Thesis (Ph. D.)--University of Chicago, Committee on Immunology, June 2003. / Includes bibliographical references. Also available on the Internet.

This thesis evaluated supplementation with two components of flaxseed during exercise training on inflammation in older adults.<P>Experiment 1: This experiment assessed secoisolariciresinol diglucoside (SDG) supplementation during aerobic exercise training on inflammation in older adults. Methods: One hundred subjects aged 50y or older were randomized to receive either SDG or placebo before completing a 6-month walking program. Fasting concentrations of interleukin-6 and tumor necrosis factor-á, glucose, triacylglycerol (TAG), high density lipoprotein (HDL), low density lipoprotein, and total cholesterol as well as leukocyte cell count were measured every two months while body composition, resting blood pressure, and a composite Z-score of six metabolic syndrome risk factors were assessed at baseline and 6 months. Results: Men on placebo increased metabolic syndrome composite Z-score (p<0.05). TAG increased (p=0.017) in men on placebo relative to men on SDG and men on SDG decreased (p=0.045) DBP relative to men on placebo. Conclusions: SDG had no effect on inflammation while it is effective in attenuating risk factors associated with metabolic syndrome in older males but not females.<p>Experiment 2: This experiment evaluated alpha-linolenic acid (ALA) supplementation during strength exercise training on inflammation in older adults. Methods: Fifty-one healthy older adults (65.4±0.8y) were randomized to receive ALA or a placebo before completing a 12 wk strength training program. Subjects were evaluated at baseline and 12 weeks for TNF-á and IL-6, muscle strength, body composition, and muscle thickness. Results: Males supplementing with ALA decreased IL-6 concentration (p=0.003). The female placebo and male ALA group had a significant increase in knee flexor thickness (p<0.05). Chest and leg press strength, lean tissue mass, and muscle thickness significantly increased, while percent fat and total body mass decreased with training (p<0.05), with no difference between ALA and placebo. Conclusions: ALA lowers IL-6 in older men, but has minimal effect on muscle mass and strength during resistance training.<p>General Conclusion: A composite score of metabolic syndrome is attenuated in males supplementing with SDG. ALA reduces IL-6 in older men. Older men, but not older women, derive specific health benefits from increased consumption of components of flaxseed consumed during an exercise program.

This thesis evaluated supplementation with two components of flaxseed during exercise training on inflammation in older adults.<P>Experiment 1: This experiment assessed secoisolariciresinol diglucoside (SDG) supplementation during aerobic exercise training on inflammation in older adults. Methods: One hundred subjects aged 50y or older were randomized to receive either SDG or placebo before completing a 6-month walking program. Fasting concentrations of interleukin-6 and tumor necrosis factor-á, glucose, triacylglycerol (TAG), high density lipoprotein (HDL), low density lipoprotein, and total cholesterol as well as leukocyte cell count were measured every two months while body composition, resting blood pressure, and a composite Z-score of six metabolic syndrome risk factors were assessed at baseline and 6 months. Results: Men on placebo increased metabolic syndrome composite Z-score (p<0.05). TAG increased (p=0.017) in men on placebo relative to men on SDG and men on SDG decreased (p=0.045) DBP relative to men on placebo. Conclusions: SDG had no effect on inflammation while it is effective in attenuating risk factors associated with metabolic syndrome in older males but not females.<p>Experiment 2: This experiment evaluated alpha-linolenic acid (ALA) supplementation during strength exercise training on inflammation in older adults. Methods: Fifty-one healthy older adults (65.4±0.8y) were randomized to receive ALA or a placebo before completing a 12 wk strength training program. Subjects were evaluated at baseline and 12 weeks for TNF-á and IL-6, muscle strength, body composition, and muscle thickness. Results: Males supplementing with ALA decreased IL-6 concentration (p=0.003). The female placebo and male ALA group had a significant increase in knee flexor thickness (p<0.05). Chest and leg press strength, lean tissue mass, and muscle thickness significantly increased, while percent fat and total body mass decreased with training (p<0.05), with no difference between ALA and placebo. Conclusions: ALA lowers IL-6 in older men, but has minimal effect on muscle mass and strength during resistance training.<p>General Conclusion: A composite score of metabolic syndrome is attenuated in males supplementing with SDG. ALA reduces IL-6 in older men. Older men, but not older women, derive specific health benefits from increased consumption of components of flaxseed consumed during an exercise program.

