Keratinocyte Costimulation and Th2-Cell Immune Deviation

点击翻译按钮获取中文摘要

EXCEED THE SPACE PROVIDED, 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.