MAST CELLS AS NOVEL EFFECTOR CELLS IN THE PATHOGENESIS OF CHRONIC GRAFT-VERSUS-HOST DISEASE

Hematopoietic stem cell transplantation (HSCT) is most commonly a treatment for inborn defects of hematopoiesis or acute leukemias. Widespread use of HSCT, a potentially curative therapy, is hampered by onset of graft-versus-host-disease (GVHD), a condition wherein the donor cells recognize the patient tissues as non-self. GVHD can manifest anywhere from weeks to decades post-transplant and is classified as either acute or chronic GVHD, both of which are significant causes of transplant-related morbidity and mortality. However, GVHD is a complex, multifactorial, and enigmatic disease. The factors driving GVHD at the cellular and molecular level are incompletely understood. Immunosuppression targeting T-cells has not always been effective and increases the risk of relapse. Prophylactic immunosuppression can be particularly detrimental in the context of cGVHD, where symptoms can appear even decades after transplant. There is great need to further understand the mechanisms of GVHD pathogenesis in order to more effectively make use of HSCT. Mast cells are an arm of the immune system that are primarily known for their role in atopic disease. However, recent studies have demonstrated new paradigms for mast cell activity, showing that they can play important roles in tissue homeostasis and wound healing. Therefore, the purpose of this dissertation is to explore the role of mast cells in the onset of fibrotic chronic GVHD. We hypothesized that mast cells, through their interactions with tissue-resident and circulating GVHD effector cells, would be detrimental in chronic GVHD by exerting proinflammatory and profibrotic effects on the surrounding tissue. We examined mast cells in vitro in mono- and co-culture models, finding that they are significantly resistant to conditioning-induced cell death, as well as capable of inducing proliferation of fibroblasts. We further tested our hypothesis in vivo in murine models of allogeneic transplant using both wild type and mast cell-deficient mice. Compared to wild type recipients, mast cell-deficient recipients had significant reductions in GVHD symptomology and skin manifestations, as well as in chemokine levels and immune cell recruitment in the skin. We show that mast cell chemokine production is blocked by drugs currently used clinically to treat chronic GVHD, and that skin from GVHD patients is enriched in mast cells. Lastly, we show that recipient-derived mast cells are capable of surviving after transplant. Taken together, these data demonstrate a role for mast cells in the onset of dermal chronic GVHD. We therefore outline methods and pathways by which mast cells could be targeted for therapeutic inhibition and discuss future studies that would further clarify the function of mast cells in chronic GVHD pathogenesis

EXAMINING HUMAN \u3ci\u3eAPOE\u3c/i\u3e GENOTYPE AND SEX AS MODULATORS OF RESPIRATORY PLASTICITY IN THE PRESENCE AND ABSENCE OF SPINAL CORD INJURY

There are over 17,000 new spinal cord injuries (SCIs) every year in the Unites States alone. Almost 60% of these injuries occur at the cervical level, potentially leading to loss of function in a variety of sensory and motor systems including upper and lower limbs, respiratory, and autonomics. In addition to the physical and emotional costs, individuals who experience these higher level injuries also face a massive financial burden, incurring over $1 million in expenses during the first year after injury in addition to substantial yearly costs for the rest of their lifetime. A myriad of therapeutic approaches targeting plasticity of spinal circuits have shown efficacy for improving functional recovery in preclinical animal models. However, translation of these strategies has proved less successful, leaving the SCI population with few effective therapeutic options to improve functional outcomes and alleviate the financial toll of their injury. We hypothesized that factors that are present in the human population, but difficult to model in preclinical studies, such as genetic diversity and sex differences, could determine how individuals respond to treatment strategies. Therefore, we investigated how sex and the human alleles of the APOE gene (ε2, ε3, and ε4), which encode unique isoforms of the lipid carrier apolipoprotein E (apoE), modulate a well-described form of spinally mediated respiratory motor plasticity that is sufficient to restore breathing function after cervical SCI. To test whether E4, the isoform of apoE associated with deficits in synaptic plasticity in the brain, also impairs spinally mediated plasticity, we exposed rats to episodic serotonin (5-HT) dosing after they had been treated intrathecally with human apoE3 or E4. IH induces long term facilitation (LTF) of respiratory motor function, which is characterized as a prolonged augmentation of breathing in spinally intact rats. LTF also rescues breathing function in the paralyzed hemidiaphragm following unilateral cervical SCI. Although rats treated with E3 and E4 did not show significant differences in their respiratory response to episodic 5-HT as assessed through diaphragmatic EMG recordings, animals treated with E4 did demonstrate a downregulation of synaptic NMDA receptors. Interestingly, this effect was only present in animals that had received a cervical SCI. Due to the necessity of NMDA receptor signaling in synaptic strengthening and the induction of LTF, this indicates that human apoE4 may prevent therapeutic strategies from inducing spinal plasticity to mediate functional recovery after SCI. To increase the clinical relevance of these studies and investigate how sex interacts with APOE genotype to modulate respiratory motor plasticity, we also evaluated LTF in male and female targeted replacement APOE mice that express the human alleles under the murine promotor. LTF was induced through exposure to therapeutic intermittent hypoxia (IH), which is currently in clinical trials for various functional outcomes in SCI subjects. There were significant effects of both genotype and sex on the respiratory response to IH. Although ε4 was inhibitory to plasticity in males, it was ε3 that proved detrimental in females in the absence of injury. In contrast, injured males showed no significant difference between genotypes while injured ε4 females experienced a decline in breathing activity compared to those expressing ε3. Together, these results support the hypothesis that sex and genetic background may determine individuals’ propensity towards or against plasticity and functional recovery after SCI. By contributing to our understanding of translational barriers for SCI therapeutics, this investigation will inform the development of personalized medicine to overcome these obstacles

