Cytokine and Chemokine Interactions in Allergic Airway Inflammation. ILAR 40 (4): 157.
This article describes classical and modern models of allergic asthma, cytokine cascades during allergic airway responses, and differential roles of chemokines during induction of allergic airway disease. Asthma is an upper airway disease characterized by episodes of airway reactivity and bronchospasm and perhaps by an underlying inflammation of the bronchi that play a central role in the clinical expression and pathogenesis of the disease. Classically, it was hypothesized that allergens bind to sensitized mast cells in the lung via the IgE Fc receptor. Binding induces mast cell degranulation with release of mediators including TNF, IL-4, PAF, leukotrienes. Degranulation induces immediate bronchoconstriction, vasodilation (leading to edema), and recruitment of leukocytes. The asthmatic patient experiences a second decline in lung function associated with the accumulation of leukocytes around large airways that may lead to end stage disease.

Established murine models involve the use of allergenic proteins (ovalbumin), Schistosoma mansoni, and cockroach allergens. Responses include early lung neutrophilic infiltration, delayed eosinophilic infiltrate, elevated levels of cytokines (IL-4, IL-5), and a number of mediators (histamine, eosinophil peroxidase). However, various laboratories have identified differences in mediator involvement. The most common model employs ovalbumin, but the model is not yet standardized and can differ drastically between laboratories. Another model utilizes cockroach antigens given IP or IT. The intratrachael approach allows for greater standardization. Utilizing both models allows for decipherance of temporal changes in cytokines and chemokines.

Cytokine cascades are complex. Numerous studies suggest that the onset of asthma is driven by CD4+ T lymphocytes. These cells differentiate into Th1 or Th2 cells that produce numerous cytokines. IL-4 induces IgE class switching, upregulates adhesion molecules (VCAM-1), and promotes eosinophil extravasation from blood. IL-13 is involved in mucus secretion and eosinophil accumulation. IL-5 is essential for terminal differentiation and survival of eosinophils and mediates systemic release of cells from bone marrow. IL-5 promotes release of and primes eosinophils. The balance between Th1 or Th2 cytokines is critical and their response is different even though they bind to the same receptor.

Chemokines are a family of small molecular weight proteins (8-10kD) that have the ability to induce the migration of different subsets of leukocytes. Potent eosinophil chemotractants include eotaxin, macrophage inflammatory protein, and monocyte chemoattractant protein. Multiple chemokines are necessary at various stages of the allergic response for the recruitment of eosinophils. These chemokines bind to two sets of receptors on eosinophils: CCR1 and CCR3. CCR1 is expressed in low levels, making CCR3 a primary focus of therapeutic targeting.
Questions:
#1. What would the ideal model of allergic airway disease exhibit?
#2. What species is traditionally associated with human models of allergic airway inflammation?
Q#1 The ideal model would exhibit:
· Early and late antigen induced airway disease
· Reversible bronchial hyperresponsiveness
· Peribronchial eosinophilia
· Chronic lung remodeling
Q#2 What species is traditionally associated with human models of allergic airway inflammation?
Answers not provided.

 Role and regulation of chemokines in rodent models of lung inflammation. ILAR 40 (4): 163.
The lung has been used as a model for acute inflammatory reactions because there is a defined cell population and there is a large body of data characterizing the lung inflammatory response. A major role of the L-8-related chemoattractant cytokines is mobilization of neutrophils from the blood. Subclasses of these cytokines are defined by the location of conserved cystein residues on the cytokines, namely CC, CXC, and CXXXC. Subclasses of chemokines have been found to posses chemotactic activity for different cell types; CXC for neutrophils, CC for monocyte/macrophage and lymphocyte. They are produced by macrophages, epithelial and endothelial cells, and fibroblasts in the lungs. Rodents do not have chemokines that are structurally identical to humans.
The functional equivalent of CXC in rodents is macrophage inflammatory protein (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC). Regulation of these cytokines is thought to be controlled by tissue macrophages and release of early response cytokines, TNF-alpha and IL-1. They may be targets for anti-inflammatory interventions.
