability to induce IFN

major function: stimulate production of IFN gamma by NKs and T cells --> stimulates macrophages to produce TNF

IL 12 also stimulates differentiation of CD4 to become IFN producers (TH1 response)

chronic inflammation and intracellular killing

comes from macrophages/DCs

stimulates NKs, CTLs, CD4+-->TH1 cell

each of these cell types secretes IFNγ

macrophage activation results and enhanced killing of phagocytosed microbes

IL 12 enhances cytolytic activity of NKs, CTLs

why is IL 12 the "dark lord" of Th1 inflammatory disease?

IL 12 stimulates CD4+ --> TH1 cells

also stimulates all other CMI cells: NKs, CTLS, Macrophages

IL-12: tx for immunosuppressed like cancer pts

also target for Crohn's disease (ANTI IL 12 therapy)

transcription factor: ROR δΤ

highly implicated in inflammatory diseases, like: RA, Crohn's, lupus, psoriasis

relatively recently discovered

GM CSF, G CSF, IL 11 (platelets) and erythropoeitin are all clinically used to support production of various bone marrow derived cells during chemotherapy and HIV/AIDS

what cell population is greatly decimated during chemo?

neutrophils are particularly lost during chemo resulting in neutropenia and increase in infection susceptibility

G CSF is highly indicated in chemo!

• increased chemotaxis
• enhanced phagocytosis
• increased cytotoxic killing
• improved Ag response

induces enzymes that block viral replication when bund to a potential virus target cell --> induction of antiviral state

antiproliferative effects

induces increased expression of MHC class I molecules on infected cells, CTL lysis

stimulates macrophages

• Hep B, Hep C, and SARS (recently)
• hairy cell leukemia
• malignant melanoma
• MS

all marked by pathogenetic abnormalities in CMI

• inhibition of IL 12 production
• augmentation of IL 10 production

add on therapy for MS pts also on IFN B who did not fully respond to it alone due to extremely high brain inflammation

H anti-CD25 (daclizumab) blocks CD25, the IL 2R a chain expressed on activated T cells