PhD

dissertationUltraviolet (UV)-irradiation of mice is known to cause a modification in their immune potential such that exposed mice lose their ability to reject transplanted UV-induced tumors. Further, this tumor susceptibility is mediated by a population of suppressor T lymphocytes (Ts) found in the spleen and lymph nodes of UV-exposed animals which will adoptively transfer tumor susceptibility to normal animals. As the induction of these Ts cells is undoubtedly a complex process, my studies were initiated to elucidate the early events involved in this process. It was found that sunscreen agents such as para-aminobenzoic acid (PABA), while able to prevent the pathological skin damage associated with the UV exposure, were without effect on the induction of tumor susceptibility. To date, however, I have been unable to detect T(,s) cells in PABA-treated UV-irradiated mice. Animals exposed to six daily UV exposures (about 3000 J/m('2)/day) have been reported to exhibit decreased antigen-presenting and accessory cell function (assayed solely from the spleen). My investigations have confirmed this finding. Further, the results demonstrated that this is: (1) probably due to UV-induced inflammation and; (2) the result of a migration of antigen-presenting cells (APC) from the spleen to the peripheral lymph nodes. These results are consistent with previous studies which found that UV-irradiation does not cause a generalized suppression in immune responses. While regional differences in APC activity may be attributable to cellular migration, a direct inactivation of epidermal Langerhans cells (the epidermal APC) also occurs (as assessed in vitro) following UV exposure. My results demonstrated that the APC function of epidermis was immediately lost in a dose-dependent manner following UV-irradiation. Further, treatment of skin with PABA prior to the UV exposure did not significantly alter the rate of Langerhans cell inactivation. Abrogation of contact sensitivity responses after a single UV exposure, however, required two to three days between exposure and sensitization. Collectively, these data indicate that early in the course of the treatments, UV-irradiation causes both a direct inactivation of epidermal APC and a migration of splenic APC to peripheral lymph nodes. Hence, these events may play a role in the cellular interactions involved in the induction of the Ts cells which mediate the UV-induced tumor susceptible state

The Exclusive Economic Zone of the Northwestern Hawaiian Islands: When Do Uninhabited Islands Generate an EEZ

Hawaii is the only state in the United Stats that consists solely of islands. These islands are unique among the states in climate and life style, and they present unique problems to those who would define their jurisdiction over the adjacent ocean areas. The eight main inhabited Hawaiian islands are entitled to territorial seas, contiguous zones, exclusive economic zones, and continental shelves, which are measured in the same way that similar zones are delineated outward from continental land territories. To the northwest of these main islands is a chain of smaller insular outcroppings that are a wildlife preserve for sea birds, monk seals, green turtles, and other unique species. Some of these formations may not be entitled to an Exclusive Economic Zone (EEZ) according to article 121 of the 1982 United Nations Convention on the Law of the Sea (LOS Convention)

Cherishing the Coast: California Goes Long

This article focuses on the California Coastal Conservancy. It explores the Conservancy’s uniquely proactive approach to coastal zone management through both oral history (collected via telephone interviews) and literature research. In general, being proactive has involved the Conservancy in activities such as identifying coastal areas or wildlife habitats in need of protection; developing plans and priorities for acquisition or restoration; assembling and supporting local stewards and partners; leading and shepherding collaborative projects to fruition; and often providing significant funding

Mouse mast cell tryptase mMCP-6 is a critical link between adaptive and innate immunity in the chronic phase of Trichinella spiralis infection