The CC chemokine subfamly is typified by MIP-1 and Monocyte chemoattractant protein-1 (MCP-1). A subunit of MIP-1, MIP-1alpha, is upregulated following injury. It is speculated that MIP1-alpha is an autocrine stimulator of TNF-alpha to enhance macrophage production of MIP-1 alpha. MIP-1 alpha may be an important mediator of virus induced inflammation.
MCP-1 is a chemotactic and activating CC chemokine for mononuclear leukocytes. Blocking MCP-1 activity leads to a marked reduction in lung injury as measured by pulmonary vascular permeability, alveolar hemorrhage and pulmonary monocyte/macrophage recruitment.
Questions:
1. Describe the mechanism that causes neutrophils to move from the blood to tissue.
2. T/F Rodent IL-8 related chemoattractant cytokines are structurally identical to humans.
3. Name two early response cytokines.
Answers:
1. IL-1 and TNF-alpha are expressed. Adhesion molecules on the surface of the vascular endothelial cells, interact with counter receptors on the neutorphils. This leads to margination, rolling and adhesion of neutrophils along the endothelial surfaces and transmigration of neutrophils through reversibly opened intercellular junctions in the endothelium.
2. F
3. IL-1 and TNF-alpha

 Use of Animal Models in the Study of Inflammatory Mediators of Pneumonia. ILAR 40 (4): 167.
Mice are frequently used although their conducting airways are lined with cuboidal epithelium not pseudostratified columnar epithelium as is found in humans.
In an attempt to closely mimic human pneumonia, most pathogens are delivered by the respiratory route. Intranasal delivery under anesthesia is a simple method that is often used but the amount of pathogen delivered can be quite variable as the animal may swallow or exhale part of the dose. Intratracheal delivery, while slightly more complicated, allows for a more consistent delivery of the pathogen.
Strain variations in response to different pathogens have also been noted. With respect to Klebsiella, CD-1,CBA/J and BALB/c are quite susceptible while C57/Bl6 are more resistant. One possible reason for this may be related to the strain specific response to lipopolysaccharide (LPS). There are multiple other mechanisms for strain variations in response to pathogens. One that is known involves C57Bl/6 mice that are more susuceptible to Cryptococcus neoformans than CBA/J or BALB/c mice. The reason for this is that a Th-2 cytokine response rather than Th-1 is associated with susceptibility.
The review also discusses mouse models that are available for studying concurrent effects of alcoholism, immunosuppression, sepsis and bronchiectasis.
Techniques for quantifying the extent of pathogen invasion and measuring the host response to the pathogen are reviewed. Some of the methods mentioned for quantifying the generation of mediators include the use of reverse transcriptase PCR or Northern blot analysis for mRNA measurements and the use of ELISA or Western blot analysis for protein measurements.
Other means of assessing the role of cytokines and other immune mediators in pneumonia include the use of neutralizing antibodies to deplete TNF-alpha or CD4+/CD8+ T-cells. The use of pharmacologic agents such as cyclophosphamide has also been described; however, these compounds are often non-specific and may deplete more than one cell type/inflammatory mediator. Conversely, mediator molecules have often been administered to animals to determine their affects on pneumonia. The limitations affecting this method of include the rapid degradation and short half-life of cytokines. The effects of cytokines are also highly dependent on the route of delivery. While adenoviral vectors have been used as a means of delivering inflammatory mediators, their antigenic properties may interfere with the goals of the study.
The use of transgenic and knockout animals is also reviewed with emphasis on the ability to control the expression of the gene to a specific region of the lung and to control the timing of expression with the use of tetracycline inducible systems. Some limitations with the use of transgene/KO animals include the time and expense involved in their creation and the possibility of unexpected phenotypes and/or aberrant responses.
Questions:
Q1: T or F, The conducting airways of mice are lined with columnar pseudostratified epithelium?
Q2: What 2 species have pulmonary intravascular macrophages?