Juvenile Delinquency Proceedings in Ohio: Due Process and the Hearsay Dilemma

This comment will explore the extent to which the exclusion of hearsay evidence in a delinquency proceeding is a practical reality in the Ohio system. In so doing, the possibilities for abuse will be highlighted and suggestions for their elimination will be made, all in the spirit of the Supreme Court\u27s mandate to provide fundamental due process safeguards to this procedure

Directions for Leadership of the Association of California Community College Administrators

California\u27s community colleges and the Association of California Community College Administrators will face some difficult challenges as we approach the 1990\u27s. ACCCA\u27s primary purpose is to present a statewide administrative perspective on issues facing all California community colleges. The purpose of this study was to determine the extent to which the Association was effective in meeting member needs through its goals and activities and to recommend some directions of leadership of the organization for the 1990\u27s. This study was conducted with an ethnographic research design and methodology. Seven past presidents were interviewed to address the history of the Association and views on future planning for ACCCA. Three hundred members were surveyed to obtain a composite view of member evaluation of the organization\u27s effectiveness. The survey assessed the extent to which ACCCA met its goals and purposes, individual member needs, representation of the organization to others and coordination efforts with other professional organizations. Some of the major findings and conclusions of the study were: (1) ACCCA has focused on and effectively pursued a leadership role on statewide issues affecting community colleges. (2) Members believe the organization is meeting its goals and purposes. (3) ADCOM, management reports, drive-in workshops and annual conferences were rated as effective services provided by the organization. (4) There was some uncertainty as to the extent ACCCA coordinates with other professional associations but the Association was rated effective in representing community colleges to state agencies. (5) There was no agreement as to whether the association should hire a salaried director or where the office should be located. Recommendations for consideration in future studies are: (1) replicate the design of the study in 1995 and assess the degree to which ACCCA\u27s leadership was effective in providing assistance to California community colleges in implementing the reforms contained in Assembly Bill 1725; (2) compare the member demographics now with those in 1995 and determine if the Association membership reflects state demographics and affirmative action guidelines; and (3) if specific recommendations of the study are implemented, conduct another member survey in several years to assess how well the Association is meeting member needs

Mast Cell Involvement in Fibrosis in Chronic Graft-versus-Host Disease

Allogeneic hematopoietic stem cell transplantation (HSCT) is most commonly a treatment for inborn defects of hematopoiesis or acute leukemias. Widespread use of HSCT, a potentially curative therapy, is hampered by onset of graft-versus-host disease (GVHD), classified as either acute or chronic GVHD. While the pathology of acute GVHD is better understood, factors driving GVHD at the cellular and molecular level are less clear. Mast cells are an arm of the immune system that are known for atopic disease. However, studies have demonstrated that they can play important roles in tissue homeostasis and wound healing, and mast cell dysregulation can lead to fibrotic disease. Interestingly, in chronic GVHD, aberrant wound healing mechanisms lead to pathological fibrosis, but the cellular etiology driving this is not well-understood, although some studies have implicated mast cells. Given this novel role, we here review the literature for studies of mast cell involvement in the context of chronic GVHD. While there are few publications on this topic, the papers excellently characterized a niche for mast cells in chronic GVHD. These findings may be extended to other fibrosing diseases in order to better target mast cells or their mediators for treatment of fibrotic disease

Personal Volcanoes and the Pedagogy of People: Perspectives on Navigating Turbulent Times

The year 2020 brought about more unexpected turbulent times than anyone could have imagined in the years prior. At the University level, students and faculty were sent home from campus as rates of COVID-19 soared around the world. This turbulent, life-changing eruption disturbed the status quo for everyone on the planet in ways not anticipated, and the effects will linger for years to come. This manuscript discusses four perspectives on navigating the pandemic that can translate to future preparedness plans for students and faculty alike

Observation of a translational energy threshold for a highly exoergic ion‐molecule reaction

This is the publisher's version, also available electronically from http://scitation.aip.org/content/aip/journal/jcp/60/9/10.1063/1.1681592

Dynamics of the ion–molecule reaction Kr+(H2,H)KrH+

This is the publisher's version, also available electronically from http://scitation.aip.org/content/aip/journal/jcp/65/4/10.1063/1.433219

Role of impact parameter in branching reactions

This is the publisher's version, also available electronically from http://scitation.aip.org/content/aip/journal/jcp/63/11/10.1063/1.431205

Observation of a stripping threshold for the reaction N2 ^++CH4→N2H^++CH3

This is the publisher's version, also available electronically from http://scitation.aip.org/content/aip/journal/jcp/64/9/10.1063/1.432690Chemical accelerator studies on isotopic variants of the reaction N2 ++CH4→N2H++CH3 are reported. Reaction cross sections, as well as velocity and angular distributions of the ionic products have been measured as a function of initial translational energy over the energy range 0.65–35 eV (center of mass). The results are similar to those recently reported for the reaction of Ar+ with CH4. The excitation function maximizes at about 5 eV (c.m.) and decreases at lower collision energies, appearing to possess a threshold at 0.1 eV. At the higher energies there is a large isotope effect favoring abstraction of H over D. The product velocity vector distribution is strongly peaked forward of the center of mass, indicating that the reaction is predominantly direct over the energy range studied. The spectator stripping model, although providing a reasonable first approximation to the reaction dynamics, overestimates the product translational energy by approximately 0.1 eV. This behavior is presumed to be caused by a basin in the potential energy hypersurface for this reaction. If, however, an N2CH4 + complex is formed at low collision energies, it appears to decompose via reaction channels other than that resulting in N2H+ formation