<p>Mast cells, best known for their pathologic role in allergy, have recently been shown to have key roles in the initiation of adaptive immune responses. These cells are located throughout the body just beneath barriers separating host from environment, possess multiple pathogen recognition systems, and store large quantities of fully active inflammatory mediators. These key features make them uniquely situated to act as sentinels of immunity, releasing the very earliest alarm signals when a pathogen is present. As a testament to the importance of these cells, mast cell-deficient mice have suboptimal immune responses, and mast cell activators can act as potent adjuvants for experimental immunizations. Specifically, mast cells have been shown to enhance the number of naive lymphocytes in infection site-draining lymph nodes, and to encourage the migration of dendritic cells to responding lymph nodes.</p><p>Although infections usually occur at peripheral sites, adaptive immune responses are initiated in distant lymph nodes. Despite the distance, signals from the site of infection result in dramatic, rapid reorganization of the node, including massive recruitment of naive lymphocytes from the circulation and extensive vascular restructuring to accommodate the increase in size. How such signals reach the lymph node is not well understood.</p><p>When mast cells degranulate, in addition to releasing soluble mediators such as histamine, they expel large, stable, insoluble particles composed primarily of heparin and cationic proteins. The work presented herein demonstrates that these particles act as extracellular chaperones for inflammatory mediators, protecting them from dilution into the interstitial space, degradation, and interaction with non-target host cells and molecules. The data show clearly that mast cells release such particles, that they are highly stable, that they contain tumor necrosis factor (a critically important immunomodulator), and that they can traffic from peripheral sites to draining lymph nodes via lymphatic vessels. Furthermore, extensive biochemical characterization of purified mast cell-derived particles was performed. Finally, evidence is presented that such particles can elicit lymph node enlargement, an infection-associated phenomenon that favors the development of adaptive immunity, by delivering peripheral TNF to draining lymph nodes. </p><p>This signaling concept, that particles may chaperone signals between distant sites, also has important implications for adjuvant design. The evidence presented here shows that encapsulation of TNF into synthetic particles similar to mast cell-derived particles greatly enhances its potency for eliciting lymph node enlargement, an indication that adaptive immunity may be improved. This delivery system should ensure that more adjuvant arrives in the draining lymph node intact, where it would lead to changes favorable to the development of the immune response. Such a system would also facilitate the delivery of multi-component adjuvants that would act synergistically at the level of the lymph node when gradually released from microparticle carriers. An additional advantage of microparticle encapsulation is that vaccine formulations of this type may require much lower doses of expensive antigen and adjuvants.</p><p>The delivery of inflammatory mediators to lymph nodes during immune responses may be an important general feature of host defense. Although the action of mediators of peripheral origin on draining lymph nodes has been described before, this is the first demonstration of a specific adaptation to deliver such mediators. Not only is the characterization of mast cell-derived particles important to basic immunology, but mimicking this adaptation may also lead to improved therapeutics.</p> / Dissertation

Thesis (Ph. D.)--Cornell University, 2001. / Vita. Includes bibliographical references (leaves 167-194).

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 81-96).

The main purpose of this study was to evaluate medication use patterns (i.e., dose escalation, medication adherence, persistence, and switching) of rheumatoid arthritis (RA) patients on etanercept (ETN), infliximab (IFX) or adalimumab (ADA) and the associated healthcare utilization costs using Texas Medicaid data. Study participants were Medicaid beneficiaries (18-63 years) with an RA diagnosis (ICD-9-CM code 714.0x) who had no claim for a biologic agent in the 6-month pre-index period (July 1, 2003 - Dec 31, 2010). The index date was the first date when the patient had the first fill for any of the study TNF inhibitors (ETN, ADA or IFX) within the study identification period (Jan 1, 2004 – Aug 31, 2010). Data were extracted from July 1, 2003 to August 31, 2011. Prescription and medical claims were analyzed over an 18-month study period (i.e., 6-month pre-index and 12-month post-index periods). The primary study outcomes were adherence, persistence, dose escalation, switching and cost (i.e., total healthcare, RA-related and TNF inhibitor therapy cost). The study covariates were demographic factors (age, gender, race/ethnicity), pre-index use of other RA-related medications (pain, glucocorticoids and disease modifying antirheumatic drugs), total number of non-study RA-related medications used at index, pre-index RA and non-RA related visits, pre-index healthcare utilization cost and Charlson Comorbidity Index score. Conditional regression analyses, which accounts for matched samples, were used to address the study objectives. After propensity score matching, 822 patients (n=274/group) comprised the final sample. The mean age (±SD) was 48.9(±9.8) years, and the majority of the subjects were between 45 and 63 years (69.2%), Hispanic (53.7%) and female (88.0%). Compared to patients on ETN, the odds of having a dose escalation were ≈ 5 [Odds Ratio= 4.605 [95% CI= 1.605-12.677], p=0.0031] and ≈ 8 [Odds Ratio=7.520, [95% CI= 2.461-22.983], p=0.0004] times higher for IFX and ADA patients, respectively, while controlling for other variables in the model. Compared to ETN, patients on IFX (p=0.0171) were more adherent while adherence was comparable with patients on ADA (p=0.1144). Compared to patients on ETN, the odds of being adherent (MPR ≥ 80%) to IFX was ≈ 2 times higher [Odds Ratio= 2.437, [95% CI=1.592-3.731], p < 0.0001] while controlling for other variables in the model. Persistence to index TNF inhibitor therapy and likelihood to switch or discontinue index TNF inhibitor therapy were comparable among the 3 study groups. In addition, the duration of medication use (i.e., persistence) prior to switching or discontinuation of index therapy was comparable among the 3 study groups. Furthermore, for each of the cost variables (total healthcare, RA-related and TNF inhibitor therapy cost), costs incurred by patients on ETN were significantly lower (p < 0.01) than those incurred by ADA patients but significantly higher (p < 0.01) than those incurred by IFX patients. Finally, a positive and significant relationship (p < 0.0001) was found between RA-related healthcare cost, adherence and persistence to TNF inhibitor therapies. In conclusion, ETN was associated with lower rates of dose escalation compared to ADA or IFX. However, adherence was better and associated healthcare costs were lower with IFX. Clinicians should endeavor to work with each individual patient to identify patient-specific factors responsible for poor medication use behaviors with TNF-inhibitor therapies. Reducing the impact of these factors and improving adherence should be included as a major part of the treatment plan for each RA patient. RA patients need to be adequately educated on the importance of adhering and persisting to their TNF-inhibitor therapy as poor medication adherence/persistence negatively impacts the RA disease process. / text