Q3: Which of the following strains/stocks is more resistant than the others to Klebsiella pneumonia?
a) CBA/J
b) BALB/c
c) C57/Bl6
d) CD-1
Answers:
A1: False, the conducting airways of mice are lined with cuboidal epithelium
A2: Swine and sheep
A3: c) C57/Bl6 mice are more resistant to Klebsiella pneumonia than the other strains; however, they are more susceptible to Cryptococcus neoformans pneumonia.

 Introduction. ILAR 40 (4): 141.
Chemokines are chemotactic cytokines in the interleukin (IL)-8 family of interleukins. Based on cysteine residue structure and position, chemokines exist as 4 different families. At least 40 different chemokines are currently known. Microarray technology, which allows for large-scale enumeration of mRNA tissue statement, provides another level of complexity in understanding what chemokines are doing in biological responses. Chemokine receptors are "promiscuous" (multiple chemokines interact with the same and with other receptors). There is also functional redundancy in chemokines, making it difficult to define their biology in experimental systems in which specific chemokines are blocked (by antibody) or absent due to induced mutations (knockouts). Some examples of chemokine complexity in biological responses include inflammatory responses to bacterial infections, to allergic triggers, and to immune-related products (i.e. immune complexes, tumor cells, angiogenic inducers). Responses involving chemokine statement almost invariably involve activation of nuclear factor kappa B (NFkB), which is required for gene activation but is tightly regulated by inhibitory factor kappa B (IkB). Mediators such as IL-1 and tumor necrosis factor (TNFalpha) activate NFkB, setting off a proinflammatory cascade. Interleukins such as IL-10 and IL-13 have opposite effects, preventing gene activation. Chemokine statement is facilitated by 2 activated macrophage products, TNFalpha and C5a. These 2 factors lead to autocrine stimulation of chemokine statement in macrophages. "Networking" of mediators is a common theme of the inflammatory response.
Questions:
1. Which of the following statements is FALSE with respect to chemokines?
a. Chemokines are chemotactic cytokines.
b. Chemokine receptors are promiscuous.
c. Chemokine gene activation requires the action of either IL-10 or IL-13.
d. Chemokines are functionally redundant.
2. What do the following acronyms stand for: NFkB, IL, IkB, TNFalpha.
Answers:
1. C. Interleukins such as IL-10 and IL-13 preventing chemokine gene activation.
2. nuclear factor kappa B = NFkB); interleukin = IL; inhibitory factor kappa B = IkB; tumor necrosis factor = TNFalpha.

 New frontiers in cytokine involvement during experimental sepsis. ILAR 40 (4): 142.
Sepsis is very common and defined by two diagnostic criteria: (1) systemic inflammatory response syndrome (SIRS), a state of severe systemic endothelial cell inflammation, and (2) documented evidence of infection. The clinical manifestations of sepsis are mostly the result of cellular interactions associated with systemic inflammation. Symptoms of sepsis include hypotension, coagulopathy, fever or hypothermia, tachycardia, tachypnea, tissue injury, and multiorgan dysfunction. Sepsis can induce a state of immunosuppression that predisposes patients to nosocomial infections, especially pneumonia. Despite medical advances, sepsis related mortality remains high.
Pathogenesis
Sepsis in initiated by microbial organisms or their components such as LPS. The manifestations of sepsis depend on the organized series of molecular and cellular events involved in cell signaling and activation. The mediators responsible for these communications include reactive nitrogen and oxygen metabolites, lipids, nucleotides, peptides, and polypeptides. Cytokines are active communication signals that act through autocrine, paracrine, or endocrine pathways to influence cellular activation, chemotaxis, cell differentiation, augmentation of phagocytosis, and cell proliferation. During the onset of sepsis, microbial components and byproducts induce the production of the early-response, pro-inflammatory cytokines, TNF-alpha and IL-1beta, which mediate hemodynamic and inflammatory changes. These cytokines also induce production of other pro-inflammatory cytokines like IL-6, IFN-gamma, IL12, and various chemokines. Although this response is necessary to address bacterial colonization locally, the release of inflammatory cytokines into the circulation can result in systemic immune cell activation, hemodynamic instability, and end-organ injury. The host relies on anti-inflammatory mediators, such as soluble TNF and IL-1 receptors, IL-10, and IL-4 to rein in the inflammatory response of sepsis. This anti-inflammatory response contributes to the immunosuppression seen in sepsis.
