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Dendritic cells (DCs), as professional antigen-presenting cells, are members of the innate immune system and function as key players during the induction phase of adaptive immune responses. Uptake, processing, and presentation of antigens direct the outcome toward either tolerance or immunity. The cells of the immune system are among the most highly radiosensitive cells in the body. For high doses of ionizing radiation (HD-IR) both immune-suppressive effects after whole body irradiation and possible immune activation during tumor therapy were observed. On the other hand, the effects of low doses of ionizing radiation (LD-IR) on the immune system are controversial and seem to show high variability among different individuals and species. There are reports revealing that protracted LD-IR can result in radioresistance. But immune-suppressive effects of chronic LD-IR are also reported, including the killing or sensitizing of certain cell types. This article shall review the current knowledge of radiation-induced effects on the immune system, paying special attention to the interaction of DCs and T cells.

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Morphological development during crystallization of thin films of poly(ethylene oxide) (PEO) / poly(methyl methacrylate) (PMMA) blends has been reported. Studies have focused on the effects of the blend composition, PMMA molecular weight, film thickness, and crystallization temperature on the observed crystal morphology. As the blend composition was varied from 90 to 30 wt% PEO, the crystal morphology varied from spherulites to needles and dendrites. Variation of the crystallization temperature and PMMA molecular weight resulted in similar changes in morphology. A morphological map demonstrating the roles of the experimental controls on the observed crystal morphology has been developed. This map was used as a tool for more detailed studies of the observed morphologies and morphological transitions. The dendritic region of the map (~ 30 = 40 wt% PEO) was studied in detail. Changes in the diffusion length were achieved through variation of the PMMA molecular weight, and were shown to influence the secondary sidebranch spacing. Sidebranch spacing measurements revealed that coarsening of the dendritic microstructure occurred well after the competition between diffusion fields of neighboring dendrite arms vanished, indicating the existence of another coarsening mechanism. These studies of dendritic sidebranching indicate that polymer dendrites develop by mechanisms similar to those in small molecules and metals. A number of in-situ observations of morphological transitions have also been reported, including a dense-branched morphology (DBM)/dendrite transition, a DBM/stacked-needle/needle transition, and a transition from dendrites with 90o sidebranching to dendrites with 45o branching or a dense-branched morphology, both of which grow at 45o to the original dendrite trunk. The DBM/dendrite transition occurred over a range of crystallization temperatures, indicating that the transition is not sharp. Crystal growth rate measurements verified this result. The DBM/stacked-needle/needle transitions demonstrated distinct jumps in the crystal growth rate, indicating a change in the growth mechanism or direction. For the transition involving a change in the growth direction, the effective level of noise (fluctuation) was found to be important in morphological selection. The results of this work have helped to define new directions for the study of crystal morphologies, especially in the areas of spherulite formation and dendritic growth. / Ph. D.

Porcine circovirus associated disease (PCVAD) is an umbrella term for a multitude of diseases and syndromes that have a negative impact on the health and economics of pig production operations throughout the world. Porcine circovirus type 2 is the causative agent of PCVAD; however the presence of PCV2 alone is rarely enough to cause clinical disease. In order for the full development of PCVAD the presence of a co-infecting pathogen is required. The mechanisms by which co-infection leads to disease remain ongoing areas of research, but it is thought that host immune modulations by PCV2 or a co-infecting pathogen are critical in the pathogenesis of PCVAD. In the first study of this dissertation the ability of PCV2 to induce regulatory T-cells (Tregs) and alter cytokine production was evaluated in vivo. The addition of PCV2 to a multiple viral challenge resulted in a significant increase in Tregs. Levels of IL-10 and IFN-γ were also found to be altered when PCV2 was added to a multiple viral challenge. In further experiments, monocyte derived dendritic cells (MoDC) were infected with different combinations and strains of PCV2 and PRRSV in vitro and evaluated for expression levels of programmed death ligand-1 (PD-L1), IL-10, CD86, swine leukocyte antigen-1 (SLA-1), and swine leukocyte antigen-2 (SLA-2). Expression levels of PD-L1 were significantly increased in PCV2 and PRRSV co-infected MoDCs. SLA-1, SLA-2, and CD86 expression levels were significantly decreased in the MoDC treatment groups containing both PCV2 and virulent stains of PRRSV. MoDC IL-10 expression was significantly increased by PCV2 and virulent strains of PRRSV co-infection. Finally, we investigated the role of the PD-L1/programmed death ligand-1 (PD-1) axis in porcine lymphocyte anergy, apoptosis, and the induction of Tregs. Lymphocyte populations with normal PD-1 expression had significantly higher percentages of anergic and apoptotic lymphocytes, and CD4+CD25HighFoxP3+ Tregs when compared to a PD-1 deficient lymphocyte population. The findings from these studies indicate host immune modulation by PCV2 in vivo and the development of a regulatory phenotype of dendritic cell following PCV2/PRRSV co-infections in vitro that may contribute to a dysfunctional adaptive immune response and the overall pathogenesis of PCVAD. / Ph. D.

The IgG Fc domain mediates a range of antibody effector functions, including antibody dependent cell-mediated cytotoxicity (ADCC), complement activation, phagocytosis, and the recently emerged general anti-inflammatory effect of immunoglobulin therapy (IVIg). The conserved N-glycan attached to Fc N297 maintains the Fc structural integrity for the effector functions, while its glycoform is known to modulate the affinity for the Fc γ-receptors (FcγRs), complement, and the C-type lectin DC-SIGN. IgG Fc exhibits protein-directed glycosylation characterized by a series of biantennary complex type glycoforms, with a small population of sialylated species. The sialylated Fc has been proposed to bind DC-SIGN and initiate an anti-inflammatory signalling pathway. The restricted Fc glycan processing is partially attributed to the hydrophobic interaction between Fc glycan and the hydrophobic Fc protein backbone. Mutations within the hydrophobic Fc protein-glycan interface dramatically increases Fc glycan processing, while concomitantly decreases Fc affinity for the FcγRs. However, it is unclear whether this disrupted Fc-FcγR interaction was due to the increased terminal glycan processing, or the perturbed Fc protein-glycan interface. Here, the integrity of the Fc protein-glycan interface was demonstrated to be important in maintaining the productive Fc-FcγR interaction independently of glycoform. This glycoform-independent effect was exploited to generate novel inhibitory Fc variants. In addition, the interaction between sialylated IgG and the putative IVIg receptor DC-SIGN was re-evaluated. Analysis shows that IVIg binds DC-SIGN in a glycan-independent, Fab-mediated manner. Furthermore, the effect of IVIg sialylation on human antigen presenting cells was examined; evidence presented here indicate that IVIg deglycosylation, not desialylation, has an anti-inflammatory effect on human dendritic cells (DCs). These data suggest the need for a general re-evaluation of the current mechanistic model of anti-inflammatory IVIg.