Keratinocyte Costimulation and Th2-Cell Immune Deviation

Summary

Principal Investigator: Anthony Gaspari
Affiliation: University of Maryland
Country: USA
Abstract: This proposal will test our hypothesis that epidermal keratinocytes can contribute to the development of a skewed immune response to haptens that cause allergic contact dermatitis, promoting the emergence of Th2-1ymphocytes under circumstances when this type of Th-lymphocyte subset would not normally contribute to an immune response. This "immune deviation" leads to the development of IgE antibody response, which is associated with the development of immediate-type allergic symptoms upon rechallenge with the hapten. Our hypothesis is based on studies of transgenic (Tg) mice whose keratinocytes (KC) over-express CD80 or CD86 driven by a keratin 14 promoter. First, CD80 Tg mice develop hapten-specific IgE and immediate ear swelling in response to sensitization and challenge with strong Thl- dominant haptens such as trinitrochlorobenzene and dinitrofluorobenzene. Such CD80 Tg mice develop chronic dermatitis associated with an accumulation of mast cells in the skin lesions, which is not observed inCD86 Tg or NTg mice. Second, CD86 Tg and non-Tg mice do not develop such IgE antibodies or immediate responses to hapten sensitization. In aim one, the fine characteristics of the IgE antibody response will be studied (kinetics of IgE response, fine quantitation of low levels of lgE, passive transfer of cutaneous anaphylaxis, and studies of contact dermatitis in mast cell deficient mice). In aim two, the physiology of CD80 expression by KC from normal, non-Tg mice in response to happen exposure will be studied and correlated with IgE responses in vivo. In aim 3, antigen presenting cell-T- lymphocyte interactions will be studied to define how these Th2-1ymphocytes emerge. In aim 4, the role of T-cell subsets in hapten-specific IgE antibody response by CD80 Tg mice will be defined by crossing gene targeted mice (CD4, CD8 or TCR delta knock-out mice) to create double Tg mice. These studies are highly relevant to human allergic skin disease because human KC can express CD80-1ike molecules that are upregulated during contact dermatitis. This model system will provide important information that is highly relevant to the understanding of development of type I allergic responses to haptens, natural rubber latex (NRL)-containing medical devices, and atopic diseases in general. Similar mechanistic studies of the molecular basis of other skin diseases such as psoriasis have led to the development of biological response modifiers that are now in clinical use.
Funding Period: 2005-03-18 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. pmc Human natural killer T cells infiltrate into the skin at elicitation sites of allergic contact dermatitis
    Michael D Gober
    Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland 21030, USA
    J Invest Dermatol 128:1460-9. 2008
  2. pmc Inflammatory papillomatous hyperplasia and epidermal necrosis in a transgenic rat for HIV-1
    Filiberto Cedeno-Laurent
    Division of Basic Science, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Dermatol Sci 53:112-9. 2009
  3. pmc Imiquimod-induced TLR7 signaling enhances repair of DNA damage induced by ultraviolet light in bone marrow-derived cells
    Rita Fishelevich
    Department of Dermatology, School of Medicine, University of Maryland Baltimore, Baltimore, MD 21201, USA
    J Immunol 187:1664-73. 2011
  4. ncbi IL-9 regulates allergen-specific Th1 responses in allergic contact dermatitis
    Juan Liu
    Department of Dermatology, University of Maryland, Baltimore, Maryland, USA
    J Invest Dermatol 134:1903-11. 2014
  5. ncbi Innate and adaptive immunity and the pathophysiology of psoriasis
    Anthony A Gaspari
    Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    J Am Acad Dermatol 54:S67-80. 2006

Scientific Experts

  • Anthony Gaspari
  • Rita Fishelevich
  • Juan Liu
  • Antonella Tammaro
  • Yuming Zhao
  • Filiberto Cedeno-Laurent
  • Michael D Gober
  • Erin Harberts
  • Nicholas Girardi
  • Paula Licona-Limón
  • Michael Girardi
  • Richard A Flavell
  • Renata B Filler
  • Angela Temann
  • Tzu Ching Meng
  • Hannah Liu
  • Jim Lee
  • Papapit Tuchinda
  • Ayako Nakazono
  • J Roberto Trujillo
  • Maria L Eng
  • Joseph Bryant
  • Odell D Jones
  • April Deng
  • Derya Unutmaz

Detail Information

Publications5

  1. pmc Human natural killer T cells infiltrate into the skin at elicitation sites of allergic contact dermatitis
    Michael D Gober
    Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland 21030, USA
    J Invest Dermatol 128:1460-9. 2008
    ..Herein, it is demonstrated that NKT cells are constantly present during the late elicitation phase of human type IV hypersensitivity reactions...
  2. pmc Inflammatory papillomatous hyperplasia and epidermal necrosis in a transgenic rat for HIV-1
    Filiberto Cedeno-Laurent
    Division of Basic Science, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Dermatol Sci 53:112-9. 2009
    ..Transgenic animal models represent a novel approach for the study of these disorders and for the quest of more effective forms of treatment...
  3. pmc Imiquimod-induced TLR7 signaling enhances repair of DNA damage induced by ultraviolet light in bone marrow-derived cells
    Rita Fishelevich
    Department of Dermatology, School of Medicine, University of Maryland Baltimore, Baltimore, MD 21201, USA
    J Immunol 187:1664-73. 2011
    ..This property is likely to be an important mechanism for its anticancer effects because it protects cutaneous APC from the deleterious effects of UVL...
  4. ncbi IL-9 regulates allergen-specific Th1 responses in allergic contact dermatitis
    Juan Liu
    Department of Dermatology, University of Maryland, Baltimore, Maryland, USA
    J Invest Dermatol 134:1903-11. 2014
    ..This study demonstrates that IL-9, through its direct effects on Th1 and ability to promote IL-4 secretion, has a regulatory role for Th1 lymphocytes in ACD...
  5. ncbi Innate and adaptive immunity and the pathophysiology of psoriasis
    Anthony A Gaspari
    Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    J Am Acad Dermatol 54:S67-80. 2006
    ..These developments include the creation of useful animal models and identification of new receptors and lymphocyte subtypes that may participate in the development of this chronic disease...