Modeling Sepsis
Many studies of sepsis utilize treatment with LPS, which induces many of the manifestations of sepsis other that the presence of a bacterial infection. This can create problems in therapeutic evaluation. Studies evaluating TNF and IL-1 neutralizing strategies showed promise in LPS models but failed in human septic patients. Many other models of sepsis involve the administration of a large bolus of bacteria. This can induce changes more consistent with toxic shock, rather than sepsis, since human sepsis patients seldom face sudden exposure to a large number of bacteria. The cecal ligation and puncture (CLP) model is induced by ligating the distal third of the cecum and puncturing it with a needle. This results is a slow leak of cecal contents into the peritoneum and mirrors many clinical cases of sepsis. This models meets the two criteria for sepsis, systemic inflammation and active microbial infection. Although many species have been used in sepsis studies, mice offer the advantages of cost effectiveness due to the large number required, and the various technologies available for mouse studies including mono and polyclonal antibodies, ELISAs, and genetic manipulations.
Cytokines in Sepsis
In sepsis, TNF, IL-1, IL-6, and IL-8 have been most strongly associated with disease progression. Infusion of TNF or IL-1 can induce many of the signs of sepsis. Although TNF and IL-1 can contribute to polymorphonulcear maturation, trafficking, and activation, they play a fundamental role in sepsis by initiating a pro-inflammatory cascade. IL-12 has been regarded as the pivotal stimulus of Th1-type cell-mediated immune responses. IL-12 may also play a role in sepsis as studies have shown that it can enhance the cytolytic activity of cytotoxic T lymphocytes and natural killer (NK) cells, and stimulate the proliferation of activated T and NK cells. Furthermore, IL-12 induces production of IFN-gamma that then results in many pro-inflammatory changes including production of TNF and IL-1. In LPS models, IL-12 and INF-gamma clearly have pro-inflammatory roles. Their function in sepsis is more complex. In sepsis models, neutralization of IL-12 and INF-gamma results in reduced bacterial clearance and increased infection-induced mortality, while the same treatment in LPS models resulted in substantial improvements in mortality. INF-gamma receptor knock out mice experience increased mortality in a fecal model of peritonitis. IL-10 is an important anti-inflammatory modulator in sepsis. Neutralization of IL-10 in models of sepsis results in exaggerated pro-inflammatory cytokine expression and death. Furthermore, the administration of IL-10 to mice with endotoxemia or bacterial sepsis confers significant protection due to the suppression of production of pro-inflammatory cytokines, including TNF-alpha, IL-1, and IFN-gamma. IL-10 production can result in immunosuppression and predispose to nosocomial infections.
Chemokines in Sepsis
Chemokines are a class of cytokines that act as leukocyte chemoattractants and also play roles in angiogenesis, fibrogenesis, immune/inflammatory responses and as inflammatory /immune cell activators. Chemokines are classified according to cysteine motifs and are grouped into C-X-C, C-C, or the more recently described C and C-XXX-C groups. Some chemokines are upregulated during sepsis, such as IL-8, macrophage inflammatory protein (MIP-1alpha), MIP-1beta, monocyte chemotactic protein (MCP-1) and MCP-2. MCP-1, MIP-1alpha, and MIP-2 are produced during CLP-induced sepsis. Neutralization of MIP-2 results in reduced neutrophil infiltration of the peritoneal cavity and reduced mortality in this model. However, administration of MCP-1 can also confer therapeutic advantage, presumably by facilitating IL-10 production. Chemokines may be more attractive therapeutic targets than cytokines because (1) they are more distal on the inflammatory cascade that cytokines and (2), there are many of them (>50).
