The objective of this proposal is to chracterize the contribution of epidermal Langerhans cells (LC) to the induction of contact hypersensitivity (CH) and unresponsiveness in mice. The dominant hypothesis around which this work constellates states that Langerhans cells, unique within the epidermis, function as antigen presenting cells whereby they deliver to immunocompetent cells an unequivocal immunogenic signal; as a corollary hypothesis, when Langerhans cells fail, or are not adequately represented in cutaneous site of antigen application, an alternative signal escapes the skin, one which is perceived by the systemic immune system as a tolerogenic one. During the past several years, we have learned that (1) cutaneous surfaces depleted of normal appearing LC fail to sustain the induction of CH and fail to express Ia alloantigens; (2) epidermal LC are rapidly mobilized from a systemic precursor pool that reconstitutes deficiencies produced by experimental manipulation; (3) in vivo low dose ultraviolet B radiation (UVB) induces hapten specific T suppressor cells; (4) susceptibility of CH by local UVB is genetically determined by several loci and is a codominant phenotype; (5) unwitting oral ingestion of hapten following skin painting results in down regulation of CH; (6) hapten-derivatized skin grafted orthotopically induces CH with great efficiency and elicits effector cells genetically restricted by H-2 antigens of the graft. Most recently, we have produced highly purified Langerhans cells from mouse skin. During the next five years, we plan to take advantage of this technological advance to (a) prepare and characterize purified Langerhans cells, as well as other epidermal cell sub-populations by a variety of in vitro approaches; (b) describe immunologic properties of purified Langerhans cells both in vivo and in vitro; and (c) to analyze the role of resident Langerhans cells in the induction and regulation of contact hypersensitivity. Results of these studies will advance understanding of the immunopathogenesis of cutaneous immune disorders, including persisitent virus infections and development of neoplasms, especially in relation to sun-exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI022072-01
Application #
3132739
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1985-09-30
Project End
1988-08-31
Budget Start
1985-09-30
Budget End
1986-08-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33101
Tarleton, R L (2001) Parasite persistence in the aetiology of Chagas disease. Int J Parasitol 31:550-4
Xie, Y; Fernandez, M E; Streilein, J W et al. (1996) Epidermal Langerhans cells from mice bearing a granulocyte macrophage-colony stimulating factor-producing mammary tumor display impaired accessory functions. Anticancer Res 16:9-16
Dai, R; van Rooijen, N; Dijkstra, C D et al. (1995) Relative roles of T cells and macrophages in cytokine-mediated functional transformation of cultured splenic dendritic cells. Cell Immunol 162:265-74
Dai, R; Streilein, J W (1995) Sensitizing capacity of Langerhans' cells obtained from ultraviolet-B-exposed murine skin. Immunology 86:661-7
Kurimoto, I; Grammer, S F; Shimizu, T et al. (1995) Role of F4/80+ cells during induction of hapten-specific contact hypersensitivity. Immunology 85:621-9
Kurimoto, I; van Rooijen, N; Dijkstra, C D et al. (1994) Role of phagocytic macrophages in induction of contact hypersensitivity and tolerance by hapten applied to normal and ultraviolet B-irradiated skin. Immunology 83:281-7
Kurimoto, I; Arana, M; Streilein, J W (1994) Role of dermal cells from normal and ultraviolet B-damaged skin in induction of contact hypersensitivity and tolerance. J Immunol 152:3317-23
Shimizu, T; Streilein, J W (1994) Influence of alpha-melanocyte stimulating hormone on induction of contact hypersensitivity and tolerance. J Dermatol Sci 8:187-93
Shimizu, T; Streilein, J W (1994) Evidence that ultraviolet B radiation induces tolerance and impairs induction of contact hypersensitivity by different mechanisms. Immunology 82:140-8
Kurimoto, I; Streilein, J W (1994) Characterization of the immunogenetic basis of ultraviolet-B light effects on contact hypersensitivity induction. Immunology 81:352-8

Showing the most recent 10 out of 40 publications