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This study investigated the association between flavonoid profiles of different cowpea (Vigna Unguiculata) varieties with anti-inflammatory properties as a possible benefit against inflammatory bowel disease. Cowpea, a drought tolerant annual herbaceous legume that originated in Africa, is known to possess high levels of polyphenolics, which have demonstrated anti-inflammatory, immunoregulatory and antioxidant properties. Black, red, white, brown and light brown cowpeas were investigated for phenolic content and composition using UV-Visible Spectroscopy and HPLC; antioxidant activation mechanism (AOX) by oxygen radical absorbance capacity (ORAC). Anti-inflammatory activity was measured via NF-κB activation in Raw 264.7 macrophages challenged with a lipo-polysaccharide. Phenols, tannins and AOX activity were generally similar within phenotypes; however among light brown varieties, 09FCV-CC-27M, had among the highest phenols, tannins and AOX, whereas IAR-48 had among the lowest. White cowpea (EARLY ACRE) variety showed the least amount of total phenol content (78.2 mg GAE/g) and condensed tannin content (4.1 mg CE/g); whereas the red varieties (IT82D-889, IT97K-1042-3) contained the highest amounts of tannins (242 and 132 mg CE/g), and phenols (431 and 454 mg GAE/g) respectively. Antioxidant activity correlated with phenol content data. Anthocyanins were only found in the black cowpea. The red varieties had the highest levels of flavonols, which were mostly quercetin derivatives; the white and light brown (IAR-48) varieties had quercetin-3-O-diglucoside as the dominantcompound. The light brown variety (09FCV-CC-27M) had the highest amount of flavan-3-ols while in the white variety no flavan-3-ols were detected. Unexpectedly, the cowpea extracts with lower phenolic and tannins content, the white and light brown (IAR-48) varieties, showed significant (p<0.05) anti-inflammatory properties in the LPS induced macrophages, inhibiting the activation of NF-κB at different concentrations (0.33, 1.67 and 3.33 μg extract/mL). Conversely, extracts with higher phenolic and tannin content did not induce anti-inflammatory response at similar concentrations, suggesting that tannins or other phenolics interfered with anti-inflammatory response at these concentrations. These results suggest that cowpea composition is an important determinant of anti-inflammatory response in inflammatory bowel disease.

Inflammatory bowel diseases (IBD) are associated with an elevated risk of colorectal cancer that increases with disease duration and severity. Tumor necrosis factor (TNF) is a major therapeutic target in IBD, but long-term anti-TNF therapy is associated with increased risks of infection and lymphoma, therefore we asked whether TNF signaling through its receptors TNFR1 and TNFR2 could impact colitis and colitis-associated cancer (CAC). In acute dextran sulphate sodium (DSS)-colitis, no major inflammatory differences were found between wildtype (WT), TNFR1- and TNFR2-deficient mice, with the exception of reduced macrophage infiltration into inflamed tissue in TNFR1-/- mice. Chronic colitis and tumor development was assessed in these mice using the carcinogen azoxymethane and 4 cycles of DSS. TNFR1-/- mice were protected against colorectal tumor development compared to WT and TNFR2-/- mice, while inflammation was similar between strains. Hematopoietic TNFR1 deficiency resulted in reduced inflammation and tumor incidence, while stromal/epithelial TNFR1 deficiency reduced indices of cancer without affecting inflammation. 8-OHDG was significantly lower in TNFR1-/- mice compared to other strains, suggesting that TNF could contribute to oxidative stress within the colon. Mice lacking leukocyte NADPH oxidase were protected against clinical illness and CAC despite similar histological inflammation, indicating that inflammation-associated oxidative stress can play a role in CAC. In conclusion, TNF signaling through TNFR1 contributes significantly to the development of colorectal cancer in a model of CAC in a manner that involves both stromal/epithelial and hematopoietic TNFR1. This is significant because anti-TNF therapies may be effective at reducing CAC in the absence of a clinical reduction of IBD symptoms.