Conclusion
In sepsis there is a delicate balance between pro- and anti-inflammatory cytokines. The pro-inflammatory cascade causes most of the sepsis-induced pathology but is necessary for the containment of infection. Chemokines are more distal mediators of the inflammatory cascade and may be better therapeutic targets.
Questions:
1. Which of the following is NOT a pro-inflammatory cytokine?
a. IL-1beta
b. IL-10
c. IL-6
d. TNF-alpha
e. IFN-gamma
2. The cecal ligation and puncture (CLP) procedure creates a model for what disease?
3. What are the two general diagnostic criteria for sepsis?
Answers:
1. b
2. Bacterial sepsis with leakage of bowel contents. This is seen in humans
with conditions such as postsurgical trauma, inflammatory bowel disease,
and bowel ischemia.
3. (i) Systemic inflammatory response syndrome (SIRS) with severe systemic endothelial cell inflammation and (ii), documented evidence of infection.

 Understanding the pathogenesis of inflammation using rodent models: identification of a transcription factor (NFKB) necessary for development of inflammatory injury. ILAR 40 (4): 151.
Although acute inflammation is a necessary homeostatic response to tissue injury, disregulated inflammatory processes can result in disease. Lung injury induced in rats by distal airway deposition of IgG immune complexes has been used for years as a model of lung inflammation that shares inflammatory pathways with conditions such as lung ischemia, bacterial infection, and LPS administration. In rats and mice, hepatic ischemia and reperfusion results in local and remote organ inflammation. This model is relevant because lever resectional surgery, transplantation, and hemorrhagic shock with fluid resuscitation are complicated by inflammatory organ injury stemming from hepatic ischemia. Both of these models share a similar inflammatory pathway: Compliment activation -> Macrophage activation -> Release of TNF alpha (TNFa) and IL-1 -> Upregulation of Vascular Cell Adhesion Molecules and Chemokines -> Tissue recruitment of neutrophils ->Neutrophil and Macrophage-derived oxidants and proteases -> Tissue damage
Regulation of Inflammatory Mediator by Nuclear Factor Kappa B (NFkB) NFkB is a general term used to describe a number of dimeric combinations of members of the Rel family of gene regulatory proteins. In unstimulated cells, NFkB is retained in the cytoplasm by interaction with one of seven inhibitory factor kappa B (IFkB) proteins. In response to a wide variety of stimuli, IFkB is phosphorylated by members of the IkB-kinase family (IKK). Phosphorylation targets IFkB for ubiquination and degradation. NFkB is then able to translocate to the nucleus, bind specific promoter elements, and induce transcription of certain genes such as TNFa, IL-1, chemokines, and vascular endothelial cell adhesion molecules.
NFkB Activation during Acute Lung Inflammation Following exposure to IgG complexes, rat alveolar macrophages rapidly demonstrate increased nuclear translocation of NFkB. This activation leads to enhance production of the proinflammatory cytokines TNFa and IL-1, which then results in upregulation of chemokines and vascular adhesion molecules within the lung. Neutralization of TNFa or IL-1 attenuated NFkB activation. Macrophage depletion virtually abolishes NFkB activation. In rats depleted of macrophages, lung installation of TNFa caused activation of NFkB in whole lung tissues. These studies suggest that NFkB activation in lung macrophages may be responsible for proinflammatory cytokine production as well as activating NFkB in other cell types. Antioxidants prevent phosphorylation and degradation of IkB in vivo and in vitro, although the exact mechanism by which this occurs is not clear. Anti-inflammatory cytokines like IL-10 and IL-13 suppress lung inflammation and prevent NFkB activation. A serine protease inhibitor, secretory leukocyte protease inhibitor (SLPI), has a similar effect.