Although the innate immune function of mast cells in the acute phase of parasitic and bacterial infections is well established, their participation in chronic immune responses to indolent infection remains incompletely understood. In parasitic infection with Trichinella spiralis, the immune response incorporates both lymphocyte and mast cell-dependent effector functions for pathogen eradication. Among the mechanistic insights still unresolved in the reaction to T. spiralis are the means by which mast cells respond to parasites and the mast cell effector functions that contribute to the immunologic response to this pathogen. We hypothesized that mast cell elaboration of tryptase may comprise an important effector component in this response. Indeed, we find that mice deficient in the tryptase mouse mast cell protease-6 (mMCP-6) display a significant difference in their response to T. spiralis larvae in chronically infected skeletal muscle tissue. Mechanistically, this is associated with a profound inability to recruit eosinophils to larvae in mMCP-6-deficient mice. Analysis of IgE-deficient mice demonstrates an identical defect in eosinophil recruitment. These findings establish that mast cell secretion of the tryptase mMCP-6, a function directed by the activity of the adaptive immune system, contributes to eosinophil recruitment to the site of larval infection, thereby comprising an integral link in the chronic immune response to parasitic infection

Dendritic cell expression of the transcription factor T-bet regulates mast cell progenitor homing to mucosal tissue

The transcription factor T-bet was identified in CD4+ T cells, and it controls interferon γ production and T helper type 1 cell differentiation. T-bet is expressed in certain other leukocytes, and we recently showed (Lord, G.M., R.M. Rao, H. Choe, B.M. Sullivan, A.H. Lichtman, F.W. Luscinskas, and L.H. Glimcher. 2005. Blood. 106:3432–3439) that it regulates T cell trafficking. We examined whether T-bet influences homing of mast cell progenitors (MCp) to peripheral tissues. Surprisingly, we found that MCp homing to the lung or small intestine in T-bet−/− mice is reduced. This is reproduced in adhesion studies using bone marrow–derived MCs (BMMCs) from T-bet−/− mice, which showed diminished adhesion to mucosal addresin cellular adhesion molecule–1 (MAdCAM-1) and vascular cell adhesion molecule–1 (VCAM-1), endothelial ligands required for MCp intestinal homing. MCp, their precursors, and BMMCs do not express T-bet, suggesting that T-bet plays an indirect role in homing. However, adoptive transfer experiments revealed that T-bet expression by BM cells is required for MCp homing to the intestine. Furthermore, transfer of WT BM-derived dendritic cells (DCs) to T-bet−/− mice restores normal MCp intestinal homing in vivo and MCp adhesion to MAdCAM-1 and VCAM-1 in vitro. Nonetheless, T-bet−/− mice respond vigorously to intestinal infection with Trichinella spiralis, eliminating a role for T-bet in MC recruitment to sites of infection and their activation and function. Therefore, remarkably, T-bet expression by DCs indirectly controls MCp homing to mucosal tissues

Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor

To establish effective therapeutic strategies for eosinophil-related disorders, it is critical to understand the developmental pathway of human eosinophils. In mouse hematopoiesis, eosinophils originate from the eosinophil lineage-committed progenitor (EoP) that has been purified downstream of the granulocyte/macrophage progenitor (GMP). We show that the EoP is also isolatable in human adult bone marrow. The previously defined human common myeloid progenitor (hCMP) population (Manz, M.G., T. Miyamoto, K. Akashi, and I.L. Weissman. 2002. Proc. Natl. Acad. Sci. USA. 99:11872–11877) was composed of the interleukin 5 receptor α chain+ (IL-5Rα+) and IL-5Rα− fractions, and the former was the hEoP. The IL-5Rα+CD34+CD38+IL-3Rα+CD45RA− hEoPs gave rise exclusively to pure eosinophil colonies but never differentiated into basophils or neutrophils. The IL-5Rα− hCMP generated the hEoP together with the hGMP or the human megakaryocyte/erythrocyte progenitor (hMEP), whereas hGMPs or hMEPs never differentiated into eosinophils. Importantly, the number of hEoPs increased up to 20% of the conventional hCMP population in the bone marrow of patients with eosinophilia, suggesting that the hEoP stage is involved in eosinophil differentiation and expansion in vivo. Accordingly, the phenotypic definition of hCMP should be revised to exclude the hEoP; an “IL-5Rα–negative” criterion should be added to define more homogenous hCMP. The newly identified hEoP is a powerful tool in studying pathogenesis of eosinophilia and could be a therapeutic target for a variety of eosinophil-related disorders