NFkB Activation during Acute Liver Inflammation In rats and mice, hepatic ischemia and reperfusion causes activation of liver macrophages (Kupffer cells) and the release of reactive oxygen species and proinflammatory cytokines. TNFa causes hepatic upregulation of adhesion molecules and neutrophil-attracting chemokines. These neutrophils release proteases and reactive oxygen intermediates that damage hepatocytes and endothelial cells and contribute to capillary plugging and hepatic hypoperfusion. The hepatic ischemia/reperfusion model was used to show that NFkB activation occurs shortly after reperfusion. Unlike in the lung, NFkB activation in the liver occurs without measurable degradation of IkB.
Conclusion Because NFkB proteins control gene expression of mediators at every level of the inflammatory response, they are potentially valuable therapeutic targets. IL-10, IL-13, and SLPI suppress NFkB activation.
Questions:
1. In the intrapulmonary deposition of IgG immune complexes model of lung injury, activation of NFkB results in many proinflammatory effects. What is the primary cell type in the lung that produces IL-1 and TNFa in response to NFkB activation?
a. Neutrophils
b. Clara cells
c. Macrophages
d. Eosinophils
e. Type II pneumocytes
2. What agent does NOT inhibit NFkB activation?
a. IL-10
b. Secretory leukocyte protease inhibitor (SLPI)
c. IL-13
d. IkB
e. IL-1
Answers:
1. C
2. E

 Use of immunodeficient mice for the evaluation of CXC chemokines in the regulation of tumor-associated angiogenesis. ILAR 40 (4): 175.
Angiogenesis is the growth of new blood vessels from existing vessels. This growth is necessary for healing and embryogenesis, but can play a role in tumorigenesis. In the normal animal there is a balance between angiogenic and angiostatic factors but in tumorigenesis a dysregulation of angiogenesis can lead to an imbalance which favors persistent net angiogenesis. This can in turn contribute to tumor growth and metastasis.
Many factors have been described that promote (vascular endothelial growth factor [VEGF], basic fibroblast growth factor [bFGF]) or inhibit (angiostatin and endostatin) angiogenesis. Another group of proteins that exhibit either angiogenic or angiostatic properties are the CXC chemokine family of cytokines. The designation CXC comes from a highly conserved motif of 4 cysteine residues, with the first two cysteines separated by one nonconserved amino acid residue. A second motif within this family determines their angiogenic potential: a glu-leu-arg (ELR) motif can precede the first cysteine residue. CXC chemokines with the ELR motif are potent promoters of angiogenesis; those that lack the ELR motif are angiostatic. Examples of ELR+ CXC chemokines include interleukin-8, epithelial neutrophil activation protein-78, growth-related oncogene alpha, granulocyte chemotactic protein-2, platelet basic protein, onnective tissue activation protein-III, thromboglobulin, and neutrophil activating protein. Angiostatic ELR- CXC chemokines include platelet factor-4, interferon-gamma-inducing protein, and monokine induced by interferon-gamma.
Using various human tumor cell/immunodeficient mouse chimeras as models for human tumorigenesis, it has been demonstrated that CXC chemokines appear to be important endogenous factors that regulate
angiogenesis in tumorigenesis in a variety of cancers. The immunodeficient mice used for these studies are SCID or nude mice, so that angiogenesis and tumorigenesis can be studied in a B- and/or T-cell independent system. Various ELR+ CXC chemokines have been studied in melanoma, ovarian carcinoma, and non-small cell lung carcinoma/mouse chimeras, and the results suggest that ELR+ CXC chemokines are significant angiogenic factors in human tumors. ELR- CXC chemokines have been studied in Burkitt's lymphoma and non-small cell lung carcinoma/mouse chimeras, with results suggesting that these chemokines attenuate angiogenesis associated with tumorigenesis. Therapy directed at inhibition of angiogenesis or augmentation of angiostasis may be a novel approach in the treatment of human tumors.
Questions:
1. What does ELR stand for when referring to CXC chemokines?
2. Name three factors that promote angiogenesis.
3. Name three factors that inhibit angiogenesis.
4. What is a CMP assay? (sorry, but the answer to this isn't in my summary--just thought it was a useful bit of info.
Answers:
1. ELR stands for the one-letter designation of the 3 amino acid residues glutamic acid, leucine, arginine. It is a highly conserved motif in some members of the CXC chemokine family of cytokines, and its presence indicates angiogenic properties.
2. vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), epithelial neutrophil activation protein-78 (ENA-78), growth-related oncogene alpha/beta/gamma granulocyte chemotactic protein-2 (GCP-2), platelet basic protein (PBP), connective tissue activation protein-III (CTAP-III), beta-thromboglobulin, neutrophil activating protein-2 (NAP-2)
3. angiostatin, endostatin, platelet factor-4 (PF-4), interferon-gamma-inducin protein (IP-10), monokine induced by interferon-gamma (MIG)
4. CMP = corneal micropocket --a model of angiogenesis, usually done in rats

 Chemokine regulation of immune-mediated demyelinating disease. ILAR 40 (4): 183.
Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T-helper (Th1) 1-mediated, inflammatory demyelinating disease of the central nervous system (CNS) that serves as a model for multiple sclerosis (MS). EAE can be induced in genetically susceptible animals by immunization with neuroantigens such as proteolipid protein, myelin basic protein, myelin oligodendrocyte glycoprotein, and the immunodominant, encephalitogenic peptide sequences of these molecules emulsified in complete Freund's adjuvant (CFA) or by the adoptive transfer of antigen-activated T lymphocytes. The disease is characterized either by a progressive ascending clinical paralysis followed by periods of remission and subsequent relapses or as monophasic, acute, and nonrelapsing. Chemokines such as macrophage inflammatory protein (MIP1)-1a, monocyte chemotactic protein (MCP1)-1, interleukin (IL1)-8, and regulated upon activation normal T cell expressed and secreted (RANTES1) are chemotactic molecules that induce leukocyte accumulation in tissue sites of inflammation. Chemokines are potent chemoattractants that can be divided into four highly conserved but distinct subfamilies CXC, CC, C, and CX3C-based on the position of the first two cysteines in the amino terminus as well as the remaining cysteines in the carboxy portion of the molecule. The animal model was created by IP injecting primed donor lymphocytes cultured in Mycobacterium tuberculosis cell medium into female SJL/J mice. The mice were then observed for EAE clinical signs and spinal cord samples were harvested for chemokine evaluation. Concerning the results, the authors noted no detectable chemokine expression in the CNS of naïve mice. IN addition, there was very little detectable chemokine protein in the CNS of preclinical mice. However, during acute EAE, both MIP1-1a and RANTES were produced in the CNS in relatively substantial quantities. The author saw a difference between acute and relapsing EAE was that CNS MCP-1 (astrocyte) production, which was not detectable during acute disease, correlated with increasing relapsing EAE severity. In comparison, MIP-1a (macrophages and T cells) and RANTES levels remained elevated during relapses but did not directly correlate with increasing relapse severity. These data suggest that there was differential chemokine production during the course of EAE and that it was specific to the affected CNS inflammatory site. This investigation emphasized the multifactorial role of chemokines during inflammatory immune responses. Originally shown to be chemotactic regulators, chemokines can now be thought of as molecules that regulate the developing as well as the ongoing immune response. Finally, the precise role chemokines during the inflammatory response are not known; however, they present as regulatory targets for manipulation during developing and progressive immune responses including autoimmune disease and allergic reactions. The chemokine expression patterns vary with different clinical presentations of EAE which may explain the variation in chemokine expression patterns in MS patients as well.
Questions:
1: SJL mice can develop B cell lymphoproliferative disease due to expression of Murine Mammary Tumor Virus (MMTV) T cell superantigen (Sag). T or F
2: The SJL mouse is used as an animal model for multiple sclerosis (MS). T or F
3. Chemokines are potent chemoattractants that are characterized by the position of the first two cysteines in there amino terminus as well as the remaining cysteines in the carboxy portion of the molecule. T or F
Answers:
1. True
2. True
3. True